Method of producing derivatives of 3-propenyl-7-[2-(2-aminothiazolyl-4)-hydroxyiminoacetamido]-3-cep

专利摘要:
This invention provides novel cephalosporanic acids and esters thereof having the general formula <IMAGE> wherein R2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl or acyl, R3 is hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, and R4 is hydrogen, pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 5-methyl-2-oxo-1, 3-dioxolen-4-ylmethyl or 4-glycyloxybenzoyloxymethyl. These compounds, especially esters, are useful as broad spectrum antibiotics in the treatment and prevention of infectious diseases of mammals, and for other purposes known in the art.
公开号:SU1428204A3
申请号:SU864027736
申请日:1986-06-23
公开日:1988-09-30
发明作者:Иимура Сеидзи；Абе Есио；Окумура Юн；Наито Такаюки；Камати Хайме
申请人:Бристоль-Мейерз Компани (Фирма)；
IPC主号:

专利说明:

the ester with 1-aksibenzotriazol in an environment of an inert organic solvent at -20 C to room temperature removes the ester diphenylmethyl protective group and in the case of the presence of trityl groups protecting the amino and / or hydroxy groups by acid hydrolysis. The desired product is isolated, where R4 is H, in the form of a mixture of 3 (2) - and 3 (E) isomers, or is divided into individual 3 (Z) - and 3 (E) isomers and the target product is isolated as of the free acid or it is converted into an alkali metal or ammonium salt, which is reacted with a compound of the formula R |, - M, where R is acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, 4-H- (tert-butoxycarbonyl) -glycyloxy -benzoyloxymethyl, ethoxycarbonyloxyethyl or 5-metnp-2-oxo-1,3-dioxolen-4-yl-methyl and M-C1, Br, I, in an environment of an inert organic solvent at -10 ° C and isolated yut tse the left product or compound in which R (tert-butoxycarbo-NIL) -glycyloxy-benzoyloxymethyl is subjected to acid hydrolysis to obtain the desired product, where R4 is 4-glycyloxybenzoyloxymethyl. 4 tab. .
one
I
The invention relates to a method
obtaining new antibiotics of the cephalosporic series, namely, the derivatives of Z-propenyl-7- 2- (2-aminothiazo -.- lil-4) -I-hydroxyiminoacetamido - -Z-cephem-4-carboxylic acid or its esters, in the form of Z- or E-isomers or their mixtures, which can be used in medicine as antimicrobial agents.
The purpose of the invention is the creation of new cephalosporin antibiotics containing, in their structure, a possibly substituted 3-propenyl group with low, minimum inhibitory concentrations against a broad spectrum of bacteria.
Example 1, Diphenylmethyl 7-ami-3- (1-propenyl) -3-cephem-4-carboxy lat,
To a solution of diphenylmethyl 7-benzylidenamino-3 (triphenylphosphoanilidene) methyl-3-cephem-4-carboxylate (compound of formula II) (2.9 g, 4 mmol) in dichloromethane (16 ml) is added 90% acetaldehyde ( 10 ml, 0.2 mol). The mixture is stirred at room temperature for 30 minutes, dissolved over sodium sulfate and concentrated in vacuo, the residue is dissolved in ethyl acetate (80 ml), isopropyl ether (160 mp) is added to the solution and then silica gel (25 g) is added. and filtered to remove solid. The filtrate is evaporated to dryness.
five
0
five
0
five
under vacuum. To a solution of the residue in ethyl acetate (48 tvi) is added a mixture of Fatty reagent (1.34 g, 8 mmol), methanol (40 ml) and acetic acid (2 ml). Transfer the mixture at room temperature for 30 minutes and concentrate to 10 ml. The residue was dissolved in ethyl acetate (100 ml). The solution is washed with an aqueous solution of sodium bicarbonate and water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on a column of silica gel (50 g), which is eluted with 1% methanol in chloroform. The eluate is taken in 18 ml fractions. Fractions 22-40 are combined and concentrated to give 718 mg of the desired 3-propenyl derivative. Yield 44%, E / Z 1/3.
Thin layer chromatography: Rf 0.56 (silica gel, ethyl acetate). High performance liquid chromatography. Solid phase: Lichrosorb RP-18 (4 X 300 mm). Acetonitrile-water (1: 1) mobile phase. Flow rate 2.5 MP / min: retention time (min) 13.2 and 15.6 (relative intensity 3.1)
IR spectrum,. (KBG), cm: 1770, 1720,
UV spectrum, L, o (, (), nm (): 214 (20500), 266 (4200), 273 (4200), 292 (3800),
NMR spectrum (mixture of 1: 3 E- and Z-iso-, measures), 5 (CDClj), h / min: 1.42 and 1.72 (relative intensity 3: 1),
 i14
(both are double doublets, J 2 and 7 Hz, CI,) - 3.37 (AB quadruplet J 18 Hz, 2-H) and 3.52 (singlet, 2-H), 4.72 (doublet J 4.5 Hz, 6-H); 4.97 (doublet, J 4.5 Hz, 7-H), 5.50 (double quadruplet, J 7 and 11 Hz, CH-), 6.06 (double doublet, J 2 and 11 Hz, 3-CH ), 6.96 and 7.00 (3: 1) (singlet, -OCHPhjj,); 7.35 (singlet, phenyl-H).
EXAMPLE 2 Diphenylmethyl 7- (g) -2- (2-aminothiazol-4-yl) -2-meth-oxymino-acetamide-J-3- (1-propenyl) -3-cephem-4-carboxylate.
A mixture of diphenylmethyl 7-amino-3- (1- -propenyl) -3-cephem-4-carboxylate (3.37 g, 8.3 mmol) and 1- (Z) -2- (2- -aminothiazole-4- or) -2-methoxyimine acetoxy benzotriazole (2.64 g, 8.3 mmol) in tetrahydrofuran (70 ml) is stirred at room temperature for 30 minutes and then evaporated in vacuo. A solution of the residue in ethyl acetate is successively washed with an aqueous solution of sodium bicarbonate and water. It is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the final product, which is dissolved in chloroform and chromatographed on a silica gel column (150 g of silica gel) with 2% methanol in chloroform . The desired fractions (thin layer chromatography: silica gel, Rf 0.49, T: 2 toluene ethyl acetate) are combined and concentrated to give 1.95 g (40%) of the desired compound (1: 2 mixture of E and Z isomers relative to 3- (1-propens1) configuration).
NMR spectrum (mixture of 1: 2 E- and Z-isomers): S (CDClj), h / min: 1.45 and 1.75 (relative intensity 2: 1, both are doublets, J = 7 Hz, C- CH ,,), 3.42 and 3.53 (2: 1) (singlet, 2-H), 4.02 (singlet, OSI,); 5.13 (doublet, J = 4.5 Hz); 5.2-6.3 (multiplet, 7-H and vinyl-H); 6.73 (singlet, thiazole-H), 6.93 (singlet, OCHPh, j); 7.30 (singlet, phenyl-H).
EXAMPLE 3 7- (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3- (1-propenyl) -3-cephem-4-carboxylic acid .
The compound of example 2 is treated with trifluoroacetic acid (5 ml) at room temperature for 40 minutes. The mixture is diluted with isopropyl ether. The resulting precipitate is0
0
8204
They are filtered, dissolved in formic acid, and passed through a packed column (50 ml) from the Prep PAK (aqueous) cartridge, which is washed with water and eluted with 15% and 20% -Shz1M methanol. Evaporation and lyophilization of 15% methanol to the foot of the eluate afforded 206 mg (15%) of the title compound (E / Z 1/17). A determined purity of 90% (by high performance liquid chromatography). M.p. 180 C (slow decomposition). ,
IR spectrum,;) ax (KBG),: 1770, 1660, 1630, 1530.
UV spectrum, A iAQKc (rI 7, phosphate buffer), nm (e): 228 (17400), 283 (16200).
NMR spectrum, S (CDCl1), h / MiiH: 1.70 (3N, doublet, J, 6 Hz, C-CH,) 3.52 (2H, AB quadruplet, J 18 Hz, 2-H), 4 , 03 (ZN, singlet, OCH,); 5.28 (1H, doublet, J 4.5 Hz, 6-H) .; 5,6- 5 6,2 (ЗН, multiplet, 7-Н and vinyl-Н); 7.30 (1H, thiazole-H). „
High performance liquid chromatography: retention time 6.8 minutes (1: 3 methanol, pH 7, phosphate buffer, Q 1.5 ml / min).
Calculated,%: C, 44.44; H, 4.20; N 16.19; S 14,83
C, gH ,, Ns 5-S2 / 2H20
Found,%: C 44.37-H 3.94; N 16.18; S 14.53,
EXAMPLE 4 Valoyloxymethyl 7- (Z) -2- (2-aminothiazol14-yl) -2-methoxyimino acetamido-3- (Z) -1-propenyl-3-cephem-4-carboxylate.
0
To a mixture of 7-L (Z) -2- (2-aminothiazol-4-rsh) -2-methoxyiminoacetamido-3- - (1-propenyl) -3-cephem-4-carboxylic acid (E / Z 1/17 , 90 mg,
5 0.21 mmol) and potassium carbonate (44 mg, 0.32 mmol) in dimethylformamide (3 mp) pivaloyloxymethyl iodide (77 mg, 0.32 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C for 40 min.
The Q is diluted with ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column (silica gel 3 g) using elution with 1% methanol in chloroform to give 85 mg (yield 75%) of the desired compound. M.p. 100-104 ° C. Certain clean
five
514282046
that 90% (using high-performance 4.5 Hz, 6-H); 5.5-6.0 (2H, multi-liquid chromatography)., 7-H and CE-CU-,}; 6.12 (1H, DubIC spectrum, dx (KBr),: 1780, 1760, 1680, 1620.
UV spectrum, -A „oki
(methanol), im (6): 232 (17800), 287 (13500).
NMR spectrum, V (CDClg), h / min: 1.23 (9H, singlet, C (CHj) 5), 2.15 (3N, doublet, J 7 Hz, sen,); 3.45 (2H, singlet, 2-H), 4.05 (3N, singlet, OCH), 5.12 (1H, doublet, J 4.5 Hz, 6-H), 5.6-6.2 (5H, multiplet, 7-H, vinip-H and OCH, jO-); 6.85 (1H, singlet, thiazole-N).
High performance liquid chromatography: retention time 8.1 min (1: 1 CH, CN, 2 ml / min).
EXAMPLE 5 1-Acetoxyethyl 7- (7.) - 2, (2-aminothiazole.) - 2-membranes relative to the ethemoid-J-3-L (Z) -1-orpropenyl-3-W cefem-4-carboxylate.
To a mixture of 7- (g) -2- (2-aminothiazol-4-yl) -2 methoxyiminoacetamido-3- - (1-propenyl) -3-cephem-4-carboxylic acid (190 mg, 0.45 mmol) and potassium carbonate (75 mg, 0.54 mmol) in dimethylformamide (5 ml) was added at 5 ° C - 1-bromoethyl acetate (90 mg, O, 54 mmol).
The mixture was stirred at 5 ° C for 1.5 hours and diluted with ethyl acetate (20 ml). The solution is washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue is dissolved in chloroform and chromatographed
years, J 12 Hz, 3-CH), 6.83 (1H, g singlet, thiazole-H); 6.98 (1H, quadruplet, J
ten
15
20
-6 Hz, the basis).
High performance liquid chromatography: retention time 7.5 min (1: 1, 1 MP / min).
EXAMPLE 6 Diphenylmethyl 7-amino-3- (Z) -1 -button-G-Z-tsefem-4-car - bauxilate hydrochloride.
To a solution of propionaldehyde (10.7 g, 18 mmol) and lithium iodide (13.4 g, 10 mmol) in a mixture of dimethylformamide / dichloromethane (50 ml / 150 ml) was added a compound of formula II (7.3 g, 10 mmol) at 0 ° C. The mixture was left at 5 ° C for 2 days and concentrated in vacuo. A solution of the residue in ethyl acetate (200 ml) is washed with water, dried over magnesium sulphate and evaporated, in vacuo, to a syrup, which is treated with carbon tetrachloride (25 ml), and filtered. The filtrate is concentrated to 50 ml and the concentrate is stirred with 6N. hydrochloric acid (4 mp) at room temperature for 30 minutes. The resulting precipitate is separated by filtration and recrystallized from chloroform-ethyl acetate to obtain 1.49 g (yield 38%) of the desired compound. M.p. 120-127 ° C.
IR spectrum, „„. (KBG), 1780, 1710.
UV spectrum, (methanol), nm (): 217 (13900), 286 (7400).
NMR spectrum, S (DMSO-dg), h / mpn:
35
NMR spectrum, S (DMSO-dg), h / mpn:
on a column of silica gel (5 g) with 1% methanol in chloroform. The target fractions 40 (3N, triplet, J. 7 Hz, CH,), are combined and concentrated. Osta- 2.00 (2H, multiplet,); 3.75 currents are dissolved in dioxane and lyophilized to obtain 103 mg (yield) of the title compound as its dioxane solvate. M.p. 105-110 ° C. Purity, rated by high performance liquid chromatography, is 85%.
IR Spectrum, (KVg),: 1760 (broadinB), 1670, 1610.
UV spectrum, COP (ethanol), nm (); 233 (15700), 292 (12800).
NMR spectrum, 5 (CDCl ,,), ppm: 1.50 (ZN, doublet, J 6 Hz, OCHCN,), 1.65 (ZN, doublet, J 7 Hz, CH-CHR ;, 2, 07 (ZN, singlet, COGCHj), 3.43
(2H, singlet, 2-H), 3.68 (4H, singlet, 1/2 dioxane), 4.05 (OTH, singlet, CAB; 5.10 (1H, doublet, J
(2H, AB quadruplet, J 16 Hz, 2-H) 5.1-5.9 (ZN, multiplet, 6-H and 7-H, SP-CH -); 6.33 (1H, doublet, J 12 G 45 3-CH) - 6.97 (1H singlet, -CHPh); 7.40 (YUN, singlet, phenyl-N).
High performance liquid chromatography: retention times of 10.4 and 12.0 minutes (relative intensity 8: 1) (4: 1 methanol - pH 7 phosphate buffer, 1 MP / min).
EXAMPLE 7 Diphenylmethyl 7- (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (g) -1-but-55 yl-3- cephem-4-carboxylate.
A suspension of Diphenylmethyl 7-amino-3- (7) -1-butenyl-3-cephem-4-cc, side of silate hydrochloride (1.4l r, 3.1 mmol in ethyl acetate (20 ml) is shaken with
50
 4.5 Hz, 6-H); 5.5-6.0 (2H, mult-plet, 7-H and CE-CU-,}; 6.12 (1H, doublet, J 12 Hz, 3-CH), 6.83 (1H, singlet, thiazole-H); 6.98 (1H, quadruplet, J
-6 Hz, the basis).
High performance liquid chromatography: retention time 7.5 min (1: 1, 1 MP / min).
EXAMPLE 6 Diphenylmethyl 7-amino-3- (Z) -1 -button-G-Z-tsefem-4-car - bauxilate hydrochloride.
To a solution of propionaldehyde (10.7 g, 18 mmol) and lithium iodide (13.4 g, 10 mmol) in a mixture of dimethylformamide / dichloromethane (50 ml / 150 ml) was added a compound of formula II (7.3 g, 10 mmol) at 0 ° C. The mixture was left at 5 ° C for 2 days and concentrated in vacuo. A solution of the residue in ethyl acetate (200 ml) is washed with water, dried over magnesium sulfate and evaporated, in vacuo, to a syrup, which is treated with carbon tetrachloride (200 ml), and filtered. The filtrate is concentrated to 50 ml and the concentrate is stirred with 6N. hydrochloric acid (4 mp) at room temperature for 30 minutes. The resulting precipitate is separated by filtration and recrystallized from chloroform-ethyl acetate to obtain 1.49 g (yield 38%) of the desired compound. M.p. 120-127 ° C.
IR spectrum, „„. (KBG), 1780, 1710.
UV spectrum, (methanol), nm (): 217 (13900), 286 (7400).
NMR spectrum, S (DMSO-dg), h / mpn:
 (MN, triplet, J. 7 Hz, CH,), 2.00 (2H, multiplet,); 3.75
 (MN, triplet, J. 7 Hz, CH,), 2.00 (2H, multiplet,); 3.75
(2H, AB quadruplet, J 16 Hz, 2-H); 5.1-5.9 (MN, multiplet, 6-H and 7-H, SP-CH -); 6.33 (1H, doublet, J 12 Hz, 3-CH) - 6.97 (1H singlet, -CHPh); 7.40 (YUN, singlet, phenyl-N).
High performance liquid chromatography: retention times of 10.4 and 12.0 minutes (relative intensity 8: 1) (4: 1 methanol - pH 7 phosphate buffer, 1 MP / min).
EXAMPLE 7 Diphenylmethyl 7- (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido) -3- (g) -1-buteyl-3-cephem -4-carboxylate.
A suspension of Diphenylmethyl 7-amino-3- (7) -1-butenyl-3-cephem-4-cd, boksoylate hydrochloride (1.4l, 3.1 mmol) in ethyl acetate (20 ml) is shaken with
ten
using a two-layer clear solution. The organic layer is separated, washed with water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. 1- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino-acetoxy-benzotriazole (1.27 g, 4.0 mmol) is added to the dried filtrate and the mixture is stirred at room temperature for 20 h. The reaction mixture is filtered and the filtrate is washed with an aqueous solution.
sodium bicarbonate, water, and saturated 15 nyl-3-cephem-4-carboxylate. NaCl (162 mg, mixed over magnesium sulfate and evaporated in vacuo.) The residue was chromatographed on a silica gel column (40 g) with chloroform-ethyl acetate 3: 1 to give 1.7 g (yield 91% ) of the target compound.
TLC (silica gel): Rf 0.25 (1: 1 chloroform-ethyl acetate) o
IR spectrum, DAstx (KBG),: 1780, 1720, 1680, 1620.
UV spectrum, L max (ethanol), nm (b): 288 (12400),
It is chromatographed on a packed column (50 mp) from a Rger PAK (water) cartridge with 20-30% methanol to give 605 mg (yield 52%) of the desired compound.
The purity assessed by high performance liquid chromatography is 90%, T, mp, -160. C (gradual decomposition),
EXAMPLE 9 Pivaloshtoxymethyl 7- (Z) -2- (2-aminothiazol-4-yl) -2-methoxy-thyminoacetate-3- (Z) -1-6yTo, 67 mmol) is added at 0 ° C. C to a mixture of 7- (Z) -2- (2-aminothiazol-4-yl) -2 -2-methoxyimionoacetamido-3- (Z) -1 -1-butenyl-3-cephem-4-carboxylic acid (197 mg, 0 , 45 mmol) and potassium carbonate (93 mg, 0.67 mmol) in dimethylformamide (4 mp). The mixture was stirred at 0-5 seconds for 1 hour and diluted with ethyl acetate (30 ml), the diluted mixture was washed with water and a sodium bicarbonate solution, dried over anhydrous magnesium sulfate
and evaporated in vacuo. Chro-NMR spectrum, S (CBC1), ppm: 0.86 30 matrices on a silica gel column (3N, triplet, J, 7 Hz, -CH,), 1.90 (2H, multiplet,,), 3 , 45 (2H,
singlet, 2-E), 4.06 (3N, singlet, OCH;); 5.15 (1H, doublet, J 4.5 Hz,
35
ke (5 g) with 1% methanol in chloroform. The desired fractions are combined and concentrated in vacuo. The remainder of the solution was dissolved in dioxane and lyophilisapis to obtain 242 mg (yield 97%) of the dioxane solvate of the target compound. TLC (silica gel): Rf 0.25 (1: 1 chloroform - ethyl acetate), Purity of products 6-n), 5.45 (1H, double triplet
J 7 and 11 Hz, CH — CHj-); 6.05 (1H,
double doublet, J 4.5 and 9 Hz, 7-H);
6.16 (1H, doublet, J = 11 Hz, 3-CH);
6.75 (1H, singlet, thiazole-H), 6.97
(1H, singlet, CHPhj); 7.35 (YUN, syn-40 rated using high-efficiency phenyl-N); 8.08 (1H, doublet, good liquid chromatography, JS 9 Hz, CONH). Tavil 85%, mp, 90-95 ° C,
EXAMPLE 8 7- (E) -2- (2-aminothiazol-4-yl) -2-methoxyimino-1-IR spectrum, i.,. (KBG), cm: 1780,
(Z) -1-butenyl-3-cefem-4-cap-45 1750, 1670. lateral acid, UV spectrum, A max (ethanol), nm ():
The mixture of diphenylmethyl 7- (Z) -2- (2- -aminothiazol-4-yl) -2-methoxyiminoacetamido-3- (E) -1-butenyl-3-cephem 50
233 (15300), 285 (11300).
-4-carboxylate (1.65 g, 2.65 mmol) and anisole (0.5 mol) are treated with trifluoroacetic acid (5 ml) at room temperature for 1 hour. The mixture is diluted with isopropyl ether (IPE). The resulting precipitate (high performance liquid chromatography: retention time 5.0 and 6.4 minutes (relative intensity 8: 1, 3: 7 methanol - pH 7, phosphate
NMR spectrum, S (CDC1,), ppm: 0.97 (EF, triplet, J = 7 Hz,), 1.23 (9H, singlet, C ()) -, 2.03 (2H, double quadruplet , J 7 and 7 Hz,), 3.43 (2H, singlet, 2H), 3.67 (4H, singlet, 1 2-dioxane); 55 4.02 (SN, singlet, OSI,); 5.10 (1H, doublet, J = 4.5 Hz, 6-H); 5.3-6.3 (5H, multiplet, 7-H-CH, CH - and), 6.82 (1H, singlet, thiazole-H); 7.97 (1H, doublet, J 8 Hz, CONH),
nyl-3-cephem-4-carboxylate. Pivaloyl oxyiodide (162 mg,
It is chromatographed on a packed column (50 mp) from a Rger PAK (water) cartridge with 20-30% methanol to give 605 mg (yield 52%) of the desired compound.
The purity assessed by high performance liquid chromatography is 90%, T, mp, -160. C (gradual decomposition),
PRI me R 9, Pivaloshtoksimetil 7- (Z) -2- (2-aminothiazol-4-yl) -2-methoxy-amino-acetamide-3- (Z) -1-6yTonyl-3-cephem-4-carboxylate . Pivaloyl oxyiodide (162 mg,
0.67 mmol) is added at 0 ° C to a mixture of 7- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyimionoacetamido-3- (Z) -1 -1-butenyl-3-cephem- 4-carboxylic acid (197 mg, 0.45 mmol) and potassium carbonate (93 mg, 0.67 mmol) in dimethylformamide (4 mp). The mixture was stirred at 0-5 seconds for 1 hour and diluted with ethyl acetate (30 ml). The diluted mixture was washed with water and a lacM solution of sodium chloride, dried over anhydrous magnesium sulfate.
30 are mapped on a silica gel column.
35
ke (5 g) with 1% methanol in chloroform. The desired fractions are combined and concentrated in vacuo. The remainder of the solution was dissolved in dioxane and lyophilisapis to obtain 242 mg (yield 97%) of the dioxane solvate of the target compound. TLC (silica gel): Rf 0.25 (1: 1 chloroform - ethyl acetate), product purity 1750, 1670. UV spectrum, A max (ethanol
233 (15300), 285 (11300).
50
NMR spectrum, S (CDC1,), ppm: 0.97 (EF, triplet, J = 7 Hz,), 1.23 (9H, singlet, C ()) -, 2.03 (2H, double quadruplet , J 7 and 7 Hz,), 3.43 (2H, singlet, 2H), 3.67 (4H, singlet, 1 2-dioxane); 55 4.02 (SN, singlet, OSI,); 5.10 (1H, doublet, J = 4.5 Hz, 6-H); 5.3-6.3 (5H, multiplet, 7-H-CH, CH - and), 6.82 (1H, singlet, thiazole-H); 7.97 (1H, doublet, J 8 Hz, CONH),
high performance liquid chromatography: retention time 17.0 min (1: 1 CHjC, 2 ml / min).
Calculated,%: C 50.41; H 5.58; N 11.76; S 10.76.
,, Hs, 0
Found,%: C 49.94; H 5.57; N 11.56; S 10.76.
Example 10. 1-Acetoxyethyl-7- (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3- (Z) -1-6yTe-nyl-3-cephem-4- carboxylate.
To a mixture of 7- (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido 3-3- (E) -1-butenyl-3-cephem-4-carboxylic acid (1.55 g, 3.54 mmol) and potassium carbonate (636 mg, 4.6 mmol) in dimethylformamide (4 ml) were added at 5 C with 1-bromoethyl acetate (769 mg, 4.6 mmol). The mixture was stirred at 5 ° C for 1 hour, diluted with ethyl acetate (30 ml), washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a column of silica gel (50 g with 1% methanol in chloroform. The desired fractions were combined and concentrated to a small volume. The residue was triturated with isopropyl ether to obtain 1.29 g (yield 70% ) the target compound in the form of a salt of isopropyl ether cotton. The purity of the product assessed by high performance liquid chromatography is 90%. mp 103-110 ° C (decomposition).
IC-spectrum,), (KBr),: 1770 (broad), 1670, 1620.
UV spectrum, X) 233 (14300), 288 (11000).
NMR spectrum, S (CDCl,), ppm: 1.00 (3N, triplet, J 7 Hz, - 1.12 (12H, doublet, J 6 Hz, CH isopropyl ether), 1.5.3 (ZN, doublet, J 5 Hz, OSSNS), 1.95 (2H, multiplet,); 2.08 (ZN, singlet, COCH); 3.43 (2H, singlet, 2H) -, 3.62 (2H , multiplet, isopropyl ether (SI); 4.08 (ZN, singlet, OCH,), 5.13 (1H, doublet, J 4.5 Hz, 6-H); 5.2 - 6.2 (ZN, multiplet , 7-H and), 6.87 (1H, singlet, thiazole-H); 7.00 (1H, quadruplet, J 5 Hz, -CHCHj).
High performance liquid chromatography: retention time 10.8 mi
(1: 1
CH ,, CN
1 ml / minH
N
Calculated. %: C, 51.83; H 6.28; 11.19; S 10.25. .C ,, Si-C6H, 40
Found,%: C 51.62; H 6.07; N 11.16; S 10.05.
Example 11. Diphenylmethyl 7- {(Z) -2-methoxyimino-2 (2-tritylaminothiazol-4-yl) -acetamido3-3- (Z) -0 3-methoxy-1-propenyl3-3-cephem-4-car - bauxyl. .
A solution of diphenylmethyl 7-f (Z) -2-Me-toxyimino-2- (2-tritylaminothiazol-4-yl) acetamido-3-triphenylphosphonio-5 methyl-3-cephem-4-carboxy lato iodide (1.19 g, 1 mmol) in methylene chloride (30 mp) shake with 1N. sodium hydroxide (5 ml) for 2 min. The organic layer is separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. Isopropyl alcohol (15 ml) and methoxyacetal-5 dehyd- (7.41 mg, 10 mmol) are added to the filtrate. The mixture is stirred at room temperature overnight and evaporated to dryness in vacuo. The residue was dissolved in chloroform and chromatographed over a silica gel column (20 g) using eluent as a mixture of ethyl acetate and toluene 1:20, yielding 570 mg (yield 66%) of the desired compound.
IR spectrum ,, (KBV),: 1775, 1720, 1670, 1525, 1175.
NMR spectrum, -5 (CDCl, + DgO), ppm: 3.24 (3N, singlet, OCH), 3.3-3.8 (4H, multiplet, S-CH and OCHg) -. 4.13 (SN, singlet, NOCH,); 5.15 (W, doublet, J 4.5 Hz, 6-H), 5.98 (1H, doublet, J 4.5 Hz, 7-H), 6.3 (1H, doublet, J 11 Hz, vinyl H); 6.8 (IH, singlet, thiazole-H) ,. 6.98 (1H, singlet CH-Ph); 7.1-7.5 (25H, phenyl-H).
Highly efficient liquid; mathematics: retention time 13.6 min (3: 1 CH CNHiO, 1 ml / min).
Example 12. 7- (Z) -2- (2-aMnHo-thiazol-4-yl) -2-methoxyiminoacetamido-1-3- (Z) -3-methoxy-1-propylene I - -3-cephem-4- gkarbonovy. acid.
A solution of diphenylmethyl 7-L (Z) -2-Me-toxyimino-2- (2-tritylaminothiazol-4-yl) acetamido3 -3- (Z) -3-MeTOKcn-. -1-propenyl 3 -3 cephem-4-carboxate (550 mg, 0.64 mmol) in anisole-trifluoroacetic acid (0.5 ml / 5 ml) is allowed to stand at room temperature for 50 minutes and diluted 0
five
0
five
0
nsopropyl ether to obtain a precipitate which is collected by filtration and washed with isopropyl ether (1 PE). The solid is dissolved in methanol and chromatographed on a packed column (AO ml) from a Prep PAX liner (aq.) With 30% methanol as eluent to give 104 mg (36%) of the desired compound. M.p. 155-159 ° C (decomposition). Purity of the product, estimated using
The OSNO; 5.23 (doublet, J 5 Hz, 6-H), 5.4-5.9 (4H, multiplet, 7-H, and vinyl-H), 6.24 (1H, doublet, J 12 Hz, vinyl -N); 6.74 (1H, singlet, thiazole-H).
Example 14. 1-Acetoxyethyl 7- (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido} -3-L (Z) -3-methoxy-1-propenyl-3- cephem-4-carboxylate. Esterification of 7- (7) -2- (2-amino-thiazol-4-yl) -2-methoxy-amino-acetamide by high-performance liquid chro-3- (d) -3-methoxy-1-propenyl-3-cetography is 90 % fem-4-carboxylic acid (300 mg,
IR spectrum, max (KBr),: 1765, 15 0.66 mmol) using 1-bromo-1660, 1630, 1530, 1040. ethyl acetate in the same way as
UV spectrum, Xd, c (, o (methanol), nm (): described in example 10, leads to 234 (16600), 276 (14500). Radiation of the target compound (154 mg,
NMR spectrum, 5 (DMSO-dg +), yield 43%). M.p. 102-105 s (decomposition ppm: 3.19 (3N, singlet, OCH), 3.83 2ozhenie). Purity of product, rated
 (ZN, singlet, OSI,) -, 3.83 (ZN, singlet, OCH); 5.17 (1H, doublet, J 5 Hz, 6-H); 5.4-5.8 (1H, multiplet, vinyl-H); 5.72 (1H, doublet, J 5 Hz, 7-H); 6.27 (1H, doublet, J = 12 Hz, vinyl-H); 6.72 (1H, singlet, thiazole-H).
High performance liquid chromatography: retention time 9.6 minutes
by high performance liquid chromatography, is 95% (1: 1-pH 7, phosphate buffer).
IR spectrum, 5 ms.x (KBr), 1775-25 1760, 1670, 1630, 1375.
UV spectrum, (methanol), (): 232 (15900), 288 (13000).
NMR spectrum, S (CDCl +), ppm: 1.51 (ZN, doublet, J 5 Hz,
i-io. 1 iji Lfdwifin r ut :: ri / i viicuyivtaocirin / i - J nnri, v /
(1: 3 „ethanol - pH 7. phosphate. Auf. R. 30 ™, I, ...,
1 ml / min).
Calculated,%: C 43.30; H 4.49; N14.85; S 13.60.
3.29 (3N, singlet,,), 3.45 (2H, broad, S-CHi); 3.87 (2H, doublet, J = 7 Hz, CHCHiO), 4.04 (3N, singlet, MCH3); 5.09 (1H, multiplet, vinyl-N), 5.97 (1H, doublet, J 5 Hz, 7-H) -, 6.8 (1H, doublet, J 12 Hz, vinyl-H), 6, 83 (1H, singlet, thiazole-H); 6.97 (1H, quadruplet, J 5 Hz, OCHCH,).
C.nH.qNsOe HjO
Found,%: C 43.04; H 4.09, - NJ4.59; S 13.89.
Example 13. Pivaloyloxymethyl 7- (g) -2- (2-aminothiazol-4-yl-2-methoxyiminoacetamido) -3- (Z) -3-tags35
3.29 (3N, singlet,,), 3.45 (2H, broad, S-CHi); 3.87 (2H, doublet, J = 7 Hz, CHCHiO), 4.04 (3N, singlet, MCH3); 5.09 (1H, multiplet, vinyl-N), 5.97 (1H, doublet, J 5 Hz, 7-H) -, 6.8 (1H, doublet, J 12 Hz, vinyl-H), 6, 83 (1H, singlet, thiazole-H); 6.97 (1H, quadruplet, J 5 Hz, OCHCH,).
Example 15. 7-G (Z) -2- (2-amisi-1-propenip-3-cepheme-4-carboxylate. 40 11 P and me 15. 15. am etherification 7- (d) -2- (2- aminothiaziazol-4-yl) -2-methoxyiminoacetamisol-4-yl) -2-methoxyiminoacetamido - (E) -1-butenyl-3-cephem-4-carboxylic acid (E-isomer).
A mixture of diphenylmethyl 7- (Z) -2- (2-3- (g) -3-methoxy-1-propensh-3-cephem-4-k arbonic acid or acid (226 mg,
0.5 mmol) by the method described in pri-45-aminothiazol-4-yl) -2-methoxy measures 9 results in obtaining the desired acetamido-3- (Z) -1-butenyl-3-chain-compounds (97 mg, 34%). M.p. 100fem-4-carboxylate, which is prepared in Example 7 (7.6 g, 1.3 mmol), trifluoroacetic acid (25 ml) and an102 ° C. The purity of the product, as assessed by high-performance liquid chromatography, is 90% ( 1: 1 methanol - pH 7, phosphate buffer).
IR spectrum, -) „a |, p. (KBB): 1775, 1750, 1670, 1530, 1370, 1120.
UV spectrum, L,. (methanol) nm (): 232 (16600), 289 (13500),
NMR spectrum, S (DMSG-dfe +), h / mpn: 1.18 (9H, singlet, 3 x CH,), 3.19 (MN, singlet, OCH3); 3.57 (2H, broad, CH.), 3.85 (AH, singlet.
The OSNO; 5.23 (doublet, J 5 Hz, 6-H), 5.4-5.9 (4H, multiplet, 7-H, and vinyl-H), 6.24 (1H, doublet, J 12 Hz, vinyl -N); 6.74 (1H, singlet, thiazole-H).
Example 14. 1-Acetoxyethyl 7- (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido} -3-L (Z) -3-methoxy-1-propenyl-3- cephem-4-carboxylate. Esterification of 7- (7) -2- (2-aminothias using high performance liquid chromatography, is 95% (1: 1 -PH 7, phosphate buffer).
IR spectrum, 5 ms.x (KBr), 1775-5 1760, 1670, 1630, 1375.
UV spectrum, (methanol), (): 232 (15900), 288 (13000).
NMR spectrum, S (CDCl +), ppm: 1.51 (ZN, doublet, J 5 Hz,
 , v /
™ I ,. . .
3.29 (3N, singlet,,), 3.45 (2H, broad, S-CHi); 3.87 (2H, doublet, J = 7 Hz, CHCHiO), 4.04 (3N, singlet, MCH3); 5.09 (1H, multiplet, vinyl-N), 5.97 (1H, doublet, J 5 Hz, 7-H) -, 6.8 (1H, doublet, J 12 Hz, vinyl-H), 6, 83 (1H, singlet, thiazole-H); 6.97 (1H, quadruplet, J 5 Hz, OCHCH,).
Example 15. 7-G (Z) -2- (2-am11 R and mep 15. aminothiazol-4-yl) -2-methoxyiminoacetate (E) -1-butenyl-3-cephem-4-ka
new acid (E-isomer).
A mixture of diphenylmethyl 7- (Z) -2- (2-aminothiazol-4-yl) -2-methoxy-acetamido-3- (Z) -1-butenyl-3-cet-
-aminothiazol-4-yl) -2-methoxy-acetamido-3- (Z) -1-butenyl-3-cet-
fem-4-carboxylate, which was prepared in Example 7 (7.6 g, 1.3 mmol), trifluoroacetic acid (25 ml) and anisole (5 ml) was stirred at 5 ° C for 1 h and diluted with isopropyl by ether. The resulting precipitate is collected by filtration, dissolved in formic acid and purified.
active high performance liquid chromatography (Waters, System 500, Prep PAX-500 / C, j,) using 40% methanol. The eluate is controlled by analytic high performance.
liquid chomatography and gr are packed into two fracdies, which are evaporated under vacuum to give 0.94 g of the Z-isomer and 1.65 g of a mixture of the Z-isomer and the corresponding E-isomer of the desired product. The mixture is dissolved in formic acid and chromatographed on a column with a gasket (50 ml) of PgerRAC (Waters) using 20-30% -gg methanol, to obtain 0.22 g (yield 4%) of the E-isomer, together with 0 , 9 g of Z-isomer. The purity of the product, as estimated using high-performance liquid chromatography, is 15–90%. Mp. 170 ° C (gradual disintegration).
IR spectrum, “d. (KBG): 1760, 1660.
UV spectrum, And dlx (pH 7 phosphate buffer 20)., Nm (): 232 (15400), 292 (19400).
NMR spectrum, O (1) 0 + NaHCO,), ppm: 1.18 (3N, triplet, J 7 Hz,,) -, 2.30 (2H, multiplet, 25
,), 3.83 (2H, singlet, 2-H); 4.15 (SN, singlet, OCH,); 5.37 (1H, Ublet, J 5 Hz, 6-H), 5.92 (1H, Ublet, J 5 Hz, 7-H) 5.9-6.4 (1H, multiplet, CHCH2); 5.66 (1H, oak-zo et, J, 3-CH), 7.18 (1H, singly years, thiazole-H).
High performance liquid chromatography: retention 6.4 minutes (3: 7 methanol - pH 7, phosphate buffer, 2.0 ml / min).
Example 16. 1-Acetoxyethyl 7- (Z) -2- (2-aminothiazol-4-yl) -2-mexyiminoacetamido-3- (E) -1-buto-n-13-3-cephem-4-carboxylate ( . ,, measures).
To a mixture of 7- (Z) -2- (2-aminothiazol-4-yl) -2-methoxy-amino acetate-J-3- (E) -1-butenyl-3-cephem-4-carboxylic acid (130 mg, 0.3 mmol) and carbo-. Nata potassium (55 mg, 0.4 mmol) in diethylformamide (2.5 ml) was added at 5 ° C with 1-bromoethyl acetate (67 mg, g
0.4 mmol). The mixture was stirred at 5 ° C for 1 hour, diluted with ethyl Q acetate (25 ml), then washed.
water and an aqueous solution of sodium laorite, dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue is dissolved in chloroform and chromatographed on a column. e with silica gel using 1% methanol in chloroform. The target fractions are combined and concentrated.
55
five
five
ABOUT
,,

Q
five
five
under vacuum to give 77 mg (yield 49%) of the title compound. The purity of the product, as assessed by high performance liquid chromatography, is 90%. M.p. 110-115 ° C.
IR spectrum, max (KBG), cm: 1760 (wide), 1670, 1510..
UV spectrum, A max (methanol), nm (b): 232 (15100), 298 (17000).
NMR spectrum, 8 (CDCl-j), ppm: 1.05 (ZN, triplet, J 7 Hz,,), 1.54 (ZN, doublet, J 6 Hz, CHCH,); 2.08 (3N, singlet, COCH,), 2.0-2.4 (2H, multiplet, -CH2CH,), 3.57 (2H, singlet, 2-H); 4.05 (SN, singlet, OCH,); 5.07 (1H, doublet, J 5 Hz, 6-H), 5.8-6-, 3 (2H, multiplet, 7-H and CH-CH -); 6.86 (1H, singlet, thiazole-H) -, 6.8-7.1 (2H, multiplet, OCH and 3-CH).
High performance liquid chromatography: retention time 7.7 minutes (1: 1 CH, jCN -HjjO, 1.5 MP / min).
Etc. imame 17. Acetoxymethyl 7- (Z) -2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetamido-3- (Z) -1-6yTe -nyl-3-cephem-3-4-carboxylate ( Z-isomer).
To a mixture of 7- (Z) -2- (2-aminothiazol-) -2-methoxyiminoacetamido3 -3- (Z) -1-butenyl-3-cephem-4-carboxylic acid (300 mg, 0.69 mmol) and carbonate potassium (95 mg, 0.69 mmol) in dry dimethylformamide (3 mp) was added dropwise at 0 ° C a solution of bromomethylacetate (105 mg, 0.69 mmol) in dry dimethylformamide (0.25 ml) and the mixture was stirred at 0 ° C for 15 minutes. A solution of bromomethyl acetate (105 mg, 0.69 mmol) in dry dimethylformamide (0.25 mp) is again added to the mixture. The reaction mixture was stirred for an additional 30 minutes and diluted with ethyl acetate (20 ml). The diluted mixture is washed with water and all (with a solution of sodium chloride, dried over anhydrous sodium sulphate and evaporated to dryness. The residue is dissolved in methanol and passed through a packed column (40 ml) of Rherrac (Waters), which is washed with water and then eluted with 50 % methanol. The eluate is controlled by high performance liquid chromatography. The target fractions are collected and evaporated to give 6 mg (yield 27%) of the desired compound. The purity of the product, assessed using high performance
liquid chromate raffia is 90%. M.p. 149-152 p.
IR spectrum, -JMOUC (KB g), cm: 1780, 1660, 1535, 1375, 1170, 1045.
UV spectrum, COP (methanol), im (E): 231 (17000), 289 (13100).
NMR spectrum, S (CDCl + 0.0), ppm: 0.99 (3N, triplet, J 7.2 Hz, SI,); 2.11 (SN, Singlet, SOOCH); 1.75-2.5 (2H, filet, ,,), 3.45 (2H, singlet, S –SI); 4.05 (3N, singlet, OCHj), 5.11 (1H, doublet, J 4.5 Hz, 6-H); 5.81 (2H,. Singlet,); 5.99 (1H, doublet, J = 4.5 Hz, 7-H); 6.18 (1H, doublet, J 12 Hz, 3-CH); 6.76 (1, H, singlet, tia; ash-H).
High performance liquid chromatography: retention time 6.3 minutes (3: 2 CH, CN - pH 7 phosphate buffer).
Calculated:%: (G 46.32; H 4.66 N 13.50; S 12.37.
 1 / 2H20
Found,%: C 46.51, H 4.44} N 13.34; s 12.25. ,
Example 18. 4-СН (tert-butoxycarbonyl) glycyloxy benzoipoxymethyl-7- (E) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-Z-L-Z (Z) -1- -butenyl-3-cephem-4-carboxylate.
A solution of chloromethyl (t-butyloxycarbonyl) glycyloxybenzoate (584 mg, .1.7 mmol) in acetone (10 ml) is stirred with sodium iodide (f, 28 g, 8.5 mmol) at room temperature for 6 hours. The injected sodium chloride is removed by filtration. The filtrate is concentrated in vacuo. The residue was dissolved in dimethylformamide (10 ml) and added at -20 ° C to a mixture of 7- (g) -2- (2-amino-thia-ZOL-4-IL) -2-methoxyiminoacetate amido3-3- ( 2) -1-butenyl-3-cephem-4-carbo; New acid (437 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol) in dimethylformamide (5 ml). The mixture was stirred for 1 hour, diluted with ethyl acetate (50 ml), washed successively with water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated in vacuo .. The residue was chromatographed on a column of silica gel (20 g ), deluge a mixture of 1: 1 toluene-ethyl acetate, to obtain 533 mg (yield 76%) of the target compound. Thin layer chromatography (silica gel)
0
-with
0.16 (1: t toluene-ethyl acetate). M.p. 110-117 ° C
IR spectrum,) (KBG),: 1770, 1740, 1670.
U.V. spectrum, „ace (methanol), nm (f): 237 (26700), 187 (11800).
NMR spectrum, S (CDClj +), ppm: 0.90 (3N, triplet, J 7. Hz, O); 1.48 (9H, singlet, C (CH,),) 2.00 (2H, double quadruplet, J 7 Hz,,) 3.43 (2H, singlet, 2-H); 3.98 (SN, singlet, OCH,); 4.13 (2H, singlet,), 5.10 (1H, oak, 5 years old, J 4.5 Hz, 6-H); 5.50 (1H,
double triplet, J 11 and .7 Hz), 5.9 -, 6.3 (4H, multiplet, 7-H, vinyl-H and) - 6.52 (1H, singlet, thiazole-H); 7.17 and 8.06 (2H, each doublet, Q J 8 Hz, benzene-H).
EXAMPLE 19 4-Glyce 1 -soxy-benzo-yloxymethyl 7- (E) -2- (2 aminothiazol-) -2-methoxy-iii-amino acid-J-3- (Z) -1 -butenyl-3-cephem-4-carboxy-5 lat dihydrochloride.
A mixture of the K- (tert-butoxycarbon14l) derivative (349 mg, 0.5 mmol) obtained in Example 18, anisole (3 drops) and 2 N. hydrochloric acid in 0 ethyl acetate (2.5 ml) was stirred at C for 15 minutes. The resulting precipitate was separated by filtration and dissolved in methanol (3 ml). After filtration, ET11L-agate etatat (39 ml) is added to the filtrate. The resulting precipitate is separated by filtration to give 166 mg (yield 46%) of the desired compound. M.p. 160 ° C (decomposition). The purity of the product, as assessed by high performance liquid chromatography, is 90%,
IR Spectrum, (KBG),: 1780, 1745, 1760, 1630.
UV spectrum, (methanol), nm (E): g 233 (27200), 287 (12900).
NMR spectrum, 5 (DMSO-dg), ppm: 0.78 (ZN, triplet, j 7 Hz,,); 2.00 (2H, multiplet,); 3.52 (2H, singlet, 2-H); 3.90 (3N, singlet, OCHj); 4.05 (2H, singlet, CHaMN); 5.22 (1H, doublet, J 5 Hz, 6-H); 5.5-6.2 (5H, multiplet, 7-H, vinyl-H X 2 and), -, 6.88 (1H,. Singlet, thiazole-H) 7.35 and 8.00 (2H each, doublet, J 8 Hz, benzene-N).
Calculated,%: C, 44.63; i H 4.30, N 9.76; N 11.57; S 8.82, C -iH ftNeOgSj - 1 / 2H ,, 0
7
Found,%: C A4,60; H 4.34; C1 9.18; N P, 13; S 8.46.
High Performance Liquid Chromatography: Retention Time 5.2 min.:. (3: 2 CH, CN HjO, 1 Mii / min).
Example 20. Diphenylmethyl 7-amino-3- (1-pentenyl) -3-cephem-4-β-carboxylate.
- To a cooled and stirred solution of 8.7 g (0.1 mmol) of anhydrous lithium bromide in 50 ml of dimethylformamide, one portion of a solution of 7.3 g (0.01 mol) of ylide of formula II in 250 MP of methylene chloride is added. 30 ml of n-butyraldehyde is added to the solution and the mixture is stirred at room temperature for 24 hours. After concentration to 50 MP, the residue is extracted with 300 ml of ethyl acetate. The extract is washed with water and with a saturated solution of sodium chloride and dried over anhydrous magnesium sulphate. Activated carbon (1 g) and
142820418.
toxyiminoacetamido-3- (1-pentenyl) -2-cephem-4-carboxylate.
A mixture of 1.7 g (3.9 mmol) of compound J-example 20 and 1.24 g (3.9 mmol)
1- (Z) -2- (2-aminothiazol-4-yl) -2-me-. toximinoacetoxy benzotriazole in 150 ml of ethyl acetate is stirred at room temperature for 20 hours 10 and the mixture is evaporated to dryness. The residue was chromatographed on a column with leica gel (Merek Ki selgel 60.60 g), eluting with chloroform and 1% methanol in chloroform successively. The 15% left fractions eluted with a mixture of chloroform-methanol and monitored by a thin layer {silica gel chromatography (1: 1 methanol-chloroform, Rf 0.50) are collected and evaporated to dryness. The residue is triturated with a mixture of ether-isopropyl ether with the receipt of 1.94 g (yield 85%) of the target compound. M.p. 115-120 C (decomposition). IR spectrum, (KBV),
1775,
Wako-gel (C-100, 10 g). The mixture of filter-25 1.720, 1670, 1610, 1380, 1530, 1220, is turned on and the filtrate is concentrated 1180, 1030.
up to 100 MP. The UV spectrum is added to the concentrate,) 01 01 icc () () 5 g (0.03 mol) of Girard reagent in 290 (14000). 100 ml of methanol containing 5 ml of NMR spectrum, S (CDCl), ppm: 0.6
acetic acid, and a mixture of stirring 2.1 (7H, multiplet, CH x 2 and CH),
3.42 (2H, broad singlet, 2-H), 4.0 (3N, singlet, OCH,), 5.15 (1H, doublet, J 4.5 Hz, 6-H), .5.3- 5.8 (3N, multiplet, and NHj); 6.02 (1H, 35 double doublet, J 4.5 and 8 Hz, 7-H 6.14 (1H, doublet, J 11 Hz, 6.80 (1H, singlet, thiazole, H); 6.98 ( 1H, singlet, CHPh); 7.2-7.5 (UN, multiplet, phenyl-H); 8.0 (1H, .doublet, J B Hz, NH).
at room temperature for 30 minutes. After evaporation to dryness, the residue is extracted with 300 ml of ethyl acetate. The extract solution is washed successively with water, in one solution of sodium bicarbonate, water and a saturated solution of sodium chloride and dried over anhydrous magnesium sulphate. After evaporation to dryness, the residue is chromatographed on a column of silica gel (Merek Kieselgel 60, 120 g), eluting with toluene-ethyl acetate (5: 1). Tse- the left fractions were collected, monitored by thin layer chromatography and evaporated to dryness to give 1.78 g (yield 41%) of the title compound as a solid foam.
NMR spectrum, 8 (CBC1), ppm: 0.72 .0 (7H, multiplet CH x 2 and C-CH,) i 3.28 (1H, doublet, J 18 Hz, 2-H) 3, 58 (1H, doublet, J 18 Hz, 2-n); 4.75 (1H, doublet, J = 4.5 Hz, 6-H);
5.01 (1H, doublet, J 4.5 Hz, 7-H); 5.2-5.7 (1H, multiplet,); 6.12 (1H, doublet J = 11 Hz,), - 7.00 (1H, singlet, CHPhj,); 7.2-7.6 (YUN, multiplet, phenyl-N).
PRI me R 21. Diphenylmethyl 7- (g) -2 (2-aminothiazol-4-yl) -2-me
2820418.
toxyiminoacetamido-3- (1-pentenyl) -2-cephem-4-carboxylate.
A mixture of 1.7 g (3.9 mmol) of compound J-example 20 and 1.24 g (3.9 mmol)
1- (Z) -2- (2-aminothiazol-4-yl) -2-me-. toximinoacetoxy benzotriazole in 150 ml of ethyl acetate is stirred at room temperature for 20 hours 10 and the mixture is evaporated to dryness. The residue was chromatographed on a column with leica gel (Merek Ki selgel 60.60 g), eluting with chloroform and 1% methanol in chloroform successively. The 15% left fractions eluted with a mixture of chloroform-methanol and monitored by a thin layer {silica gel chromatography (1: 1 methanol-chloroform, Rf 0.50) are collected and evaporated to dryness. The residue is triturated with a mixture of ether-isopropyl ether with the receipt of 1.94 g (yield 85%) of the target compound. M.p. 115-120 C (decomposition). IR spectrum, (KBV),
1775,
25 1.720, 1670, 1610, 1380, 1530, 1220, 1180, 1030.
2.1 (7H, multiplet, CH x 2 and CH),
3.42 (2H, broad singlet, 2-H), 4.04 (3N, singlet, OCH,), 5.15 (1H, doublet, J 4.5 Hz, 6-H), .5.3- 5.8 (3N, multiplet, and NHj); 6.02 (1H, double doublet, J 4.5 and 8 Hz, 7-H), 6.14 (1H, doublet, J 11 Hz,) -, 6.80 (1H, singlet, thiazole, H); 6.98 (1H, singlet, CHPh); 7.2-7.5 (YUN, multiplet, phenyl-N); 8.0 (1H, .doublet, J B Hz, NH).
EXAMPLE 22 7-f (Z) -2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetami- (E) -1-pentenyl-3-cephem-4-carboxylic acid (Z-isomer).
A mixture of 2.5 g (4.27 mmol) of the compound of Example 21, 2.5 ml of anisole and 7.5 ml of trifluoroacetic acid was stirred at room temperature for 10 minutes and concentrated to 3 MP. The residue is diluted with 100 ml of isopropyl ether to obtain 2 g of trifluoroacetate of the target compound (5: 1 mixture of Z- and E-isomers). The crude product is dissolved in aqueous methanol and the solution is chromatographed on a PrepPAKC g packed column (Waters, 300 ml), eluting successively with water, 10, 20, 30 and 40% methanol. The eluate is controlled by high
I CH1 / 4
eff. |}) liquid chromatography; Fractions containing Z-isomer in 40% methanol eluate are collected and evaporated to dryness, the solid residue is dissolved in methanol and filtered. 200 ml of isopropyl ether is added to the filtrate and the resulting solid is separated by filtration, washed with isopropyl ether and dried under vacuum over P.0 to give 695 mg (39% yield) of the product, which, as assessed by high performance liquid chromatography, has
90% clean. M.p. 150-155 ° C (decomposition).
IR spectrum, l, o, kc (KVg), 1770, 1670, 1630, 1530, 1370, 1180, 10DO.
UV spectrum, X „s1x (pH 7 phosphate buffer), nm (g): 229 (16000), 283 (15000).
NMR spectrum 8 (+), ppm: 1.01 (ZN, triplet, J 7 Hz, CHjCH,) j 1.3-1.7 (2H, multiplet, CHjCH CH,), 2.0-2 , 3 (2H, multiplet, J CH-CHjCH,); 3.46 (1H, doublet, 18 Hz, 2-H); 3.76 (1H-, doublet, 18 Hz, 2-H) i 4.14 (3N, singlet, SI,), 5.38 (1H, doublet, J 4.5 Hz, -H); 5.5-5.9 (1H, multiplet,); 5.92 (1H, doublet, J = 4.5 Hz, 7-H); , 09 (1H, doublet, J 11 Hz) i 7.16 (1H, singlet, thiazole-H).
Calculated,%: С 46,94; H 4.82; N 15.21; S 13.92.
C, gH ,,% 05S2-1 / 2H2: 0
Found,%: C 46,93; 47.07; H 4.66; 4.71; N 15.00; 15.00; S 13.34; 13.36.
High performance liquid chromatography: retention time 9.9 minutes (2: 3 methanol - pH 7 phosphate buffer, 1 ml / min).
Example 23. 7- (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetam- (E) -1-pentenyl-3-cephem-4-carboxylic acid (E-isomer) ,
E isomer containing fractions of 40% methanol eluate (from example 22) are collected and evaporated to dryness to obtain 455 mg of a mixture of cis and trans isomers (1: 1). The crude product is rechromatographed on a packed Rgherrak C g column (Waters, 300 ml), eluting with 35% methanol and monitored by high performance liquid chromatography. The target fractions, the trans-isomer, are selected and con-820420
center to 10 ml and lyophilize to obtain 89 mg (yield 5%) of the product, which, as assessed by high performance liquid chromatography, is 75% pure. M.p. (gradual decomposition).
IR spectrum ,, ak (. (KVg),: 1770, 1660, 1630, 1530, 1380, 1040. 0 UV spectrum, | (pH 7, phosphate buffer), nm (): 228 (17000), 292 ( 22,000)
NMR spectrum, J (+), ppm: 1.05 (EF, triplet, J = 7 Hz, 5,); 1.2-1.8 (2H, multiplet,); 2.1-2.5 (2H, multiplet CH-CH.j.CH2), - 3.81 (2H, singlet, 2-H); 4.16 (ZN, singlet, OCH,) -, 5.37 (1H, doublet, J 4.5 Hz, 6-H); 5.91 (1H, 0 doublet, J 4.5. Hz, 7-H); 5.9-6.3 (1H, multiplet,); 6.67 (1H, doublet, J = 16 Hz, 3-CH-C); 7.17 (1H, singlet, thiazole-H).
High Performance Liquid Chromatography 5: Retention Time
12.3 min (2: 3 methanol - pH 7 phosphate buffer, 1 ppm).
PRI mme R 24. 1-Acetoxyethyl 7- (Z) -2- (2-aminothiazol-4-yl) -2-me- o toxyimino acetamido | -3- (Z) -l-neHTe nyl-3- cephem-4-carboxylate (Z-isomer).
To the stirred mixture of the product, example a 23 Z-isomer (225 mg, 0.5 mmol) and 69 mg (0.5 mmol) of potassium carbonate in 5 ml of dimethylformamide were added at 0-5 ° C. 84 mg (0.5 mmol) 1-acetoxyethylbromine {-sca in 1 ml of dimethylformamide and the mixture is stirred at room temperature for 2 hours.
five
0
30 min. A solution of 84 mg (0.5 mmol) in 1 ml of dimethylformamide is again added to the mixture and the mixture is stirred at 5-10 ° C for 30 minutes. The mixture is then extracted with 400 ml of ethyl acetate. The extract was washed successively with an aqueous solution of sodium bicarbonate, water, and a saturated solution of sodium chloride and over magnesium sulfate. After evaporation to dryness, the oily residue of chromate graphene-i is placed on a column of silica gel (Kiesel gel 60, 30 g), eluting with chloroform and 1% methanol in chloroform successively and controlled finely 5 ","
layer chromatography and high performance liquid chromatography. The target fractions of the eluate with 1% methanol in chloroform are taken and evaporated
0
21142820422
dry up The residue is triturated with a mixture of female pressure results in
of the final product in the oil, which is chromatographed on a silica gel column (eluted with chloroform) from the semi-compound as an amorphous powder, IR spectrum, (KBr),:
1780, 1720, 1680.
Example 26. (2-Aminothiazol-4-pc) -2- (E) -isopropyloxyiminoacetamido-3- (Z) -1-propenylJ-cephem-4-carboxylic acid.
A mixture of the compound of Example 25 (400 mg,
ether-n-hexane to obtain 91 mg ce-
left junction. Raw side
fractions are rechromatographed so
in the same way with the addition of 41–9 mg (49% yield) of the target
but 63 mg of product. The total yield of the product is 154 mg (57% yield).
Purity of product assessed by
-High performance liquid chromate
is 80%. M.p. 100110 ° С (decomposition). . IR spectrum, d (KVg), 1765,
1670, 1610, 1530, 1380, 1240, 1210,
1180, 1100, 1070, 1040.15 0, 47 mmol) and the 85% formic acid UV spectrum, Lmax (methanol), nm (6): lots (2 MP) are mixed at rooms 233 (17000), 280 (13000). . temperature for 3 hours and
NMR spectrum, 5 (CDCl), ppm: 0.90 s. Mixture hydrochloric acid is added.
(ZN: triplet, J 7 Hz,), 1,2- (0.08 mp). The mixture is stirred additionally, 8 (MN, multiplet, CHCH and 20 for about 4 hours and evaporated
under reduced pressure. The residue was triturated with isopropyl ether to give a crude product, which was purified by column chromatography on silica gel C-18 (eluent 30% aqueous methanol), then concentrated under reduced pressure to obtain
CHjCHiCHj); 1.8-2.1 (2H, multiplet,
CH-CH2 CH2.); 2.06 (SN, singlet,
COCHj); 3.43; (2H, broad singlet
2-H); 4.05 (SN, singlet, OCH,); 5.08
(1H, doublet, J 4.5 Hz, 6-H), 5.32
(2H, broad singlet, NHj); 5.5-5.7
(1H, multiplet,); 5.94 (1H,
double doublet, J 8 and 4.5 Hz, 7-H);
6.13 (1H, doublet, J 11 Hz,) i
6.84 (1H, singlet, thiazole-H), 6.97 DA (decomposition). Purity of product, oce (1, H, quadruplet, J 7 Hz, CH-CH),
7.48 (1H, doublet, J 8 Hz, I).
High performance liquid chromatography: retention time 8.1 min (7: 3 methanol - pH 7 phosphate buffer, „
target compound in the form of needles. Yield 70 mg (33%). M.p. 170-1754
1 ml / min).
EXAMPLE 25 Diphenylmethyl 7- 2- (2-tritylaminothiazol-4-Sh1) -2 -2 (7) -isoproxy1 Oxyiminoacetamine chromatography is 90%.
IR spectrum, -O l10 (KS (KVg),: 1760,. 1660, 1540, 1380,
UV spectrum, AMOX (pH 7, phosphate buffer), nm (e,): 232 (370), 284 (357).
 NMR spectrum, (G (0.0 + NaHCO,), ppm: 1.50 (6H, doublet, J 6 Hz, isopropyl); 1.76 (ZN, doublet, J
(d) -1-propen-1 -3-cephem-4-car-4Q 6 Hz, CH — CH j), 3.65 (2H, AB quad-boxylate ruble, J 18 Hz, 2-H); 5.42 (1H,
To a mixture of 2- (2-tritylaminothiazol. Doublet, J 4 Hz, 6-H), 5.80-6.40 -4-yl) -2- (g) -isopropyloxyimino-oxus (3H, multiplet, vinyl-H , 7-H); 7.15 hydrochloric acid (754 mg, 1.60 mmol) and (1H, singlet, thiazole-H). dichloromethane (7 ml), penta-g was added. EXAMPLE 27 Diphenylmethyl
 - - (2-tritylaminothiazol- -Sh1) -2- (Z) -allyloxymino-acetamido-3- (Z) -1-propenyl-3-cephem-4-carboxylate.
To a mixture of 2- (2-tritylaminothiazole)
phosphorus chloride (332 mg, 1.60 mmol) at -10 ° C. The mixture is left to stand for 20 minutes at the same temperature and Diphenylmethyl 7-amino-3- (Z) -1-npo-JQ is added dropwise to the solution.
penyl-3-cephem-4-carboxylate hydrochloride (443 mg, 1 mmol) and K, 0-bis- (trimethylsilyl) acetamide (0.74 ml, 4.4 mmol) in dichloromethane (5 ml) at -10 C. The reaction mixture is left to stand for 30 minutes at the same temperature and poured into ice-water. Extraction of the mixture with ethyl acetate, after the second evaporation of the extract with a pony
-4-yl) -2- (Z) -allyloxyiminoacetic acid (750 mg, 1.60 mmol) and dichloromethane (5 ml) phosphorus pentachloride (332 mg, 1.60 mol) was added at -10 ° C. Mixture allowed to stand for 20 minutes at the same temperature and added dropwise to a solution of diphenylmethyl 7-amino-3- (Z) -l-nponeHmTj-3-cephem-4-carboxylate hydrochloride
of the final product in the oil, which is chromatographed on a silica gel column (eluted with chloroform) from the semi-compound as an amorphous powder, IR spectrum, (KBr),:
1780, 1720, 1680.
Example 26. (2-Aminothiazol-4-pc) -2- (E) -isopropyloxyiminoacetamido-3- (Z) -1-propenylJ-cephem-4-carboxylic acid.
A mixture of the compound of Example 25 (400 mg,
target compound in the form of needles. Yield 70 mg (33%). M.p. 170-1754
Jq
55
-4-yl) -2- (Z) -allyloxyiminoacetic acid (750 mg, 1.60 mmol) and dichloromethane (5 ml) phosphorus pentachloride (332 mg, 1.60 mol) was added at -10 ° C. Mixture allowed to stand for 20 minutes at the same temperature and added dropwise to a solution of diphenylmethyl 7-amino-3- (Z) -l-nponeHmTj-3-cephem-4-carboxylate hydrochloride
(A43 mg, 1 mmol) and N, 0-6HC (trimethyl-C1-syl) acetamide (0.7A ml, 4.4 mmol) in dichloromethane (5 ml) at -10 ° C. The reaction mixture is left to stand for 30 min at the same temperature and pour in lead with ice. Extraction of the mixture with chloroform and extraction of the extract under reduced pressure yields a crude product in the form of an oil, which is chromatographed on a column of silica gel, eluting with chloroform, to give 817 mg (yield 95%) of the title compound as an amorphous powder.
IR spectrum, (KBG), cm: 1780, 1720, 1680.
EXAMPLE 28 (2-aminothiazol-4-yl) -2 (g) -allyloxyimino-aceta7; 7-meso-3- (2) —1-propenyl-3-cephem-4-carboxylic acid.
A mixture of the compound of Example 27 (810 mg, 0.95 mmol) and 85% formic acid (2 ml) was stirred for 3 hours at room temperature, and hydrochloric acid (0.1 MP) was added to the mixture. The mixture is stirred for 3 hours and evaporated under reduced pressure. Rubbing residue with
ten
benzotriazole (135 mg, 1.0 mmol) in a mixture of dichloromethane (20 mp) and tetrahydrofuran (7 mp) at room temperature was added dicyclohexylcarbodiimide (210 mg, 1.0 mmol). The mixture is stirred for 80 minutes, filtered and the filtrate is concentrated to dryness. The residue is triturated in tetrahydrofuran (10 mp) - and diphenylmethyl 3-propenyl-3-cephem-4-carboxylate hydrochloride (443 mg, 1 mmol) and sodium bicarbonate (34 mg, 1 mmol) are added. Water (10 drops) is added and the solution is stirred at room temperature for 12 hours. The reaction mixture is diluted with ether and filtered. The filtrate is concentrated to an oil. The oil is chromatographed on silica gel (230-400 msec S1I 0.062-0.04 mm), eluting with an IOT mixture of 2: 1 hexane-ethyl acetate to obtain the acylation product (400 mg). This product was dissolved in 25 formic acid (1.6 ml), stirred vigorously for a minute and 12N was added. hydrochloric acid (50 μl). The mixture is stirred at room temperature for 3 hours.
15
20
isopropyl ether leads to half- 30 diluted with water (2 ml) and toluene as a crude product, which is a plant) ml and evaporated at 30 ° C to dryness.
The residue is triturated with isopropyl
Collect in a small amount of methanol and chromatograph on a C-18 silica gel column (eluting with 30% aqueous methanol). The eluate is concentrated under reduced pressure and dried upon freezing to obtain 215 mg (yield 50%) of the title compound as an amorphous powder. M.p. 140 C (decomposition). The determined purity of the product is 80%.
IR spectrum, (KBG), cm: 1770, 1660, 1620.
 UV spectrum, X llax (pH 7, phosphate buffer), nm (l ° O: 232 (378), 285 (326).
NMR spectrum, (+ NaHCO), ppm: 1.78 (3N, doublet, J = 6 Hz,
40
ether, the resulting precipitate is collected and washed with isopropyl ether. The solid is chromatographed on a C-18 cligel gel, eluting with 3: 7 methanol-water, to give the title compound as an amorphous solid, 100 mg (23% yield), m.p. 158 C (decomposition). The purity of the product, as assessed by high performance liquid chromatography, is 90%.
IR spectrum. (KBG): 3600-2600, 1765, 1660, 1620, 1385, 1355, 1035.
UV spectrum ,. (methanol), nm (b): 235 (16100), 256 (13800).
NMR spectrum, S (4- NaHCO),
Hz)
1.77 (3N, doublet, J = 6 Hz); 3.45 and 3.75 (2H, AN quadruplet, J 18 Hz),
45
С СН-СНа) -, 3.62 (2Н, АВ quadruplet ,./g,. „M 7
J. , 8 c, 2-H). 5.50-6.30 t ol-50 T GjU J;
tiplet, vinyl-H, 6,7-H); 7.18 (1H, singlet, thiazole-H).
Example 29. 7- (g) -2- (2-amino-thiazol-4-yl) -2- (Z) -ethoxyiminoacetate-amido-3- (Z) -1-propyln-J-3-cepheme-4- carboxylic acid.
To a solution of (g) -2- (2-N-tritylaminothiazol-4-yl) -2-ethoxyiminoacetic acid (458 mg, 1.0 mmol) and 1-hydroxy4, 40 (3N, quadruplet, J 7 Hz) -5.40 (1H, doublet, J 5 Hz); 5.75-6.20 55 (ZN, multiplet), 7.13 (1H, singlet). EXAMPLE 30 7- (Z) -2- (2-amino-nothiazol-4-yl) -2-cyclopropyl-methyl-amino-amino-acetamido-3- (Z) -1-propenyl - -3-cephem-4 - carboxylic acid.
benzotriazole (135 mg, 1.0 mmol) in a mixture of dichloromethane (20 mp) and tetrahydrofuran (7 mp) at room temperature was added dicyclohexylcarbodiimide (210 mg, 1.0 mmol). The mixture is stirred for 80 minutes, filtered and the filtrate is concentrated to dryness. The residue is triturated in tetrahydrofuran (10 mp) - and diphenylmethyl 3-propenyl-3-cephem-4-carboxylate hydrochloride (443 mg, 1 mmol) and sodium bicarbonate (34 mg, 1 mmol) are added. Water (10 drops) is added and the solution is stirred at room temperature for 12 hours. The reaction mixture is diluted with ether and filtered. The filtrate is concentrated to an oil. The oil is chromatographed on silica gel (230-400 msec S1I 0.062-0.04 mm), eluting with an IOT mixture of 2: 1 hexane-ethyl acetate to obtain the acylation product (400 mg). This product was dissolved in 5 formic acid (1.6 ml), stirred vigorously for a minute and 12N was added. hydrochloric acid (50 μl). The mixture is stirred at room temperature for 3 hours.
five
0
ether, the resulting precipitate is collected and washed with isopropyl ether. The solid is chromatographed on a C-18 cligel gel, eluting with 3: 7 methanol-water, to give the title compound as an amorphous solid, 100 mg (23% yield), m.p. 158 C (decomposition). The purity of the product, as assessed by high performance liquid chromatography, is 90%.
IR spectrum. (KBG): 3600-2600, 1765, 1660, 1620, 1385, 1355, 1035.
UV spectrum ,. (methanol), nm (b): 235 (16100), 256 (13800).
NMR spectrum, S (4- NaHCO),
Hz)
1.77 (3N, doublet, J = 6 Hz); 3.45 3.75 (2H, AN quadruplet, J 18 Hz),
. / g,. „t 7
 ГjU J;
4.40 (3N, quadruplet, J = 7 Hz) -5.40 (1H, doublet, J = 5 Hz); 5.75-6.20 55 (ZN, multiplet), 7.13 (1H, singlet). EXAMPLE 30 7- (Z) -2- (2-amino-nothiazol-4-yl) -2-cyclopropyl-methyl-amino-amino-acetamido-3- (Z) -1-propenyl - -3-cephem-4 - carboxylic acid.
25142820A
To solution (g) -2- (2-Н-tritylamino26
thiazol-4-yl) -2-cyclopropsyl methylimino-acetic acid (A84 mg, 1.0 mmol) and 1-hydroxybenzotriazole (135 mg, 1.0 mmol) in a mixture of dichloromethane (20 ml) and tetrahydrofuran (7 ml) Dicyclohexylcarbodiimide (210 mg, -1.0 mmol) is added at room temperature. The mixture is stirred for 80 minutes, filtered and the filtrate is concentrated to dryness. The residue was dissolved in tetrahydrofuran (10 ml), and diphenylmethyl 3-propenyl-3-CeP y and p 31 was added. Diphenylmethyl 7- (2-tritylamine-thiazol-4-yl) -2-pro-pargyloxyimino-acetamido-3- (Z ) -1-propenyl-3-cephem-4-carboxylate.
To a cooled solution of 750 mg (1.65 mmol) of diphenylmethyl 7-amino-3- (Z) -1-propenyl-3-cethem-4-carboxylate hydrochloride and 1.05 ml of 1Q; - (5 mmol), 750 mg (1.65 mmol) of 2- (2-tritylaminothiazol-4-sh1) -2- (2- -propargyloxyimo) acetic acid is added to a solution of H, 0-bis (trimethylsilsh1) acetamide in 17 ml of dry metilenene hydrochloride.
phen-4-carboxylate hydrochloride (443 mg, 15 s and 415 mg (2.0 mmol) of 1.0 mmol pentachloride) and sodium bicarbonate (84 mg, phosphorus in 17 ml of dry methylene chloride and the mixture is stirred for 1 h at room temperature. The reaction mixture is poured into an aqueous solution of sodium bicarbonate (30 mp) and diluted with 60 ml of ethyl acetate. The organic layer is washed with water (30 ml x 2) and hydrochloric acid (20 ml), dried over magnesium sulfate and concentrated
eluting with 2: 1 hexane-ethyl acetate, 25 under reduced pressure. The oily residue is chromatographed on a silica gel column (Wakogel 200, 20 g), which is eluted with chloroform. The fractions containing the target product,
at room temperature, and 30 are added and combined and concentrated at 12 n. hydrochloric acid (50 µl). Mixture under pressure to obtain 90.5 mg
1.0 mmol). Water (10 drops) is added and the resulting solution is stirred at room temperature for 12 hours. The reaction mixture is diluted with ether and filtered. The filtrate is concentrated to an oil. . The oil is chromatographed on silica gel (230–40.0 mesh or 0.062–0.04 mm).
to obtain an acylation product (500 mg). This product is dissolved in formic acid (2,, 0 ml) and stirred vigorously for 60 minutes.
(yield 97%) of the title compound. M.p. 155 C (decomposition).
stirred at room temperature for 3 hours; diluted with water (2 ml) and toluene (20 mp) and extract (yield 97%) of the title compound. mp. 155 C (decomposition).
IR spectrum: - MoiKc (KVg), is washed dry at 30 ° C. The residue is triturated, 280, 21-20, 1780, 1720, 1670.
with isopropyl ether and the resulting precipitate is collected and washed with isopropyl ether. The solid is chromatographed on silica gel C-18, eluting with 4: 6 methanol-water to give the title compound as an amorphous solid, 80 mg (19% yield). M.p. 150 C (decomposition). The purity of the product according to high performance liquid chromatography is 85%.
IR Spectrum, (“s1x (KVg),: 3600-2600, 1765, 1660, 1620, 1530, 1350, 1025, 1010.
UV spectrum, (- (methanol), nm (): 50 portions of formic acid and concentrated under reduced pressure. The residue is chromatographed on a column with reversed phase silica gel from a RgerPA1C-500 / C, 8 cartridge (Waters). Column
236 (17,200), 286 (14,400).
NMR spectrum, 5 (+ NaHCO,), ppm: 0.25-0.85 (4H, multiplet); 1.2-1.6 (1H, multiplet); 1.75 (3N, doublet, J = 6 Hz), 3.45 (2H, AB quadgg, eluted with water and a 30% aqueous metridet, J = 18 Hz); 4.17 (2H, doublet, zero successively. Fractions co- J = 7 Hz); 5.40 (1H, doublet, J holding the desired product, combined 5 Hz); 5.75-6.20 (GZ, multiplet); and lyophilized to obtain 105 mg of 7.14 (1H, singlet). (Yield 22%) of the title compound.
26
EXAMPLE 31 Diphenylmethyl 7- (2-tritylaminothiazol-4-yl) -2-pro-pargyloxyiminoacetamido-3- (Z) -1-propenyl-3-cephem-4-carboxylate.
To a cooled solution of 750 mg (1.65 mmol) of diphenylmethyl 7-amino-3- (Z) -1-propenyl-3-cethem-4-carboxylate hydrochloride and 1.05 ml; - (5 mmol), H , 0-bis (trimethylsil 1) acetamide in 17 ml of dry metilenene chloride, a solution of 750 mg (1.65 mmol) of 2- (2-tritylaminothiazol-4-sh1) -2- (2- -propargyloxyimo) acetic acid is added and concentrated at suitable pressure to give 90.5
(yield 97%) of the title compound. M.p. 155 C (decomposition).
IR spectrum: - MoiKc (KVg), cm, 280, 21-20, 1780, 1720, 1670.
EXAMPLE 32 7- (g) -2- (2a ™ notiazol-4-yl) -2-propargyloxyminoacetamido-3- (Z) -1-propenyl-3-cephem-4 -carboxylic acid.
A solution of 900 mg (1.18 mmol) of the compound of Example 31 in 3 ml of 85% formic acid is stirred at room temperature for 1 hour.
0.3 ml of concentrated hydrochloric acid is added to the reaction mixture and the suspension is stirred for 4 hours at ambient temperature. The mixture is filtered, washed with a small
Survive under reduced pressure. The residue is chromatographed on a column with reversed phase silica gel from a RgerPA1C-500 / C, 8 liner (Waters). Column
elute with water and 30% aqueous methanol successively. The fractions containing the desired product are combined and lyophilized to obtain 105 mg (yield 22%) of the title compound.
3400
IR spectrum, d, a (KiU-), cm 3280, 1770, 1670, 1630.
UV spectrum, L plx (pH 7, phosphate buffer), nm (6): 229 (17000), 285 (14200).
NMR spectrum, 8 (+ NaHCOj), ppm: 1.75 (ZN, doublet, J 6 Hz, CH CH-CH3), 3.61 (2H, AB quadruplet, 2-H), 4.98 ( 2H, singlet, 0-CH,) 5.39 (1H, doublet, J 5 Hz, 6-H), 5.80 He, fliplet, CH CH-CH,); 6.92 (1H, doublet, J 5 Hz, 7-H); 6.08 (1H, doublet, J = 11 Hz, CH CHCHP 7.22 (1H, singlet, thiazole-5H).
EXAMPLE 33 Diphenylmethyl 7- (Z) -2- (2-tritylaminothiazol-4-yl) -2 -2 trityloxyminoacetamido-3- (Z) -1 -1 propenyl 3 -Z-cephem-4-carboxylate „
To a mixture of 2- (2-trityl aminothiazol-4-yl) -2- (g) -trityloxyiminoacetic acid (873 mg, 1.30 mmol) and dichloromethane (5 ml), phosphorus pentachloride (287 mg , 1.43 mmol) at -5 ° C. The mixture is left to stand for 20 minutes at the same temperature and is added dropwise to a solution of diphenylmethyl 7-amino-3- (1-propenyl) -Z-cephem-4-carboxyplate hydrochloride
(443 ml, 1 mmol) and H, 0-bis (trimethylsilyl) acetamide (0.74 ml, 4.4 mmol) in dichloromethane (5 ml) at -5 ° C. The reaction mixture is left to stand for 20 minutes at the same temperature and poured into ice water. Extraction of the mixture with ethyl acetate and evaporated Hrfe extract under reduced pressure affords the crude product as an oil, which is chromatographed on a silica gel column (eluted with chloroform) to give the desired compound as an amorphous powder. Yield 510 mg (48%).
IR spectrum, -) dAax (nejol), cm: 1780, 1720, 1680.
Example 34 7- (g) -2- (2-amino-thiazol-4-yl) -2-hydroxyiminoacetam- (g) -1-propenyl 1-3-cephem-4-carboxylic acid.
A mixture of the compound of Example 33 (810 mg, 0.76 mmol) -and 2 ml of 85% formic acid was stirred for 1 hour at room temperature. 0.1 ml of hydrochloric acid is added to this reaction mixture. The mixture was stirred for 2 hours and evaporated under reduced pressure, the residue triturated with diisopropyl ether to give the crude product.
-
,





ten
15
This product is purified by chromatography on a C-18 silica gel column (eluted with a mixture of 20% water and methanol).
The eluate is concentrated under reduced pressure and freeze dried to give the indicated product as an amorphous powder. Yield 109 mg (35%). M.p. 170 C (with decomposition). Assessment of purity 75%.
IR spectrum, s (KBV),: 1770, 1760, 1630.
UV spectrum, A d (oi.s (phosphate buffer, pH 7), nm (e, 7m): 225 (450), 282
35
(370).
NMR spectrum (DjO + sodium bicarbonate), shift (Y), ppm: 1.78 (ZN, doublet, J 6 Hz, CH CH-CH,); 3.64
20 (2H, AB quartet, J 18 Hz, 2-H) -, 5.40 (1H, doublet, J- 4 Hz, 6-H); 5.70-6.25 (3N, multiplet, 7-H, h-NSh1-H), 7.14 (1H, doublet, thiazole-H). PRI me R 35. 1-Acetoxystil
25 7- (g) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido3 -3- (d) -1 -1-propenyl 3-3-cephem-4-carboxylic acid ester.
To a stirring solution of the compound of example 34 (270 mg, 0.68 g-adol), sodium carbonate (105 mg, 0.99 mmol) and solution of 1-acetoxyethyl bromide are added to 2 ml of dried dimethylformamide 397 mg, 2.38 mmol) in 0.6 ml of dimethylformamide, in three portions at intervals of 16 minutes. The progress of the reaction is followed by thin layer chromatography (Merck, kieselgel 60, F254 eluent – acetonitrile: water 10: 1). The mixture was stirred for an additional 30 minutes and three major spots were observed with Rf values of 0.11, 0.58 and 0.75. After diluting with ethyl acetate
45 (50 ml) the precipitate is filtered off and the filtrate is washed 3 times with water and then saturated with an aqueous solution of sodium chloride and dried over magnesium sulfate. The filtrate is evaporated to dryness under vacuum and the residue is dissolved in a small amount of chloroform. This solution is fed to a chromatographic column with 20 g of kieselgel 60, which is eluted with chloroform and then with a mixture of 1:20 methanol and chloroform. The fractions for which a thin layer chromatograms (those) are spotted at Rf 0.58 are combined, concentrated to a small
40
29142820430
volume. Diffractions are added to the concentrate for which a peak of isopropyl ether is observed and a precipitate is obtained with a retention time of 4.5 minutes and collected by filtration / concentrated to a volume of about 61 mg (19%) of the desired complex p. 2 ml. To the concentrate was added 20 ml of acetoxyethyl ether. Mp, 120-diisopropyl ether, obtained 125 ° C. Purity Evaluation by the method of liquid 190 mg (72% yield) of the indicated high resolution companion chromatography in the form of a solvate with diisopropylization. Stuffing column: TSK-gel vym ether. -120 T (4 X 250 mm), mobile phase: S Estimated purity 85%. a mixture of acetonitrile and phosphate buffer — IR spectrum, d, (KBr): 3280 ra (pH 6/2: 3) - 75%. (weak peak), 1770 (strong), 1680
IR spectrum, t), akc (KVg), (average), 1540 (average), 1215 1765, 1665, 1610, 1530, 1375. (strong).
UV spectrum, Lmaco (ethanol), them 15 F spectrum, A ((in methanol), them (b): 223 (19000), 264 (12000), 285 (b): 231 (17600), 293 (9700) . (12000). NMR spectrum (in a mixture of deuterium-chlorine NMR spectrum (in deuterium chloroform), form +), ppm: 1.5 (MN, oak, MD: 1.50 (MN, doublet, J 5.0 Hz, years, J 6 Hz, SNSN,); 1.65 (ZN,. SNCH,), 1.65 (ZN, doublet, J 6.0 Hz, 20 D-doublets, J 7 and 1 Hz, SNCHN), 2.07 (ZN, singlet, SAN,), SNCHN) -, 2.05 (ZN, singlet, SISI), 3.45 (2H, br. signal, SCH); 5, 08 2.2 (LC, acetyl singlet); 3.44 (2H, (1H, doublet, J 5.5 Hz, 6-H); 5.5-wide signal, SCH); 5.1 (1H, doublet, 6.0 (2H, multiplet, 7-H and CH); 5 Hz, 6-H); 5.5-6.0 (1H, multi- 6.15 (1H, doublet, J 10 Hz, 3 -CH); 25 plet,), 5, 9 (1H, doublet, 6.96 (2H, multiplet, thiazol-H and J 5 Hz, 7-H); 6.15 (1H, doublet, -OCCHH,). J 11 Hz,), 6.89 ( 1H, multiPm and mper 36. 1-Acetoxyethyl tipelet, OCHCH), 6.92 (1H, singlet, ether 7- (g) -2- (2-aminothiazol-4-yl) -thiazole-H).
-2-acetoxyiminoacetamidoZ-3- (E) - zo Calculated,%: C 50.04; H 5.57; 1-propenylZ-3-cephem-4-carboxylic N 1 1, 31; S 10.35. acids. Ca4Ha, Nj08Sa 4/5 (CH.,), / CH) jO
In the stirred mixture, respectively: Found,%: C 49.73; H 5.47, free acidic acid (300 mg, N 10.90; S 10.28.
0.49 mmol) and potassium carbonate (34 mg, “Example 37: 7- (Z) -2- (2-amine- 0.24 mmol) in dried dimethylformatia-thiazol-4-yl) - 2- (acetyloxyimino-acetamide (5 ml) is added at 0 ° C with an amido solution) 3-3- (Z) -1-propenylJ-3-cefem-1-acetoxyethylbromide (81 mg, -4-carboxylic acid., 0 , 49 mmol) in dried dimethylforma-
MFA (0.1 ml). Another Q is added to the mixture. A suspension of 200 mg (1.30 mmol) of 4- molisa at 45-minute intervals of 1-hydroxy-1H-potassium carbonate hydrate and potassium bromide. The reaction mixture is ash, 631 mg (1630 mmol) 2 - (2-tri-analyzed by the method of liquid chromate amino acid thiazol-4-yl) -2-acetoxyiminotography of high resolution (HPLC) of acetic acid and 268 mg (1.30 mmol) (phase - Likhrosorb RP-18, 4 x 300 mm, dicyclohexylcarbodiimide mix- eluent mixture 4: 1 (acetonitrile: water). - roll for 1 h at 5 s. To the mixture. After the addition, the mixture is stirred and 510 mg (1.26 mmol) of dife- is added, within 30 minutes. The reaction mixture, 7-amino-3- (Z) nylmethyl ester - for which the main peak -1-propenyl) -3-cephem-4-carboxylic acid is observed. With a retention time of 4.5 minutes, g, acid. The mixture was stirred for ethyl acetate (40 ml), washed three times at room temperature and washed with water and the saturated solution was diluted with 50 ml of ethyl acetate. The sodium chloride reactor, dried over the sulfated mixture, was washed with 1N. salted magnesium and added to a small acid (25 ml), water (25 ml) and volume. The concentrate is analyzed on brine (25 ml), dried by a supras-chromatographic column with 8 g of magnesium sulfate, and concentrated by a silica gel 60, eluting with a mixture of 1:20 under reduced pressure. The residue was partitioned with methanol, chloroform. The eluate was analyzed by a chromatographic column with 30 g HPLC, and the silica gel was combined and eluted with a mixture of
3 1428204, 32
10: 1 toluene and ethyl acetate. Combine under reduced pressure the fractions for which development is observed. The residue is triturated with 10 ml of diisopte with a Rf value of 0.20 with ana-propyl ether, to give the desired
lyse (eluent mixture 10: 1 toluene: acetoxy ethyl ester, which is ethyl acetate), and evaporated in vacuo. red is filtered and dried. You residual oil (about 1.15 g) consumption of 15 mg (63%). Spectral data
created in a mixture of 8 ml of 95% tri-product consistent with the data
fluoroacetic acid and 2 ml anisolal of the compound obtained in the example; the mixture is stirred for 1 hr.
in an ice bath. The solution is concentrated as described in Example 39. Pivaloyloxymethyl-under reduced pressure and triturated with 7-t (Z) - (2- (2-aminothiazol ester with dinzopropyl ether (AO ml) and -4-yl) -2-hydroxyminoacetamido | - n-hexane) (10 ml), to obtain 432 mg of 3- (Z) -1-propenyl 3-cepam-4-carbox of unpurified product, which is pure acid.
on a column with Bondapak C-18, B mix mixture
elute with 30% aqueous methanol of Example 34 (200 mg, 0.49 mmol) and
Combined fractions for which sodium on-carbonate (26 mg, 0.24 mmol)
observed peak with retention time in dry dimethylformamide (5 ml)
Yi and 6.9 min (HPLC), concentrated and added at -5 s with pivaloyloxymethyl-ylofiliziruyut, getting 153 mg (27%) iodide (118 mg, 0.49 mmol) and the mixture
This substance is in the form of an amorphous mixture for 45 minutes. To the mixture. M.p. 155 ° C (with decomposition) .sodium carbonate is added again.
Estimated purity 65%, retention time (13 mg, 0.12 mmol) and iodide (59 mg,
vania 6.9 min: Likhrosorb column (250.12 mmol) and the mixture is stirred at
RP-18 300 mm. eluent 3: 7 mixture of meta-same temperature. After 30 Mifc at
but: buffer, pH 7). analysis of the mixture by TLC detected
IR spectrum, (KBG),: 3260, the following spots with Rf values 0.60
1775, 1765, 1665. (main), 0.70 (less) and 0.80
UV spectrum, moms (ethanol), nm (B): 30 (smaller) (column with silica gel 60,,
230 (20100), 292 (12700). Merck, F, eluent-mixture acetonit NMR spectrum (deuterodimethylsulfonic-water: water 20: l). The mixture is diluted with ethyl oxide), S, M.6 .: 1.63 (3N, double oak-acetate (25 ml) and solution 3 times
years, J 1 and 6 Hz, CHCH5), 2.16; washed with water and saturated solution (3N, singlet, acetoxy); 3.55 (broad. Sodium chloride chloride, dried over sulfing sieve, 2H, 2-H); 5.22 (1H, doublet, volume, magnesium, and evaporated to dryness. J 5 Hz, 6-H); 5.70 (1H, multiplet, current dissolved in a small amount
SLNS); 5.76 (1H, doublet-doublets, chloroform and passed through a column J - 5 and 8 Hz, .7-H); 6.10 (1H, doublet, ku with 13 g of kieselgel 60, which is 11 Hz, 3), 7.05 (1H, syn-40 are washed with chloroform (50 mp) and an eluirucleous, thiazole-H); 7.28 (2H, singlet with a mixture of 1:20 methanol: chloroform
UN); 9.80 (1H, doublet, J 8 Hz). (150 mp). Combine the fractions, for coexample 38. 1-Acetoxytylthioulio, there is observed a spot value of 7- (2) -2- (2-aminothiazol-4-yl) -em Rf 0.60 ester by TLC and evaporated.
-2-acetoxymino-acetamido3-3- (Z) -45 The residue is dissolved in benzene and grown-1-propenyl 3-cephem-4-carboxylic acid freeze-dried to obtain 63 mg (acid residue 25%) of the indicated compound. M.p.
To a solution of 20 mg (0.05 mmol) soy-101-104 ° C. Estimated purity 80%
Example 37 in 0.2 ml dry-retention time 4.6 minutes per column
dimethylformamide was added 6 mg of gpc Develosil 4 x 100 mm, eluent (0.05 mmol) of potassium carbonate, a mixture of a mixture of 3: 2 acetonitrile: phosphate buffer
stirred for 5 min at 5 (pH 7), method - GHUR. To the mixture are added 10 µm of 1-acetoxy-IR spectrum, max (KBr),:
ethyl bromide and suspension. stirred 1780, 1755, 1670, 1530, 1120. 1 hour at the same temperature. Pe-.gg UV spectrum, Hddax (methanol), nm
the stock mixture is added with ethyl acetate (): 270 (12000).
volume (5 ml), successively washing - NMR spectrum (deuterochloroform +
are 3 times with water (2 np) and brine, +), 5, ppm: 1.22 (9H, singlet,
dried over magnesium sulphate and, three methyl groups; 1.56 (ZN, oak7, 02 P
33
years-doublets, J 1 and 7 Hz,.); 3.45 (2H, multiplet, S-CH); 5.11 (1R, doublet, J 4 Hz, 6-H); 5.5-5.9 (4H, multiplet, 7-H, CHCHN} and 6.14 (1H, doublet, J 11 Hz, 3-CH), (1H, singlet, thiazole-H). P and m p 40. Acetoxymethyl ester of 7- (Z) -2- (2-aminothiazol-4-III) - f 2-hydroximinoacetamido-3- (2) -1 - -propenyl-3-cephem-4-carboxylic acid.
To the stirred suspension, the compounds of example 34 (280 mg, 0.68 mmol and sodium carbonate (36 mg, 0.34 mmol) In dried dimethylformamide (5 ml), a solution of acetoxymethyl bromide in dried dimethylformamide (104 mg, Oj68 mmol 100 µl.) After 30 minutes, more sodium carbonate (18 mg, 0.17 mmol) and a solution of bromide (52 mg, 0.34 mmol in 50 µl) are added in small portions. The mixture is stirred at the same temperature within 30 min. The reaction mixture in which, when analyzed by TLC (Kieselgel 60, Merck, F, 254, eluent is acetonitrile-water 1 0: 1) four patches were detected with Rf values of 0.1 (VMU-28232), 0.15, 0.60, and 0.75, diluted with ethyl acetate (25 mp), washed with water (3 times) The solution is dissolved in a small amount of chloroform and fed to a column of silica gel 60 (18 g), which is washed with chloroform (50 ml) and eluted with a mixture of 1:20 methanol: chloroform (250 ml) Combine the fractions observed for TLC analysis of the Ptn with Rf values of 0.60 and evaporate in vacuo. The residue was dissolved in benzene and lyophilized to obtain (45 mg (14%) of the title compound. Mp 107-110 ° C. Estimated purity 70%, retention time 6.0 minutes on a 4 x 300 mm Lichrosorb column, eluent - a mixture of 2: 3 acetonitrile: water, method - HPLC.
IR spectrum, - MSTX (KBG),: 1770, 1665, 1530, 1370, 1200, 1000, 985.
UV spectrum, (methanol), nm (): 268 (10900).
NMR spectrum (deuterochloroform + + O), S, M.D .: 1.65 (ZN, singlet, J 7 Hz, CHCH3), 2.1 (ZN, syn1










0
five
5 o
204
Glet, cash
34
COCH,) i 3.43 (2H, broad, S-CH); 5.1 (1H, doublet.
sigJ
 5 Hz, 6-H) i 5.3-5.95 (4H, multiplet, 7-H, CNCH), 6.15 (1H, doublet, J- 11 Hz, 3-CH); 6.96 (1H, singlet, thiazole-N).
EXAMPLE 41. Diphenylmethyl ester of 7-amino-3- (E) -1-butenyl-3-cepheme-4-carboxylic acid, hydrochloride.
A mixture of 7-amino-3- (g) -1-butenylZ-3-cephem-4-carboxylic acid diphenylmethyl ester, hydrochloride (from Example 6) (2.9 g, 6.5 mmol) and benzophenone (1.2 g, 6.5 mmol) in 300 ml of Meganoz is irradiated with a low-pressure mercury lamp (UV irradiation with a wavelength of 2537 A, power 6 W) at room temperature for 26 hours. The solvent is evaporated in vacuo and the residue is dissolved in chloroform. The solution is treated with activated carbon and filtered. The filtrate is diluted with ether to remove a precipitate of 2.2 g (76%) of the indicated E-isomer of the compound contaminated with 10% Z-isomer impurity. This mixture is used in the next step without further purification.
IR spectrum, (. (KBG), 1780, 1720, 1625.
UV spectrum, Xd, s (methanol), nm (5): 298 (10200).
NMR spectrum (deuterodimethylsulfoxide), o, MD: 0.97 (3N, triplet, J = 7 Hz, methyl); 2.15 (2H, multiplet, CHjCH); 3.84 (2H, broad singlet, 2-H); 5.15 (1H, doublet, J 5 Hz, 6-H), 5.30 (1H, doublet, J 5 Hz, 7-H); 6.65 (1H, doublet, J = 16 Hz, 3-CH); 6.97 (1H, singlet, OCH) | 7.45 (YUN, singlet, phenyl-N).
HPLC: Lichrosorb RP-18 phase (4 x 5 X 250 mm), eluent mixture 3: 2 acetonitrile: phosphate buffer (pH 7), 2 ml / min. Retention times: Z-isomer 5.1 min. K-isomer 6.7 min.
PRI me R 42. Diphenylmethyl ester of 7- (Z) -2- (2-aminothiazol-4-yl) -2 -2-methoxyiminoacetamido-3- (E) -1- -butenyl-3-cephem-4- carboxylic acid.
A suspension of crude 7-amino-3- (E) -1-butenyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (1.97 g, 4.3 mmol) in 30 ml of ethyl acetate is shaken with water. , with a solution of sodium bicarbonate.
five
0
0
five
getting a clear two-layer solution. The organic layer is separated, washed with water and then with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue is dissolved in 20 ml of dimethylformamide. 1- (2) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetoxy | benzotriazole (2.07 g, 6.5 mmol). The mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate (100 ml). Dilution 10
triple and. it was lyophilized to obtain 277 mg (59%) of the title compound: 3-trans-butenrcephalosporim, which is identical to that described in Example 15. So pl. above 170 ° C. (gradually decomposes). Estimated purity 90%.
IR spectrum, o, (KBV),: 1770, 1660.
UV spectrum, (phosphate bu4) ep, pH 7), nm (): 232 (15700), 292
(22400).
NMR spectrum (DjO + bicarbonate
sodium), (, MD: 1.18 (ZN, triplet, thief, washed with an aqueous solution of hydro- 15 j Hz, CH. CH,), 2.30 (2H, multiplet,,); 3.83 (2H, synglet, 2-H), 4.15 (MN, singlet, -IR,), 5.37 (1H, doublet, J 5 Hz, 6-I) -, 5.92 (W, doublet, J 5 Hz, 7-H); 5.9-6.4
(1H, multchlet CHCH, j), 5.66 (1H,
sodium carbonate, then with water and with an aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on a column of 50 g of silica gel, eluted with a 2: 1 mixture of toluene: ethyl acetate, to obtain 1.58 g (61%) of the title compound. IR spectrum, (KBG),: 1770, 1720, 1670.
UV spectrum, (methanol); nm (): 297 (18800).
NMR spectrum (deuterochloroform + + DjO), J, MD: 0.97 (3N, triplet, j 7 Hz, CH.jCH,); 2.12 (2H, multipl. T); 3.52 (2H, synglet, 2-H), 4.00 (EH, synglet, AXIS), 5.10 (1H, doublet, J 4.5 Hz, 6-H); 5.93 (1H, doublet, J = 4.5 Hz, 7-H); 5.7 - 6.3 (1H, multiplet, CH-CH2), 6.74 (| H, synglet, thiaz ol-H), 6.96 (1H, synglet, OCH), 7.25 (YUN, synglet Phenyl H).
EXAMPLE 43. (g) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetam- (E) -1-butenyl cephaem-4-carboxylic acid.
A mixture of 7- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido | -3- (E) -1-bute- Hvij-3-cephem-4-carboxylic acid diphenylmethyl ester (650 mg, 1.1 mmol), 3 MP of trifluoroacetic acid and 1 ml of anisole are stirred at 30 minutes and diluted with diisopropyl ether. The precipitate is collected by filtration. It is dissolved in 3.0 ml of formic acid and Tecki chromatography is cleaned on a packed column (100 ml) —PrepPRAK cartridge (Waters company), which is washed with water and then eluted with 30% methanol. The eluate is analyzed by HPLC and the fracdies are combined, concentrated 20
35
doublet, J 16 Hz, 3-CH), 7.18 (1H, synglet, thiazole-H).
 one
Calculated,%: C 45.73, H 4.51; 25 N 15.69; S 14.36.
C, j H, gN50yS -1 / 2H20p
Found,%: With 45.63; H 4.28; N 15.33; S 14.27.
EXAMPLE 44 1-Acetoxyethyl 30 ether 7-f (Z) -2- (2-amino-thiazo-4-yl) -2 -2-methoxyimino acetamido-3- (E) -1 -1-butenyl-3- cephem-4-carboxylic acid. A mixture of the compounds of Example 43 (438 mg, 1 mmol) and potassium carbonate (2.07 mg, 1.5 mmol) in 10 mp of dimethylformamide is treated with 1-acetoxyethyl bromide (250 mg, 1, 5 mmol) according to the method similar to that described in 4Q example 16, and receive 350 mg (67%)
target ether, which is identical to that obtained in example 16. So pl. 110- 115 ° C. Estimated purity by HPLC analysis 90%.
45 NK-spectrum, (KBG),: 1760 (broad), 1670., 1610.
UV spectrum, max (methanol), nm (b): 232 (16600), 298 (19300).
NMR spectrum (in chloroform),
50 a, MD: 1.05 (ZN, triplet, J 7 Hz,,); 1.54 (ZN, doublet, J 6 Hz, SNSI,), 2.08 (ZN, synglet, SOSI,), 2.0-2.4. (2H, multiplet,); 3.57 (2H, synglet, 2-H); 4.05 (MN,
55 synglet, OCH), 5.07 (1H, doublet, J 5 Hz, 6-H); 5.8-6.3 (2H, multiplet, 7-H and); 6.86 (1H, synglet, thiazole-N); 6.9-7.1 (2H, multiplet, OCH and 3-CH).
triple and. it was lyophilized to obtain 277 mg (59%) of the title compound: 3-trans-butenrcephalosporim, which is identical to that described in Example 15. So pl. above 170 ° C. (gradually decomposes). Estimated purity 90%.
IR spectrum, o, (KBV),: 1770, 1660.
UV spectrum, (phosphate bu4) ep, pH 7), nm (): 232 (15700), 292
(22400).
NMR spectrum (DjO + bicarbonate
sodium), (, MD: 1.18 (ZN, triplet, j Hz, SN.CH,), 2.30 (2H, multi20
five
doublet, J 16 Hz, 3-CH), 7.18 (1H, synglet, thiazole-H).
 one
Calculated,%: C 45.73, H 4.51; 5 N 15.69; S 14.36.
C, j H, gN50yS -1 / 2H20p
Found,%: With 45.63; H 4.28; N 15.33; S 14.27.
EXAMPLE 44 1-Acetoxyethyl 0 Ester 7-f (Z) -2- (2-amino-thiazo-4-yl) -2 -2-methoxyiminoacetamido-3- (E) -1 -1-butenyl-3- cephem-4-carboxylic acid. A mixture of the compounds of Example 43 (438 mg, 1 mmol) and potassium carbonate (2.07 mg, 1.5 mmol) in 10 mp of dimethylformamide is treated with 1-acetoxyethyl bromide (250 mg, 1, 5 mmol) according to the method similar to that described in Q example 16, and receive 350 mg (67%)
target ether, which is identical to that obtained in example 16. So pl. 110- 115 ° C. Estimated purity by HPLC analysis 90%.
5 NK-spectrum, (KBG),: 1760 (broad), 1670., 1610.
UV spectrum, max (methanol), nm (b): 232 (16600), 298 (19300).
NMR spectrum (in chloroform),
0 a, MD: 1.05 (ZN, triplet, J 7 Hz,,); 1.54 (ZN, doublet, J 6 Hz, SNSI,), 2.08 (ZN, synglet, SOSI,), 2.0-2.4. (2H, multiplet,); 3.57 (2H, synglet, 2-H); 4.05 (MN,
5 synglet, OCH), 5.07 (1H, doublet, J 5 Hz, 6-H); 5.8-6.3 (2H, multiplet, 7-H and); 6.86 (1H, synglet, thiazole-N); 6.9-7.1 (2H, multiplet, OCH and 3-CH).
37
Calculated,%: C A9.21 H 5.23; N 12.75; S 11.68.
C, H, 5NstbS, -1 / 4 (CH).,
Found,%: C A9, A4; H5.28; N 12.24; S 11.70.
PRI me R 45. 7-Amino-3- (E) - 1-propenyl l-3-cepheme-4-carboxon acid.
A solution of 7-amino-3- (Z) -1-propenyl-3-cephem-4-caronic acid. The 4: 1 mixture of Z- AND E-isomers (1.2 g, 5 mmol) and sodium benbicarbonate (504 mg, 6 mmol) was added in 60 ml of 50% dimethylformamide 1- (Z) -2 - (2-aminothiazol-4-5-yl) -2-methoxyiminoacetoxy benzotriazole (954 mg, 3 mmol) and a mixture of pe10
stir for 30 minutes. Four portions at intervals of 30 min. Add an additional amount of active ester (1.81 g, 6 mmol). The mixture is further stirred for 2 hours at room temperature and is passed through a Colon Zofenone (900 mg, 5 mmol) in methanol.
u-gol ch1 s. , ku, filled with the chuck
(800 mp) containing 1 ml 6 n. Sol - 15 „„,.,. x -..-., ...
PrepPK-S, j (300 mp, Waters). Column
washed with water and then successively elution with 10 and 20% methanol. Fractions of the eluate of 20% methanonic acid, irradiated with a mercury lamp
low pressure (UV radiation.
2537 A, power 6 W) at room
temperature for 44 hours. The reaction mixture is evaporated to dryness, and the precipitate is 20 / which, when analyzed by the method GHUR,
AbbBka: Likhrosorb R-18 phase (4 x X 300 mm). The mobile phase - methanol / / buffer with pH 7 (35:65) gives a peak with a retention time of 5.57 minutes, collected 2g and evaporated to dryness. The residue is dissolved in methanol and filtered. The filtrate is concentrated to a volume of 5 mp and the residue is triturated with a mixture of ether and diisopropyl ether to give 805 mg (63%) of the title compound, m.p. 180 C. (with gradual decomposition), 80% purity by HPLC data under the conditions indicated above. .
The tatok is distributed in a mixture of 0.15 and. hydrochloric acid (200 mp) and 200 ml of ether. The aqueous layer is separated, treated with active carbon and filtered. The filtrate is alkalinized with a dilute sodium hydroxide solution to a pH of 3 and cooled to form a precipitate. It is collected by filtration and washed with acetone,
thirty
35
obtaining 476 mg of the indicated E-isomer, melting - at (with gradual decomposition). A second product yield (195 mg) is obtained by concentrating the filtrate to 30 mp. The total yield of 671 mg (56%). This product contains 5% of the corresponding 2-isomer.
IR spectrum, max (KBV), 1800, 1620, 1540, 1420, 1360.
UV spectrum, A max St phosphate buffer — Q t) e, pH 7), nm (E): 292 (15,000).
NMR spectrum (+ sodium carbonate), 8, MD 1.78 (3N, doublet, J 6 Hz, CH-CH,) -, 3.62 (2H, synglet, 2-H), 5.03 (1I, doublet, J
AbbBka: Likhrosorb R-18 phase (4 x X 300 mm). The mobile phase - methanol / / buffer with pH 7 (35:65) gives a peak with a retention time of 5.57 minutes, collected 2g and evaporated to dryness. The residue is dissolved in methanol and filtered. The filtrate is concentrated to a volume of 5 mp and the residue is triturated with a mixture of ether and diisopropyl ether to give 805 mg (63%) of the title compound, m.p. 180 C. (with gradual decomposition), 80% purity by HPLC data under the conditions indicated above. .
IR Spectrum, (KBG), cm: 1770, 1670, 1630, 1540, 1380, 1040.
UV spectrum, X MO KS (methanol), nm (6): 234 (17000), 293 (20000).
NMR spectrum (DjO + sodium carbonate), S, ppm: 1.93 (ZN, doublet-doublet, 6 and 1.5 Hz, CH-CH3); 3j76 (2H, singlet, 2-H); 4.12 (SN, singlet, OCHj); 5.32 (1H, doublet, J = 4.5 Hz, 6-H); 5.86 He, doublet, J 4.5 Hz, 7-H), 5.8-b, 3 (1, H, multiplet, CH-CHj), 6.61 (1H, doublet-doublets.
4.5 Hz, 6-H); 5.3-6.2 (2H, multi-16 and 1.5 Hz) ,, 7.13 (1H, plet, CH and 7-H), 6.52 (1H, doublet, singlet, tiazrl-N) .
  . “Calculated,%: C 45.38; H 4.05;
N 16.54; S 15.14.
CibHt-jNjOfSi 50
J 16 Hz,).
Calculated,%: C 48.18; H 5.25;
  N About Found,%: C 45,57; 45.41; H4.37i
C, OH, NiO, S 1 / 2H OIS P4-IS 7fi-H 1-Qo P ft
Found,%: C 47.88; H 4, 6 13.90, 13.62.
m 1p 7Q. with 10 -GP P M and M 47. 1-Acetoksiztilny
rilU, /: 7, oi /., oJ .. -, Gh part1 /,
PRI MER 46. 7- (g) -2- (2-amino-7- (2) -2- (2-aminothiazol-4-ip) -,
thiazol-4-yl) -2-methoxyiminoacetate-gg-2-methoxyiminoacetamido-3- (E) -1 to T -3- (E) -1-propenyl-3-cephem-4-car-propenyl-3-cephem- 4-carboxylic acids and acid.
In a stirred solution of the compound of Example 45 (720 mg, 3 mmol) and
Lots.
To a stirred mixture of 317 mg, 40.75 mmol) of the compound of Example 47 and
142820438
sodium bicarbonate (504 mg, 6 mmol) in 60 ml of 50% dimethylformamide, 1- (Z) -2- (2-aminothiazol-4-5-yl) -2-methoxyiminoacetoxy benzotriazole (954 mg, 3 mmol) and a mixture of re
stir for 30 minutes. Four portions at intervals of 30 min. Add an additional amount of active ester (1.81 g, 6 mmol). The mixture was further stirred for 2 hours at room temperature and passed through a column (which, when analyzed by the HPLC method,
AbbBka: Likhrosorb R-18 phase (4 x X 300 mm). The mobile phase - methanol / / buffer with pH 7 (35:65) gives a peak with a retention time of 5.57 minutes, collected and evaporated to dryness. The residue is dissolved in methanol and filtered. The filtrate is concentrated to a volume of 5 mp and the residue is triturated with a mixture of ether and diisopropyl ether to give 805 mg (63%) of the title compound, m.p. 180 C. (with gradual decomposition), 80% purity by HPLC data under the conditions indicated above. .
IR Spectrum, (KBG), cm: 1770, 1670, 1630, 1540, 1380, 1040.
UV spectrum, X MO KS (methanol), nm (6): 234 (17000), 293 (20000).
NMR spectrum (DjO + sodium carbonate), S, ppm: 1.93 (ZN, doublet-doublet, 6 and 1.5 Hz, CH-CH3); 3j76 (2H, singlet, 2-H); 4.12 (SN, singlet, OCHj); 5.32 (1H, doublet, J = 4.5 Hz, 6-H); 5.86 He, doublet, J 4.5 Hz, 7-H), 5.8-b, 3 (1, H, multiplet, CH-CHj), 6.61 (1H, doublet-doublets.
  16 and 1.5 Hz) ,, 7.13 (1H, singlet, tiazl-H).
-propenyl-3-cephem-4-carboxylic acid
Lots.
To a stirred mixture of 317 mg, 40.75 mmol) of the compound of Example 47 and
- (Triphenphosphosphoranilidene) methyl - -3-cephem-4-carboxylic acid.
A solution of 7- {(g) -2- (2-tri-1-aminothiazol-4-yl) -2-methoxyimino acetamido 3- -Ctriphenylphosphonio) methyl-3-cephem-4-carboxylic acid iodide 1- {((g) -2- (2-tritz1-amino-thiazol-4-yl) ester , 5 mmol) in - 40 ml of dichlorstanum and inject 10 with 10 ml of 1N sodium solution of sodium padroxide until the spot of the starting material on those disappears (silica gel, eluent mixture 10: 1
 for another 30 minutes and diluted with chloroform: methanol. The residue was separated by ethyl acetate (150 ml). Dilute the solution and concentrate while the solution is washed with water and water pressure. The residue is ground
104 mg (0.75 mmol) of potassium carbonate in 5 ml of dimethylformamide at 0-5 ° C are added a solution of 167 mg (1 mol) of 1-acetoxyethylbromide in 0.5 mp of dimethylformamide and the mixture is stirred at 5 ° C for 15 minutes . Additional portions of potassium carbonate (204 mg, 1.5 mmol) and a solution of bromide in dimethylformamide (334 mg, 2 mmol, 1 ml) are introduced in two portions for 15 minutes in order to complete the reaction. The mixture is stirred at
a solution of sodium chloride, dried with magnesium sulfate and concentrated to dryness. The oily residue is dissolved in a small amount of chloroform and purified by silica gel column chromatography (silica gel 60, measuring 40 g), which is washed with chloroform and eluted with a 50: 1 mixture of chloroform: methanol. The target fractions observed for TLC showed a spot with an Rf value of 0.40 (silica gel, eluent 10: 1 chloroform: methanol) and a peak with a retention time of 7.7 minutes with HPLC (1: 1 mixture of acetonitrile: pH buffer 7), collected and evaporated to dryness to give an oily residue, which is triturated with a mixture of ether and diisopropyl ether, to obtain 200 mg (70.5%) of the desired ester. M.p. 140 ° C (with decomposition). Estimated 80% purity (HPLC method).
IR Spectrum, (KBG), 1770, 1670, 1620, 1540, 1380, 1210, 1100, 1070, 1040.
UV spectrum, Lddd ,,, (methanol), nm (): 234 (17000), 297 (19000).
NMR spectrum (deuterochloroform), (S, MD: 1.53 (ZN, doublet, J 5 Hz, C-CH,); 1.86 (ZN, doublet, J 6 Hz,
with n-hexane and the product is collected by filtration to obtain 2.5 g (93%) of the title compound.
20 IR spectrum, o (kc (KVg),: 1760 1740, 1560.
UV spectrum, L ma KS (dichloromethane), nm (a): 310 (8800), 388 (15000). PRI amy 49. Diphenylmethyl
25 ether 7- (Z) -2- (2-tripylaminthiaz (: l-4-yl) -2-I toxoiminotocetamIvdol-3- (Z) - acetoxy-1-propenyl-3-cep-4-carboxylic acid .
A mixture of diphenylmethyl ether
30 (7.) - 2- (2-tritylaminothiazol-4-yl) -2 -2-methoxyiminoacetam 1 to 3- (triphenylphosphoranylidene) methyl 3-cephem-4-carboxylic acid (2.13 g, 2.9 mmol and acetoxyacetaldehyde (0.61 g, 6.0 mmol) in 10 ml of dichloromethane are stirred for 3 hours at room temperature. The mixture is concentrated under reduced pressure, and the residue is purified by chromatography on a column of syngole.
Q Licagel. The column was eluted with n-hexane: chloroform (1: 2) and the fractions containing the desired product were combined. By evaporation of the solvent
 under reduced pressure get
35
4g 1.0 g (56%) of the substance indicated. СН СН-СН5), 2.08 (ЗН, singlet, ООСН,) IR spectrum, - Dlax (liquid),:
I 3.55 (2H, broad singlet, 2-H), 4.05 (3N, singlet, OCH), 5.07 (1H, doublet, J 4.5 Hz, 6-H) j 5.38 ( 2H, shir. Singlet, NH); 5.95 (1H, doublet, J 4.5 Hz, 7-H); 5.7-6.2 (1H, multiplet, CH, CH-methyl); 6.81 (1H, singlet, thiazole-H); 6.9-7.1 (2H, multiplet, CH-CHO, and CH CH-CH,); 7.55 (1H, doublet, J = 8 Hz NH).
I
PRI me R 48. Diphenylmethyl
Ester 7- (g) -2- (2-tritylaminothiazol-4-yl) -2-methoxy
55
1785, 1735, 1675, 1430, 1230, 1180.
NMR spectrum (in CCl4), a, ppm: 6.0 (1H, doublet, J 13 Hz),
PRI me R 50. Diphenylmethyl 7-amino-3- (g) -3-acetoxy-1-pro-phenyl-3-cephem-4 carboxylic acid.
To a cooled mixture of lithium bromide (8.6 g, Oj1 mol) in dried dimethylformamide (40 ml) a solution of 7-benzylideneamino-3- (triphenyl phosphoranyl-1-zdene) MeTtmJ-3-cephem-4-car diphenylmethyl ether is sequentially added. carboxylic acid (7.3 g, 10 mmol) in
with n-hexane and the product is collected by filtration to obtain 2.5 g (93%) of the title compound.
20 IR spectrum, o (kc (KVg),: 1760, 1740, 1560.
UV spectrum, L ma KS (dichloromethane), nm (a): 310 (8800), 388 (15000). PRI amy 49. Diphenylmethyl
25 ether 7- (Z) -2- (2-tripylaminthiaz (: l-4-yl) -2-I toxoiminotocetamIvdol-3- (Z) - acetoxy-1-propenyl-3-cep-4-carboxylic acid .
A mixture of diphenylmethyl ether
30 (7.) - 2- (2-tritylaminothiazol-4-yl) -2 -2-methoxyiminoacetam 1 to 3- (triphenylphosphoranylidene) methyl 3-cephem-4-carboxylic acid (2.13 g, 2.9 mmol and acetoxyacetaldehyde (0.61 g, 6.0 mmol) in 10 ml of dichloromethane are stirred for 3 hours at room temperature. The mixture is concentrated under reduced pressure, and the residue is purified by chromatography on a column of silica gel. The column is eluted with n-hexane: chloroform (1: 2) and combine the fractions containing the desired product. When the solvent is evaporated
 under reduced pressure get
35
4g 1.0 g (56%) of the substance indicated. IR spectrum, Dlax (liquid),:
50
55
1785, 1735, 1675, 1430, 1230, 1180.
NMR spectrum (in CCl4), a, ppm: 6.08 (1H, doublet, J 13 Hz),
EXAMPLE 50 Diphenylmethyl 7-amino-3- (g) -3-acetoxy-1-propyl-3-cephem-4 carboxylic acid.
To a cooled mixture of lithium bromide (8.6 g, Oj1 mol) in dried dimethylformamide (40 ml) a solution of 7-benzylideneamino-3- (triphenyl ™ phosphoranyl-zdene) MeTtmJ-3-cephem-4-cad. carboxylic acid (7.3 g, 10 mmol) in
411428204 2
dried methylene chloride (200 ml). Example 51. Diphenylmethyl and acetoxyacetaldehyde (3.06 g, ether 7- (g) -2- (2-akshnothiazol-4-yl) -0.03 mol) and the mixture is stirred at room temperature for 44 hours. After concentration volume of 50 MP oily residue is diluted
-2-methoxyiminoacetamido3-3- (g) -C-3-acetoxy-1-propenyl-3-cephem-4-carboxylic acid.
A mixture of 7-amino-3- (g) -3-acetoxy-1-propene n-1-3-cephem-4-carboxylic acid diphenylmethanol ester
ethyl acetate and the solution is washed with water, a saturated solution of chloride
A mixture of 7-amino-3- (g) -3-acetoxy-1-propene n-1-3-cephem-4-carboxylic acid diphenylmethanol ester
“Atri, dried over magnesium sulfate and 10 (2.32 g, 5 mmol), and benotriazole are concentrated to a volume of 100 mp. Eol-4-yl) -2-methoxyimino acetic acid solution of Girard reagent (5 g, lots (1.9 g, 6 g) is added to the pe-1-yl ester of (g) -2- (2-aminothiamixed concentrate). mmol) in 100 ml of wasopo, 03 mol) and 100 ml of methanol containing tetrahydrofuran are mixed with 1 ml of acetic acid, and the mixture is stirred at room temperature for 20 h at room temperature and the solvent is evaporated to 40 min After evaporation. After extraction with ethyl acetate no solvent, the residue is dissolved (200 mp), the solution is washed with aqueous j in 300 ml of ethyl acetate and this solution is saturated with sodium bicarbonate solution, saturated with aqueous bicarbonate solution and sodium hydrogen chloride, water, saturated solution The solution is dried with magnesium sulfate and rum sodium chloride and dried with sulfate and concentrated to give oily magnesium. When the solvent is boiled down, the residue, which is purified by chromatography, the obtained oil residue is purified on a column with 80 g, and chromatographed on a syl- tide column (silica gel 60, Merck) by means of silica gel (silica gel 60, measuring 100 g), successively eluted with chlorine - by elution with chloroform. form and a mixture of chloroform: methanol. The eluate is analyzed by TLC (elu- (50: 1). The target fractions eluted
a mixture of (50: 1-) chloroform: methanol, 30 is combined and concentrated to give a residue. The latter is triturated in a mixture of ether and diisopropyl ether, obtaining 1.97 g (61%) of the substance indicated, melting at (gradual 2.8 g (60%) of the indicated substance, gg decomposition).
a property having a mp 130-135 0 (with IR spectrum, (kc (KVg), 1780 by decomposition) .. 1730, 1670, 1610, 1530, 1370, 1220,
ent-chloroform: methanol 30: 1), the fractions for which there is a spot with an Rf value of 0.30 are combined and concentrated to give an oily residue, which is triturated with a mixture of ether and diisopropyl ether and in -t
1770
IR spectrum,) to (ns (KVg), cm 1720, 1390, 1370, 1220, 1100.
UV spectrum, XdO1Is (methanol), them CU: 286 (7500).
NMR spectrum (deuterochloroform) o, MD: 1.83 (2H, broad singlet, NH, j,); 2.02 (SN, singlet, COOH), 3.27 (1H, doublet, J 18 Hz 2-H), 3.65 (1H, doublet, J 18 Hz, 2-H); 3.9-4.9 (2H, multiplet, CH O-acetyl); 4.78 (1H, doublet, J = 4.5 Hz, 6-H); 5.02 (1, H, doublet, J 4.5 Hz, 7-H) 5.3-5.8
1030.
UV-peck gr} (d (. (Methanol), nm (): 40,296 (14,000) ..
NMR spectrum (deuterochloroform), o, ppm: 1.97 (GZ, singlet, AXIS,); 5.15 (1H, doublet, J 4.5 Hz, 6H) 6.03 (1H, doublet of doublets, J 4.5 i. 45 9 Hz, 7-H); 6.27 (1H, doublet, J = 11 Hz, CH OH-OH, j), 6.78 (1H, singlet, thiazole-H); 6.94 (1H, singlet, CH-phenyl); 7.2-7.6 (YUN, multiplet, phenyl-N) | 8.03 (1H, doublet, J 9 Hz,
(1 OH, multiplet, phenyl-N).
(1H, multiplet, CH-OH2), 6.27 (1H, gg H).
doublet, J 11 Hz, OH CH-OH), 6.97P r and mep 52. 7- (g) -2 (amino (1H, singlet, OH-phenyl), 7.2-7.6 thiazole-4 -yl) -2-methoxyiminoacetamido D-3- ((Z) -3-acetoxy-1-propenyl - 3-cephem-4-carboxylic acid.
AO Mixed diphenylmethyl ether
7- (g) -2- (2-aminothiazol-4-yl) -2-me-.
toxyiminoacetamido-3- (E) -acetoc
Calculated,%: C 64.64; H N 6.03; S 6.90.
Cw M aOfS
Found,%: C 64.79-, H 5.33;
N 5.89; S 6.94,
55
si-1-propenyl} -3-cephem-4-carboxylic acid (1.88 g, 2.9 mmol), 3 ml
Example 51. Diphenylmethyl ester of 7- (g) -2- (2-akshnothiazol-4-yl) -
-2-methoxyiminoacetamido3-3- (g) -3-acetoxy-1-propenyl-3-cephem-4-carboxylic acid.
A mixture of 7-amino-3- (g) -3-acetoxy-1-propene n-1-3-cephem-4-carboxylic acid diphenylmethanol ester
1030.
UV-peck gr} (d (. (Methanol), nm (): 296 (14000) ..
NMR spectrum (deuterochloroform), o, ppm: 1.97 (GZ, singlet, AXIS,); 5.15 (1H, doublet, J 4.5 Hz, 6H) 6.03 (1H, doublet of doublets, J 4.5 i. 9 Hz, 7-H); 6.27 (1H, doublet, J = 11 Hz, CH OH-OH, j), 6.78 (1H, singlet, thiazole-H); 6.94 (1H, singlet, CH-phenyl); 7.2-7.6 (YUN, multiplet, phenyl-N) | 8.03 (1H, doublet, J 9 Hz,
H).
toxyiminoacetamido-3- (E) -acetoc
si-1-propenyl} -3-cephem-4-carboxylic acid (1.88 g, 2.9 mmol), 3 ml
9 ml of trifluoroacetic kisloanzola and
You are stirred at room temperature for 10 minutes and the mixture is concentrated to a volume of 5 ml. After dilution of 50 MP of diethyl ether and 100 ml of diisopropyl ether, the resulting precipitate is collected by filtration and 1.5 g of crude trifluoroacetate of the desired compound are obtained, which is purified by chromatography on a column filled with prepPAC-8 cartridge (400 ml, Waters) which is successively eluted with water and 20% methanol. The target fractions eluted with 20% methanol are collected and concentrated to give a solid, which is dissolved in 100 ml of methanol, this solution is treated with activated carbon and concentrated to a volume of 10 mp. Diethyl ether (200 ml) is added to the rapidly cooled concentrate. and the precipitate formed is collected by filtration, washed with diethyl ether and dried in vacuum over phosphorus pentoxide to obtain 938 m (67%) of the substance indicated, melting during (gradual decomposition)
IR spectrum, O (KVg), 1720, 1670, 1620, 1530, 1370, PZO, 1030,
UV spectrum, L for dds (phosphate buffer, pH 7), nm (B): 231 (17000), 284 (16000),
NMR spectrum (+ sodium carbonate), J, m, d,: 2.22 (3N, singlet,; COCH); 3.47 (1H, doublet, J 18 Hz, 2-H); 3.76 (1H, doublet, J 18 Hz, 2-H); 4.13 (ZN, singlet, OCH ,,), - 5.39 (1H, doublet, J 4.5 Hz, 6-H), 5.92 (1H, doublet, J Hz, 7-H); 6.36
(1H, doublet, J = 11 Hz, CH, CH-CH); 7.14 (1H, singlet, thiazole-N),
Vytseleno,%: C 44.07; H 4.11; N 14.28; S 13.07,
C, 8 H, gNjO, 5, .1 / 2H20 Found,%: C 44.29; H 4.07-, N 13.98; S 13.03,
B, 7- (Z) - -2- (tritylaminothiazrl-4-yl) -2-methoxyimino-acetamido-Z-3- (Z) -3-acetoxy-1-propenyl methyl-3-cephem-4- Carboxylic acid (1.0 g, 1, .12 mmol) is dissolved in 85% formic acid (5 ml) and the solution is stirred for 2 hours at room temperature. Hydrochloric acid (0.1 ml) and stirring are added.
1770

28204
IQ 20 25 g

44
After a further 5 hours of excess formic acid, by evaporation, the mixture is triturated with diisopropyl ether to precipitate a crude product. The precipitate is collected by filtration and purified by chromatography to obtain 154 mg (31%) of the indicated compound, identical to that obtained by Method A,
Example 53, 7- (2) -2- (2-aminothiazol-4-np) -2-methoxyiminoacetamido-3-L (Z) -15-3-acetoxy-2-propenyl-3-cephem- 4- carboxylic acid,
Potassium carbonate (312 mg, 2.25 mmol) and a solution of 1-acetoxyethyl bromide (501 mg, 3 mmol) are added to a stirred and cooled solution of the compound of example 52 (352 mg, 0.75 mmol) in dimethylformamide (5 mp). in dimethylformamide (1.5 ml) in three portions at intervals of 15 minutes and the mixture is stirred for another 30 minutes. After diluting with ethyl acetate (200 mp), the solution is washed with water, with a saturated solution of sodium chloride, dried and evaporated to dryness. The oily residue is purified by chromatography on a column of silica gel (40 g, silica gel 60, Merck) by successive elution with chloroform and chloroform: methanol (50: 1), Co5 and pafoT fractions, for which a peak with a retention time of 6.1 is observed. minute by HPLC analysis (Phyla Lihrosorb RP-18, 4 X 300 mm, eluent — 50% acetonitrile buffer, pH 7) and evaporated to dryness to obtain a residue, triturated with ether, to obtain 236 mg (68%) of the indicated compounds. Estimated at a purity of 60%, This compound contains about 25% of the U2-isomer as an impurity, mp. 110 ° C (gradual decomposition).
IR spectrum, MQX.C (KBV),: 1780, 1760, 1740 ,. 1670, 1610, 1530, 1370, 1230, 1P70, 1030,
UV spectrum, Ti .. (methanol), nm (5): 268 (15000).
NMR spectrum (deuterochloroform), o, ppm: 1.51 (3N, doublet, J 6 Hz, CH-CH) 2.04 (ZI, singlet, COOH.); 2.08 (ZN, singlet,. COCH,), 3.03 and 3.60 (1.5H, AH-quartet, J 18 Hz, 2H), 4.05 (ZN, singlet, OSI,); 6.17 (0, 3N, singlet,); 6.26 (1H, oak35
40
45
50
55
years, J 11 Hz, CH CH-CH ,,).
Example 34 / and 7-amino-3- (Z) -3-acetoxy-1-propenyl-3-cepheme-4-carboxylic acid phenylmethyl ester. To a solution of 7-amino-3- (g) -3-acetoxy-1-propenyl-3-cephem-4-carbonoioic acid diphenylmethyl ester (2.7 g, 5.8 mmol) and acetophenone (120 mg, 6 mmol) in 1 liter of methanol is added 6 ml of 1 But hydrochloric acid. 0 The solution is irradiated (UV) using a low pressure p-jyT lamp (2357 A, 6 W) with stirring and room
A mixture of diphenylmethyl ether, 7-a ino-3- (K) - -acetoxy-1-propenyl-3-cephem-4-carboxylic acid (930 mg, 2 mmol) and 1- (Z) -2- (2 -aMH-notiazol-A-yl) -2-methoxyiminoacetoxy (benzotriazole) (954 mg, 3 mmol) in dried tetrahydrofuran (40 ml) is stirred at room temperature for 4 hours and the mixture is concentrated to dryness. The residue is dissolved in ethyl acetate (100 ml), the solution is washed with an aqueous solution of sodium bicarbonate, water and a saturated solution
temperature for 22 h and evaporated to dryness. The residue is dissolved in 5 sodium chloride and dried over 300 MP sulfate with ethyl acetate, and the solution is washed with magnesium. After evaporation of the solution
sodium bicarbonate water, water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate,
After removal of the solvent, it is quenched with chloroform and a mixture of
(1: 1) chloroform-methanol. The target fractions are collected and evaporated to dryness and the residue is triturated with diethyl ether to obtain 910 mg (70%)
-one
the current is fed to a chromatographic column with 100 g of silica gel (Kiesel-: gel 60, Merck) and eluted with chloroform. Combine the fractions for which a spot is observed with a Rf value of 0.45 in the TLC analysis (eluent-chloroform: methanol-30: 1) and concentrate to obtain a residue. By trituration of the residue with diethyl ether, 910 mg (34%) of the title compound are obtained, melting at 157 ° C. (with decomposition). The latter fractions, for which a spot with a Rf 0 value of .40 on TLC, is observed gives 583 mg (22%) of the starting Z-isomer.
IR Spectrum, (KBb), cm 1760, 1730, 1710, 1360, 1240, 1210, 1090.
UV spectrum, X mwc (methanol), nm (E): 301 (15000).
NMR spectrum (deuterochloroform), about MD: 1.8 (2H, br. Singlet, NHj); 202 (3N, singlet, COCH,) j 3.56 (2H, singlet, 2-H), 4.73 (1H, doublet, J 4.5 Hz, bH); 4.95 (1H, doublet, J 4.5 Hz, 7-H) i 6.87 (1H, doublet, J 16 Hz, CH CH-CH2.), 7.05 (1H, siglet, CH-phenyl) i 7.3-7.6 (YUN, cartoon, phenyl).
Calculated,%: C 64.64; And 5.21; N 6.03; S 6.72.
C L
Found,%: C 64.28; H 5.21; N 5.88; S 6.82.
And p and meper 55. Diphenylmethyl ether 7- (2) -2- (2-aminothiazol-4-yl) -2 -2-methoxyiminoacetamido-3- (E) -3-acetoxy-1-propennl -3- cephem-4-- -carboxylic acid.
A mixture of diphenylmethyl ether, 7-a ino-3- (K) - -acetoxy-1-propenyl-3-cephem-4-carboxylic acid (930 mg, 2 mmol) and 1- (Z) -2- (2 -aMH-notiazol-A-yl) -2-methoxyiminoacetoxy (benzotriazole) (954 mg, 3 mmol) in dried tetrahydrofuran (40 ml) is stirred at room temperature for 4 hours and the mixture is concentrated to dryness. The residue is dissolved in ethyl acetate (100 ml), the solution is washed with an aqueous solution of sodium bicarbonate, water and a saturated solution
sodium chloride and dried with magnesium sulphate. After evaporation of the solution
the remainder of the residue is fed to a chromatographic column with silica gel (40 g, Kieselgel 60, Merck) and eluted successively with chloroform and mixture
(1: 1) chloroform-methanol. The target fractions are collected and evaporated to dryness, and the residue is triturated with diethyl ether to obtain 910 mg (70%)
this substance melting at 110 ° C (gradual decomposition).
IR spectrum, - ftoij c (KBV),: 1780, 1730, 1680, 1610, 1530, 1380, 1220.
UV spectrum ,, (- (methanol), nm (): 297 (22000).
NMR spectrum (deuterochloroform), o, ppm: 1.99 (3N, singlet, acetyl); 3.56 (2H, singlet, 2-H) (4.04 (3N, singlet, methoxy-) J 4.52 (2H, doublet, J 6 Hz, CH CH-CH) i 5.18 (1H, doublet , J 4.5 Hz, 6-H), 5.97 (1H, doublet-doublet, J 8 and 4.5 Hz, 7-H); 5.7-6.2 (1H, multiplet, CH CH- CH) -,
6.83 (1H, sygglet, thiazole-H), 6.96 (1H, singlet, CH-phenyl).
EXAMPLE 56 7- (2) -2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetami-L (E) -3-acetoxy-1-propenyl-3-cephem-4 carboxylic acid
 A mixture of 7- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido-3- (E) -3-acetoxy-1-propenyl | -3-cephem-4-carbonyl diphenylmethyl ester
Acids (870 mg, 1.34 mmol) and 0.8 ml of anisole are dissolved in 2.4 ml of trifluoroacetic acid and this solution is stirred at room temperature for 15 minutes. Reaction mixture
it is treated and purified in a manner similar to that described in Example 52 (Method A) to obtain 429 mg (66%) of the indicated substance melting at 180 ° C (constant decomposition).
71428204
IR spectrum, maize (KVg), (1H, singlet, thiazole-N) $ 7.56 (1I,
1770, 1730, 1670, 1630, 1530, 1370, doublet, J 8 Hz, NH),
1240, 1030.P r ı me R 58. Diphenylmethyl
UV spectrum, L doc. (fusion buffer, g ester 7-G (2) 2- (2 trit11-inothiazole
-4-g-sh) -2-trityloxyaminoacetamido - -3-chloromethyl-3-cephem-4-carboxylic acid.
292
pH 7), nm (B): 231 (17000), (26000).
NMR spectrum (DjO + sodium carbonate), o, ppm: 2.20 (3N, singlet.
To a mixture of (Z) -2- (2-TpHTR; iaMHHOTHaCOCH,), 3.75 (2H, singlet, 2-H); 4,10io sol-4-t) -2-trittoxyiminoacetic
(OG, singlet, methoxy-); 4.75 (2H, singlet, CHjO-acetyl); 5.32 (1H, doublet, J = 4.5 Hz, 6-H); 5.88 (1H, oak acids (6., 71 g, 10 mmol) and 1-gidlet, J 4.5 Hz, 7-H); 5.9-6.3 (1H, multiplet, CH, CH-CH); 6.73 (1K, doublet, J 16 Hz, CH CH-CHj), 7.09 (1H, singlet, thiazole-H).
PRI me R 57. 2- Acetoxyethyl ester 7- (Z) -2- (2-aminothiazol-4
15
roxybenzothiazole monohydrate (1.53 g, 11 mmol) in 50 ml of tetrahydrofuran was added dicyloshexylcarbodimet (in 2.06 g, 10% mol) at and the mixture was stirred for 2 hours at the same temperature. Then filtered to obtain a solution of the active ester. A suspension of diphenylmethyl ether-yl) -2-methoxyiminoacetamido-3- (E) -20 P 7-amino-3-chloro-3-cepham-4-cap-3-acetoxy-1-propenyl | -3-Def-4 - Lateral acid hydrochloride (4.51 g, -carboxylic acid; 10 mmol) in ethyl acetate (50 mp);
Add a saturated aqueous solution of Example 56 (241 mg, 0.5 mmol) of sodium hydrogen carbonate (3 times in dried dimethylformamide (4 ml) 25 to 10 mp) to the stirred solution with water and then dry. The solution was added with a carbonate. The solution was poured into a solution of the complex active (140 mg, 1 mmol) and a solution of 1-acetone ether, which was obtained earlier, with sietilbromid four times with in- and stirring, then the mixture with 15 minutes each The mixture is stirred for 2 days at 5 ° C. Lye at the same temperature still in the temperature. After evaporation, the residue is fed for 1 hour. After dilution of the ethylade-chromatographic column with 100 g of tatom, the solution is washed with water and saturated sodium chloride. , dried with magnesium sulfate and concentrated to dryness. The residue is fed to a chromatographic product, concentrated on a shaken column with 30 g of silica gel (pressure. With trituration with a gelgel 60, Merck) and subsequently eluted with chloroform and chloroform: methanol (50: 1). The target fractions eluted with chloroform-methanol were collected and evaporated to dryness, and the residue was triturated with diethyl ether to obtain 185 mg (65%) of the indicated substance gel (cs-shikagel 60), and the column was eluted with a mixture (2: 1) chloroform: n is hexane. The fractions containing the target
melting at 120 ° C (gradual decomposition).
IR spectrum, ax (KBV),: 1770, 1680, 1620, 1500, 1390, 1240, 1080, 1040.
UV spectrum, Hmax (methanol), nm (): 232 (18000), 295 (21000)
NMR spectrum (deuterochloroform), S, MD: 1.56 (3N, doublet, J = 6 Hz, CH-CHj); 2.08 (6H, singlet, acetyl); 3.6 (2H, shir. Sing / pc, 2-H); 4.06 (3N, singlet, methoxy-); 5.07 (1H, doublet, J 4.5 Hz, bn); 5.39 (2H, broad singlet, NHj); 5.7-6.4 (2H, multiplet, CH CH-CH2, and 7-H); 6.81
45
50
55
n-hexane receive 10.0 g (94%) of the specified substance in the form of an amorphous powder with
IR spectrum, - (KBV), cm: 1780, 1720, 1680, 1490.
UV spectrum ,, (dihpormetan), nm (): 245 (23000).
NMR spectrum (deuterochloroform), and,. MD: 3.4 (2H, AB-ksartet, J 12 Hz, 2-H) 5.02 (1H, doublet, J 4 Hz), 6.01 (1H, double doublet, J 4 and 6 Hz, 7-H), 6., 45 (1H, singlet, thiazole-H), 7.00 (1H., Singlet, CH-C.Nd.), 7.1-7.7 (40H, phenyl-H).
Example 59. Diphenylmethyl ester 7- (Z) -2- (2-tritylamine, thiazol-4-yl) -2-trityloxyiminoacetamide, about 1 - -3- (triphenylphosphorifenipidene) -ketyl-. -3-cephem-4-carboxylic acid.
A mixture of 7- (Z) -2- (2-tritylamino-thiazole-4-1sh) diphenylmethyl ester; -2-trityloxyimino-acetamide J-3-chloro methyl-3-cephem-4-carboxylic acid
To a mixture of (Z) -2- (2-TpHTR; iaMHHOTHazol-4-t) -2-trittoxyiminoacetic
acids (6., 71 g, 10 mmol) and 1-hyd15
Squeeze a saturated aqueous solution of sodium bicarbonate (3 times 10 mp), with water and then dry. The solution was poured into the solution of the ester complex that was obtained earlier, with stirring, then the mixture was kept for 2 days at 5 ° C. After evaporation, the residue was fed to a chromatographic column with 100 g of product, concentrated under reduced pressure. When rubbing the residue with
sklikagel (cs-shikagel 60), and the column elute with a mixture (2: 1) chloroform: n-hexane. The fractions containing the target
Squeeze a saturated aqueous solution of sodium bicarbonate (3 times 25 10 mp), with water and then dry. The solution was poured into the solution of the ester complex that was obtained earlier with stirring, then the mixture was kept for 2 days at 5 ° C. O After evaporation, the residue was fed to a chromatographic column with 100 g of product, concentrated under reduced pressure . When rubbing the residue with 0
45
0
five
n-hexane receive 10.0 g (94%) of the specified substance in the form of an amorphous powder with
IR spectrum, - (KBV), cm: 1780, 1720, 1680, 1490.
UV spectrum ,, (dihpormetan), nm (): 245 (23000).
NMR spectrum (deuterochloroform), and,. MD: 3.4 (2H, AB-ksartet, J 12 Hz, 2-H) 5.02 (1H, doublet, J 4 Hz), 6.01 (1H, double doublet, J 4 and 6 Hz, 7-H), 6., 45 (1H, singlet, thiazole-H), 7.00 (1H., Singlet, CH-C.Nd.), 7.1-7.7 (40H, phenyl-H).
Example 59. Diphenylmethyl ester 7- (Z) -2- (2-tritylamine, thiazol-4-yl) -2-trityloxyiminoacetamide, about 1 - -3- (triphenylphosphorifenipidene) -ketyl-. -3-cephem-4-carboxylic acid.
A mixture of 7- (Z) -2- (2-tritylamino-thiazole-4-1sh) diphenylmethyl ester; -2-trityloxyimino-acetamide J-3-chloro methyl-3-cephem-4-carboxylic acid
49
(9.9 g, 9.3 mmol), sodium iodide (11 g, 73 mmol) and 100 ml of acetone are stirred for 30 minutes at room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 ml) and the mixture was washed with a 10% M aqueous solution (2 x 50 ml) and water. 3.93 g of triphenyl phosphine (15 mmol) was added to this mixture and the mixture was stirred for 3 hours at room temperature. After evaporation, the residue is triturated with diisopropyl ether and the precipitate is collected by filtrate to give a phosphonium salt (4.2 g). It is dissolved in dichloromethane (100 ml) and the solution is washed with 1 and. sodium hydroxide solution (about 50 ml) until the phosphonium salt is completely converted into a ylide. The course of the reaction is followed by TLC analysis (Merck, silica gel 60,. Eluent chloroform: methanol 10: 1). The organic layer is separated, washed with water and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give 12.0 g (94%) of the indicated substance.
IR Spectrum, -, Aaks (KVg), cm 1740, 1650, -14 “0.
UV-spectrum, Chlax (dichloromethyl), nm (6): 310 (92000), 388 (16200).
Example 60. Diphenylmethyl ester 7- (Z) -2- (2-tritylamino-thiazol-4-yl) -2-trityloxymino-acetamido - -3- (Z) -3-acetoxy-1-propene-3-cep- 4-carboxylic acid.
A mixture of 7- (Z) -2- (2-tritylaminothiazol-4-yl) -2 -2 trityloxyminoacetamido-3- (triphenylphosphoranylidene) methyl 3-cephem- diphenylmethyl ester. -4-carboxylic acid (2.58 g, 2 mmol), and acetoxyacetaldehyde
142820450
MD: 2.00 (GI, singlet, acetyl), 3.20 (2H, LV-quartet, J 18 Hz, 2-H) -, 5.1 (1H, doublet, J 4 Hz, 6- H);
5 6.20 (1H, doublet, J 11 Hz, CH), 6.48 (1H,-singlet, thiazop-H); 6.95 (UI, singlet, CH- (phenyl)); 7.1-7.6 (40H, phenyl-H).
EXAMPLE 61. 7- (Z) -2- (2-amino10 thiazol-4-yl) -2-hydroxyiminoacetamis-P-3- (Z) -3-acetoxy-1-propenyl - -3- cephem-4-carboxylic acid.
A mixture of 7- (Z) -2- (2-tritylaminothiazol-4-NL) diphenylmethyl ether 15 -2-trityloxyiminoacetamido | -3- (Z) -3-acetoxy-1-propenyl-3-cephem-4 -carboxylic ktsslota (3.29 g, 2.94 mmol) and 15 ml of 85% formic acid are stirred for
20 2 hours at room temperature. Concentrated hydrochloric acid (0.6 ml) is added to the solution and the mixture is stirred for 2 hours. After evaporation of the solvent, the residue was grown with diisopropyl ether to obtain 1.2 g of the crude product. This product is purified by chromatography on a C 18 silica gel column (20 mm x 200 mm) by elution with 1760, 30 of 20% methanol. The fractions containing the desired product are combined and concentrated to a small volume under reduced pressure. 412 mg is obtained by lyophilization of the concentrate.
2g (30%) of the substance indicated, melting at 180 ° C (with decomposition). Estimated purity 60%.
IR spectrum, O1K: s (KVg), cm: 1760, 1620, 1530, 1370, 1240.
40 UV spectrum, 7 MQX (phosphate buffer, pH 7), nm (b): 279 (15300).
NMR spectrum (dimethyl sulfoxide-dg), o, MD: 2.00 (3N, singlet, acetyl), 4.50 (2H, doublet, J 8 Hz, CH, 0) i
(612 mg, 3 mmol) in 10 Mil dichlorome-5 5.15 (1H, doublet, J 4 Hz, 6-H), then mix is stirred overnight at 6.30 (1H, doublet, J 12 Hz, CH- ), room temperature and concentrate 6.65 (1H, singlet, thiazole-H); 7.00
(2H, singlet, NH,); 9.40 (1H, doublet, J = 8 Hz, 7-CONH); 11.30 (1H, syn-50 g silica gel (silica gel 60, Merck), carbon, N-OH).
and the column was eluted with a mixture (9: 1) of toluene. Example 62. 1-Acetoxyethylol: ethyl acetate. Upon evaporation of the fractional 7-G (Z) -2- (2-amino-iso-isolations containing the desired product), 1.0 g (45%) of the indicated substance is obtained.
under reduced pressure. The remainder is fXaioT to chromate on a graphical column with
IR spectrum, (KBG), cm 1730, 1680, 1520, 1220.
UV spectrum ,, cc (dichloromethane), nm (6): 305 (12200).
NMR spectrum (deuterochloroform), §,
-4-yl) -2-hydroxyiminoacetamido) - -3- (Z) -3-acetoxy-1-propenyl-3-cet-1780, gg of fem-4-carboxylic acid.
In a stirred solution of the compound of Example 61 (280 mg, 0.6 mmol) in dried dimethylformam (e (2 ml); sodium carbonate was added at -5 ° C
51142820A. 52
(105 mg, 1 mmol) n solution of 1-acetoc-IR spectrum, - „civ-c (KVg), cm: 1760, diethyl bromide (386 mg, 2.37 mmol) 1660, 1630, 1530
in dimethylformamide (2 ml), three pores - UV spectrum, (Phosphate buffer, qi mi at intervals of 20 min and a mixture of pH 7), nm (6): 223 (20000), 290
for 10 minutes
(21,000).
HMR-spectrum (), O, ppm: 1.38 (3N, doublet, J = 7.0 Hz) 3.73 (2H, broad singlet); 5.30 (1H, broad singlet); 5.85 (1H, doublet, J 5.0 Hz), 5.80-6.30 (1H, multiplet); 6.57 (1H, doublet, J 16 Hz); 7.06 (1H, singlet) .I
Calculated,%: C 41.28-, H 4.16; N 16.05; S 14.65.
C, yH, 5NjOfSj-1,
Found: C, 41.46J; H, 3.60i; N, 15.86; S 14.83.
 ....., PRI me R 64. Pivapoyloxymati75 mg (23%) of the product melted at 20 luvy ether 7- (g) -2- (2-aminothiazolmixed still in
After dilution with ethnpacetate, the solution is washed with water and concentrated under reduced pressure. Trituration of the residue with diisopropyl ether 10 gives 195 mg of crude product, which is very good (chromatographically on a column of silica gel (25 g). This column is eluted with scoroform containing 1-2% methanol, and the fractions containing the desired product Combined and evaporated under reduced pressure. Trituration of the residue with diisopropyl ether gives
15
-4-yl) -2-hydroxy-imine acetamido-3- (Z) -3-acetoxy-1-prop.nyl-3-cephem-4-carboxylic acid.
To an ice-cooled mixture of the compound of Example 61 (170 mg, 0.36 mmol) and sodium carbonate (20 mg, 0.19 mmol) in dried dimethylformamide (2 mp) were added pivaloyloxymethylndnd (87 mg, 0.36 mmol) and mixture of mixture2,05 (3N, singlet, acetyl), 5.10 (1H, 30, watered for 10 min at the same temperature.
doublet, J 4 Hz, 6-H); 6.30 (ill. Add an additional amount
pivaloyloxymethyl iodide (87 mg) and sodium carbonate (20 mg) and stir the mixture for another 10 minutes. Dilution mixture
thiazol-4-yl) -2-hydroxyiminoacetam-35 with ethyl acetate, washed with water
(E) -1-Propenyl-3-cephem-4-car- and evaporated under reduced pressure.
 (with decomposition). Estimated purity 70%.
IR spectrum, (KBG), cm: 1780-1730, 1670, 1530, 1380, 1240.
UV spectrum,) ss (dihpormetan), nm (e): 249 (17300).
NMR spectrum (deuterochloroform), o, ppm: 1.0 (3N, doublet, J = 5 Hz, CH-CH); 2.03 (3N, singlet, acetyl);
doublet, J 12 Hz; CH-); 6.95 (1H, singlet, thiazole-N).
Example 63 7- (g) -2- (2-amino-carboxylic acid.
A mixture of the crude compound of Example 33 containing 20% E-isomer (9.2 g, 8.7 mmol) in 85% formic acid (60 ml) was stirred for 1 h at room temperature and centrifuged in vacuo. The residue is treated with 90% trifluoroacetic acid (60 ml) for 1 hour at room temperature and drunk in ice-water (300 mp). The undissolved substance is filtered off. The filtrate is fed to a reverse phase chromatography column (Waters, PrepPAC C, g 300 ml) and the column is eluted with 20% methanol. The polar fractions were combined, concentrated in vacuo, and the residue triturated with diisopropyl alcohol to obtain 1.15 g (33%) of the Z-isomer, and i ieHee polar fractions give 143 mg (4%) of the starting material. Melting point above (decomp.).,.
When chromatographic separation of the residue on a column of silica gel, eluted with a mixture of chloroform and
40 methanol, receive the product in the form of an amorphous powder. Yield 110 mg (52%). M.p. 95-100 ° C (decomp.).
IR spectrum, (KBG),: 1780, 1740, 1670, 1530.
45 UV spectrum ,, cc (ethanol), nm (): 280 (11400).
HMR spectrum (deuterochloroform), o, MD: 1.20 (9H, singlet, t-butyl); 2.0 (ZN, singlet, acetyloxy),
50 3.45 (34, singlet, 2-H) -, 4.50 (2H, doublet, J 7 Hz, CH O-acetyl) J 5.10 (1H, doublet, J 5 Hz, 6-H); 5.3-6.0 (4H, multiplet, 7-H, vinsht-N,); 6.25 (1H, doublet, J 12 Hz,
gg vinyl-H) -, 7.0 (1H, singlet, thiazole-H); 11.5 (1H, doublet, J = 8 Hz, CONH).
EXAMPLE 65 7- (g) -2- (2-aminothiazol-, 4-yl) -2-g 5-hydroxyiminoacetam-
ten
15
and evaporated under reduced pressure.
When chromatographic separation of the residue on a column of silica gel, eluted with a mixture of chloroform and
methanol, receive the product in the form of an amorphous powder. Yield 110 mg (52%). M.p. 95-100 ° C (decomp.).
IR spectrum, (KBG),: 1780, 1740, 1670, 1530.
UV spectrum ,, cc (ethanol), nm (): 280 (11400).
HMR spectrum (deuterochloroform), o, MD: 1.20 (9H, singlet, t-butyl); 2.0 (ZN, singlet, acetyloxy),
3.45 (34, singlet, 2-H) -, 4.50 (2H, doublet, J 7 Hz, CH O-acetyl) J 5.10 (1H, doublet, J 5 Hz, 6-H); 5.3-6.0 (4H, multiplet, 7-H, vinsht-N,); 6.25 (1H, doublet, J 12 Hz,
vinyl-H) -, 7.0 (1H, singlet, thiazole-H); 11.5 (1H, doublet, J = 8 Hz, CONH).
EXAMPLE 65 7- (g) -2- (2-aminothiazol-, 4-yl) -2-g 5-hydroxyiminoacetam-
 - 142820А54
(K) -3-acetoxy-1-propensh1 - yield 975 mg of an inorganic product. -Z-cephem-4-carboxylic acid. After chromatographic purification on
reverse phase column (silica gel) and elution with 10% methanol in water followed by concentration of the fraction containing the target prolyl. To a solution of 1-hydroxybenzotriazole (223 mg, 1.44 mmol) and (g) -2- (2 - three thylaminothiazol-4-yl) -2-trityloxyiminoacetic acid (1.06 g, 1.44 mmol) in 14 ml of tetrahydrofuran. Dicyclohexylcarbodiimide (300 mg, 1.44 mmol) is added and the mixture is stirred for 1 hour at 5 C. To this mixture is added 7-amino-3- (E) -acetoxy-1-propenyl 3-3-cefem-4-cardi diphenylmethyl ester; 418 mg (51%) of this substance is obtained in the form of amorphous oroshka,
ten
(
(KBG): 1765,
IR spectrum,), 1730, 1650 „
UV spectrum, “X mahe (Phosphate buffer, pH 7), nm (6): 290 (23400).
1 H-NMR (deuterodimethylsulphocarboxylic acid (670 mg, 1.44 mmol). 15 spd), 5, m 2.03 (3N, singlet. After stirring for 4 hours, acetyloxy); 3.65 (2H, AB-quartet, at room temperature, the reaction 2-H); 4.61 (2H, AB-quartet, CH O-acetone mixture is filtered, diluted with 50 ml of ethyl acetate and washed with water. When the organic layer is concentrated, an oil is obtained, which is purified on a chromatographic column of silica gel. When eluted with a mixture (10.1 a) toluene: ethyl acetate get
20
til); 5.15 (1H, doublet, J 5 Hz,) i 5.75 (1H, double doublet, J 5 and 8 Hz, 7-H); 6.15 (1H, multiplet, vinyl-H), 6.65 (1H, singlet, thiazole), 6.85 (1H, doublet, J 15 Hz, vinyl-H), 7.05 (2H5 singlet, N11).
And pimer 66. Pivaloyloxymeth1, 607 g (99%) of diphenylmethyl ether, 25 methyl ester of 7- (g) -2- (2-acyhnothiazolum 7- (g) -2- (2-tritylaminothiazol-4 --4-yl) -2-hydroxyiminoacetate to -3 yl) -2-trityloxyminoacetamido - 3- (E) -3-acetoxy-1-propene1 -3-cephem-4-carboxylic acid in the form of amorph- (E) -3-acetoxy-1 propenyl-3-cef-4-carboxylic acid.
To a cooled and stirred mixture of the compound of Example 65 (200 mg, .0.43 mmol) and. sodium carbonate. (22.7 mg, 0.22 mmol) in dimethylformamide (2 ml) pivaloshthoxymethylide (91 mg) is added and the mixture is stirred at 5 ° C for 30 minutes. The reaction mixture is diluted with 40 g-t of ethyl acetate, washed with water and sodium chloride solution, sequentially. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on a column of silica gel. When eluted with chloroform-methanol (1-3%), 123 mg (50%) of the product was obtained as an amorphous poroj. IR spectrum
powder.
IR Spectrum, (KBg),: 1770, 1730,
HMR-spectrum (deuterochloroform), m, d, d: 2.0 (3N, singlet, acetyloxy), 3.33 (2H, singlet, 2-H); 4.54 (2H, AB quartet, CH OCOCH,), 5.04 (1H, doublet, J 5 Hz, 6-H); 6.0 (1H, multiplet, vinyl-H), 6.02 (1H, double doublet, J 5 and 7 Hz, 7-H), 6.40 (1H, singlet, thiazole-H), 6.82 ( 1H, doublet, J = 15 Hz, vinyl-H), 7.00 (1H, singlet, (phenyl), SI); 7.3 (25H,. Singlet, phenyl).
Remove lock.
A mixture of 7- ((2) 2 (2-tritylaminothiazol-4-yl) -2 -2-trityloxyminoacetamido-3- (E) -phenylmethyl ester 3-acetoxy-1-propenyl-3-cephem-4-carboxylic acid (1 , 98 g, 1.75 mmol) - in 20 ml of formic acid is stirred for 2 hours at room temperature. 0.16 m of concentrated hydrochloric acid (1.92 mmol) is added to the mixture and the mixture is stirred for 1 hour at room temperature. After filtration and concentrating the filtrate followed by trituration of the concentrate with diisopropyl ether, the result is 418 g
ten
IR spectrum,), 1730, 1650 „
5 Lovy ester of 7- (g) -2- (2-Ashnothiazol) -2-hydroxyiminoacetate to -30
five
0
- (E) -3-acetoxy-1 propenyl-3-cep-4-carboxylic acid.
To a cooled and stirred mixture of the compound of Example 65 (200 mg, .0.43 mmol) and. sodium carbonate. (22.7 mg, 0.22 mmol) in dimethylformamide (2 ml) pivaloshthoxymethylide (91 mg) is added and the mixture is stirred at 5 ° C for 30 minutes. The reaction mixture is diluted with 40 g-t of ethyl acetate, washed with water and sodium chloride solution, sequentially. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on a column of silica gel. When eluted with chloroform-methanol (1-3%), 123 mg (50%) of the product was obtained as an amorphous poroj. IR spectrum
IR spectrum, (KBG),: 3300, 2970, 1780, 1740.
UV spectrum, (, s (methanol), im (): 296 (18500).
PMR spectrum (deuterodimethylsulfoxide), MD: 1j22 (9H, singlet, tert-butyl) J 2.08 (3N, singlet, acetyloxy), 3.60 (2H, singlet, 2-H) 4 , 66 (2H, AB-quartet, CH O-acetyl); 5.06 (1H, doublet, J 5 Hz, 6-H); 5.85 (1H, double doublet, J 5 and 7 Hz, 7-H); 5.88 (2H, AB - quartet,), 6.0 (1H, multiplet, vi5
0
55142820456
Nip-Yu, 7.00 (1H, singlet, thiazole); benzotriazole (600 mg, 4.0 mmol) 7.1 (1H, doublet, J 15 Hz, vinyl-H). in 1A ml of tetragndrofuran
EXAMPLE 67 Acetoxymethyl Dicyclo-hexylcarbodiimide (824 mg, 7- (g) -2-aminothiazol-4-Cl) g A, O mmol) and the mixture is stirred for 1 h to toxiimoacetamido) -3- (E) -3 -atsotok- in a bath with ice. Cy-1-propenyl-3-cephem-4-carboxylic acid, 7-amino acid diphenylstilty ester of 7-amino acid is added to the suspension. -3- (g) -3-acetoxy-1-propenyl | -3-keC cooled and stirred fem- 4-carboxylic acid (1.30 g, a solution of 240 mg (0.5 mmol) of the compound 2.80), the mixture is stirred for 4 hours in Example 52 in 4 ml of dried at room temperature, filtered dimethylformamide is added at 0 and diluted with ethyl acetate (60 mp). potassium carbonate (138 mg, 1 mmol) and the organic phase is washed with water, a solution of acetoxymethyl bromide (306 mg, dried over magnesium sulfate and concentrated 2 mmol) in dimethylformamide (2 ml) is 15 triturated under reduced pressure. The remaining four portions at intervals of the current are purified chromatographically for 15 min. After dilution with 100 ml of silica gel (80 g, ethyl acetate wacogel, the mixture is washed with water and C200), which is eluted with a mixture (6: 1) with an effective solution of sodium chloride toluene acetate. Combine and dry over magnesium sulphate. After 20 C, the product was contained, and the solvent was concentrated in vacuo, and the oily was concentrated in vacuo to obtain 2.01 g (77%) of the residue and was purified on chromatographic methyl ether 7 - {(Z) -2-silica gel (kieselgel 60, tilaminothiazol-4-yl) -2-acetoxyimno-Merck 30). The column was eluted with chlorofor-acetamido-3 (Z) -3-acetoxyl-1-propem and a mixture of chloroform-methanol (50: 1-25 nyl-3-cephem-4-carboxylic acid. 20: 1) sequentially. Eluted IR spectrum,) Q (. (KBr), 1780, with a mixture (50: 1) of chloroform-methanol fraction-1730.
This solution is collected and evaporated. The residual PMR spectrum (deuterochloroform), o, is triturated with a mixture of ether and n-hexamers: 2.0 (3N, singlet, acetyl) i 2.15 na, to obtain 72 mg (26%) of the desired pro- ZOR (ZN, singlet, acetyl), 3.45 (2H, AB--, duct, melted at 90-95 ° C (with quartet, 2-H); 4.20 (2H, AB-quartet, decomposition) Estimated purity of 80%. 2-H), 4.20 (2H, AB-quartet,. CH O-aceIC spectrum, - (KBr), 1770, teel); 5.12 (1H, doublet, J 5 Hz, 1730, 1670, 1530, 1370, 1230, 1080. .6-H), 5.70 (1H, multiplet-, 3-CH-CH),
UV spectrum, L „d. (methanol) nm (a): 5.90 (1H, double doublet, J 5 and 230 (17000), 278 (130,000) .7 Hz, 7-H); 6.26 (1H, doublet, J
PMR spectrum (deuterochloroform), 12 Hz,); 6.95 (1H, syn. M. A: 2.02 (3N, singlet, acetyloxy), glut, thiazole), 7.30 (25 N, singlet, 2.12 (3N, singlet, OOSN); 3 , 33 (1H, phenyl), doublet, .18 Hz, 2-H); 3.60 (1H, oak-40
years, J 18 Hz, 2-H); 4.04 (3N, syn- Unlock, glut, methoxy); 4.4-4.6 (2H, multi- Blend difenshtmetilo zogo ester lash, CH, OOSNz) 5.12 (1H, doublet, 7- (g) -2- (trityl shotiazol-4-yl) - J 4, 5 Hz, 6-H); 5.38 (2H, br. Syn-2-acetoxyiminoacetamido3-W (Z) –glt NHj); 5.82 (2H, singlet, -.3-acetoxy-1-gvopenyl-3-cephem-4-acetyl)} 5.4-5.9 (1H, multiplet, -carboxylic acid (3.2 g, 3.43 mmol)) i 5.98 (1H, double doublet, in 5 ml of anisole and 20 mp trifluoroacetic acid — J 8 and 4.5 Hz, 7-H); 6.29 (1H, oak acid is stirred for 1 h at 5 C. years, J 11 Hz, CH CH-CH2), 6.82 (1H, When removing the solvent followed by the singlet, thiazole-H), 7, 55 (1H, doublet, by trituration of the residue with tOO ml di- J 8 Hz, NH). 1.25 g are obtained from isopropyl ether
Example 68 7- (g) -2- (2-amins) - salts of trifluoroacetic acid. The thiazol-4-yl) -2-acetyloxyiminoacetate product is purified using the | -3- (g) -3-acetoxy-1-propenyl chromatoamide — graphical column c. Bonapac-3-cephem-4-carboxylic acid. 55 eluted with water, 10%
Acylation , methanol in water and 20% methanol
To a mixture of (7) -2- (tritylaminothiazol- in water, in the indicated sequentially-4-yl) -2-acetoxyiminoacetic acid. Corresponding fractions of the compound (1.95 g, 4.0 mmol) and 1 hydroxynon are concentrated in vacuo and lyo57
filize to get 395 mg (23%) of the specified substance.
IR spectrum, (KBG), cm: 3300, 1770, 1670.
UV spectrum, A tc, vc buffer, PH 7), nm (): 228 (20300), 284 (15300).
Nuclear Magnetic Resonance Spectrum (deuterodimethylsulfok ™ seed), 8, MD: 2.0 (3N, singlet, acetyl), 2.15 (3N, singlet, acetyl); , 4.51 (2H, AB-quartet, CH, 0-acetyl); 5.22 He doublet, J 5 Hz, 6-H); .5,60 (1H, multiplet,) j 5.80 (1H, double doublet, J 5 and 7 Hz, 7-H); 6.32 (1H, doublet, J 12 Hz,); 7.05 (1H, singlet, thiazole).
EXAMPLE 69: 1-Acetoxyethyl ester of 7- (2) -2- (2-aminothiazol-4-nl) -acetoxyiminoacetamido3-3- (Z) 3-acetoxy-1-propenyl 3 -ce - fem 4-carboxylic acid.
Sodium carbonate (51 mg, 0.49 cmol) and acetoxyethyl bromide (82 mg, 0.49 mmol) are added to -10 ° C to a solution of the compound of Example 68 (248 mg, 0.49 mmol) in 25 mp of dried dimethylformamide. The mixture was stirred at 5 ° C for 30 minutes and 82 mg (0.49 mmol) of 1-acetoxyethylbromide was added to the suspension. After further stirring for 30 minutes, the reaction mixture was diluted with ethyl acetate (50 ml), washed 3 times (30 mp) with water and brine, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product is purified and chromatographed on a column of silica gel eluted with 3% methanol in chloroform. When removing the solvent from the corresponding eluent. with subsequent drying during freezing, 157 mg (54%) of the indicated substance are obtained. M.p. 125 ° C (decomp.).
IR spectrum,) d, a1cc (KBG),: 3430, 3290, 1770, 1680.
UV spectra, Xmax, (phosphate buffer, pH 7), them (6): 228 (21900), 287 (12700).
PMR spectrum (deuterodimethyl sulfoxide), 5, MD: 1.51 (ZN, doublet, J 6 Hz, 4-СООСНСН,) 2.02 (ZN, singlet, acetoxy), 2.06 (ZN, singlet, acetoxy); 2.22 (3N, singlet, acetoxy); 3.47 (2H, tir. Singlet, 2-H); 4.46 (1H, doublet, J 6 Hz, -. ... 4-COOSNSN); 4.55 (2H, AB-quartet, CH, |, 0 acetyl); 5.12 (1H, doublet. J
,
™.
n-
0,
,
n;
42820458.
 6 Hz, 6-H), 5.70 (1H, multiplet,); 5.95 (1H, double doublet.
ten
15
25
thirty
J 5 and 7 Hz, 7-H) i 6.25 (1H, doublet, J 12 Hz,); 6.92 (1H, singlet, thiazole).
PRI mme R 70. (5-Metsh1-2-oxo-1, 3-dioxolen-4-yl) methyl ester 7- (2) -2- (2-aminothiazol-4-yl) -2-guide - roxyimino acetamido-3- (Z) -1-propene nn1 | -3-cephem-4-carboxylic acid.
In an ice-cooled and perennial solution of compound (I) (RH, RjH) (512 mg, 1.25 mmol) in 2 ml of dimethylformamide, sodium carbonate (238.5 mg, 4.5 mmol) and in 3 portions at 15 min intervals, a solution of 4-brog-1methyl-5-methyl-1,3-dioxolen-2-one (869 mg, 4.5 mmol) in 6 mp 20 dimethylformamide. The mixture is diluted with 50 ml of ethyl acetate, washed with water and brine, and dried with magnesium sulfate. The filtrate was concentrated in vacuo. The residue is dissolved in a large amount of chloroform and purified on a silica gel chromatographic column (30 g, kieselgel 60). The desired fractions eluted with a mixture (30: 1) of chloroform and methanol are combined and concentrated in vacuo to give 182 mg (29%) of the desired product. M.p. 115-120 ° C (decomp.).
IR Spectrum, (iac) (KBG),: 1770, 1735, 1530, 1210, 1190.
UV spectrum, Lddacke, ethanol, nm (): 225 (shoulder 19000), 287 (12000),
PMR spectrum (CDCl +), S, ppm: 1.62 (ZN, doublet, J 6.0 Hz); 2.18 (SA, singlet); 3.45 (2H, broad singlet); 4.68 (2H, singlet); 5.10 (1H, doublet, .J "5.5 Hz); 5.50-5.90 (1H, multiplet); 5.85 (1H, doublet, J 5.5 Hz); 6.12 (1H, doublet, J 12 Hz), 6.95 (1H, singlet).
EXAMPLE 71: 1-Ethoxycarbonyl hydroxyethyl ester of 7- (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino acetamide-f (Z) -1-propyl-3-cef8 -4-carboxylic acid.
Sodium carbonate (40 mg, 0.625 mmol) is added in dimethylformamide (1 ml) at 0–5 ° C to a stirred solution of the compound of example 34 (256 Mrj 0.625 mmol) in 2 ml of dimethylformamide at 0-5 C. gg After stirring the mixture for 20 min at 5 ° C 40 mg of sodium carbonate. and solution ei. - iodoethyl carbonate (183 mg) and the mixture was mixed for 40 minutes. This mixture is diluted with 50 mp.
35
40
45
50
59
etchtacetate, washed. i twice with water (50 ml each), dried with magnesium sulfate and filtered. The filtrate is concentrated in vacuo. The residue is dissolved in a small amount of chloroform and purified on a column of 20 g of snipicagel (kieselgel 60). Combine the desired fractions eluted with a 30: 1 mixture of chloroform and methanol and concentrate in vacuo to obtain 56 mg (17%) of the desired product. M.p. 105-1U S.
IR spectrum, “aks (KVg),: 1760, 1525, 1370, 1270.
UV spectrum, (ethanol), nm (): 222 (20000), 286 (11000).
PMR spectrum (CDCl t), 5, ppm 1.33 (3N, triplet, J = 7 Hz); 1.57 (ZN, doublet, J 5 Hz); 1.70 (3N, doublet, J = 7 Hz); 3.45 (2H, broad singlet); 4.23 (2H, quartet, J 7 Hz) 5.10 (1H, doublet, J 5.0 Hz); 5.87 (1H, doublet, J 5.0 Hz), 5.50-6.00 (1H, multiplet) 6.16 (1H, doublet, J 12 Hz, 6.92 (1H, quartet, 5 Hz) ; 7.00 (1H, singlet).
Tests of new cephalosporins as prothin microbial substances were carried out on compounds 1-89:
1.7B- (2) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido3 -3- (Z) -prop-1-ene-yl-3-cephem-4-carboxylic acid; .
2.1-acetoxyethyl 7B- (Z) -2- (2- -aminothiazol-4-yl) -2-methoxyiminoacetamido-3- (Z) -prop-1-it-1-yl-3-cephem 4-carboxypate
3. pivapoyloxymethyl 7 /} - (Z) -2- - (2-aminothiazol-4-yl) -2-methoxyimino-acetamido-3-C (Z) -pro-1-en-1-yl | - -3 -cepheme-4-car bauxyl,
, 4. 7p- (Z) -2- (2-aminothiazol-4-yl) -2 -2-methoxyiminoacetamido-3-C (E)--prop-1-ene-1-pc-1-yl-3- cephem-4-carboxylic acid,
5.1-acetoxyflux1 7Y- (Z) -2- (2- -aminothiazol-4-yl) -2-methoxy-imino-acetamide-J-3- (E) -prop-1-one-1-yl - -3-cephem-4 carboxylate;
6. Pivaloyloxymethyl 7c- (Z) -2- - (2-aminothiazol-4-yl) -2-methoxyimino-acetamido -3- (E) -npon-l.-eH-1-mf - -3-cephem- 4-carboxylate}.
7.7fi- (Z) -2- (2-aminothiazol-4-Sh1) -2-methoxyiminoacetamido-3- (Z) -but--1-en-1-yl3-3-cephem-4-carboxylic acid.
28204
60
;


ten
8. Acetoxymethyl 7ft- (Z) -2- (2-aMH-notiazol-4-Sh1) -2-methoxyiminoacetate-amido-3- (Z) -but-1-en-1-yl-3-cephem- - 4-carboxylate
9.1-acetoxy from 7A- (Z) -2- (2- -aminothiazol-4-yl) -2-methoxyimino-acetamido-3- (Z) -but-1-it-1-yl - -3-cephem-4 carboxylate
10. pivaloyloxymethyl (Z) 2- / - (2-aminothiazol-4-Sh1) -2-methoxyiminoacetamido-3 (Z) -but-1-en-1-yl-3-tsefem-4-carboxylate,
11.4-glycyloxybenzosh1oximeSh1 15 7ft- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino acetamido-3- (Z) -ffyT-1-eH -1 -1 yl-3-cephem-4-carboxylate ;
12.7 | i- (Z) -2- (2-aminothiazole-4-ShI) -2-methoxy-aminoacetate-3 G (E) 20 but-1-en-1-yl-3-cephem-4-carboxylic acid
13. Acetoxymethyl 7/5-C (Z) -2- (2- -aminothiazol-4-yl) -2-methoxyiminoacetamido-3- (E) -but-1-he-1-yl-3-25-cephem -4-carboxylate
14.1-acetoxyethyl 7p- (Z) -2- (2- -aminothiazol-4-yl) -2-methoxyimino-acetamido-3- (E) -but-1-ene-pc-3-tsefem-4- carboxylate
3015. Pivaloyloxymethyl 76-r (Z) -2-.
(2-aminothiazol-4-yl) -2-methoxyimino-acetamido-3- (E) -but-1-en-g1-yl - -3-cephem-4-carboxylate I
16. 4-glycyloxybenzoyloxymethyl
g (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3-C (E) -but-1-E--1-yl-3-cephem-4-carboxylate,
17.7p- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3-L (Z) -pent-1-ene-1-yl-Z-cephem-4-carboxylic acid
18.1-acetoxyethyl 7B- (Z) -2- (2- -amknothiazol-4-Sh1) -2-methoxyimino-acetamido -3- (Z) -pent-1-ene-1-yl - -3-cephem-4 carboxylate J
19. Pivaloyloxymethyl 7A-f (Z) -2- - (2-aminothiazol-4-yl) -2-methoxyimino-acetamido-3- (Z) -ent-1-en-1-yl-3-cefem-4 -car b xylate
20.7 (3- (Z) -2- (2-amiothiazol-4-yl) -2-methoxy-aminoacetate-3- (E) - -pent-1-in-1-yl-3-cepheme-4-carboxic acid ,
21.1-acvtoxyethyl, 7L- (Z) -2- (2- -amino-thiazal-4-yl) -2-methoxy-imino-acetamido-3- (E) -pent-1-en-1-nl - -3-cephem 4-carboxylate)
22 o pivaloyloxymethyl (Z) -2- - (2-aminothiazol-4-yl) -2-methoxyimino 40
45
50
55
6 1A2820A 2.
aceto rado -3- (E) -ent-1-on-1-yl -37. 7p- (g) -2- (2-am Notiazol-A 3-cephem-A-carboxylate, -yl) -2-oxminoacetamido1-3- (7.) 23o 7P) - (g) -2- (2- amino-ol-4-yl) -3-acetoxyprop-1-en-1-yl-3-cephem-2-methoxy-amino-acetamido-3- (X) -4-carboxylic acid,
-2-methoxy-amino-acetamido - and - - -3-methoxyprop-1-ene-1-yl-3-cephem-4-carboxylic acid,
24.1-acetoxyethyl 7L- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino; acetamido -3- (g) -3-methoxyprop-1 en-- u 1-yl -3-cephem-4-carboxylate,
25. Pivaloyloxymethyl 75- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido-3- (g) -3-methoxyprop-1-e--1-yl-3-yephem- 4-carboxylate
26.7B C (2) -2- (2-aminothiazol-4 -. R, -j -, - - -,
-yl) -2-methoxyiminoacetamido-3- (E) -1 -1-en-1-yl-3-cephem-4-carboxylate; -3-methoxyprop-1-en-1-yl 3-cephem-4- - (Z) -2- (2-aminothiazol-4-carboxylic acid; Il) -2-oxynminoacetamido-3- (Е) 27 .1 -Acetoxyethyl 7 | i- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3- (E) -3-methoxyprop-1-en-1-yl) -3-cephem -4-carboxylate.
15
38. aceto-xymethyl 76- (Z) -2- (2-amino-thiazol-4-yl) -2-oxy-amino acid-a fH-3- (Z) -3-aOtoxyciprop-1-en-1-yl3 -3- cephem-4-carboxylate,
39o 1-acetoxyethyl 7P) - (Z) -2- (2-a-rhinothiazol-4-yl) -2-hydroxyimoacetate - amido-3- (Z) -3-acetoxycpprop-1-en--1 nl -Z- cephem-4-carboxylate,
40. Pivaloyloxymethyl 7P) - (Z) -2- - (2-aminothiazol-4-yl) -2-oxyimino-acetamido-3- (Z) -3-acetoxyciprop20
-Z-acetoxyprop-T-en-T-yl -3-cephem- - 4-carboxylic acid,
42. acetox1-methyl 7gr- (Z) -2- (2--amino-thiazol-4-yl) -2-oxy-amino acid-amido-3- (E) -3-acetoxyprop-1-encijj, c: i clinJa / l , UJJ LV J / - ji ur.ujrtitpv-1 il 3 3 cefem-4-carbox-1 | - --- - -.- 29.) - 2- (2-aminothiazole-4-a№iAoJ-3- (E) -3-acetotociprop-1-en--SH) -2-oxymino-ethotamido-3-3 G (Z) - 1-Sh1 -3-cephem-4-carbox-1at- -prop-1-en-1-t -3-cephem-4-carboxylic 30 pivaloyloxymethyl (Z) -2-acid (2-aminothiazole) 4-yl) -2-oxyimino 30 .1-acetoxyethyl (Z) -2- (2 aminothiazol-4-yl) -2-oxyiminoacetate-amido-3- (Z) -pro-1-ene or Jl-3-cefem- 4-carboxylate
31, pivaloyloxymethyl 7B- (Z) -2- - (2-aminothiazol-4-yl) -2-oximemino-acetamide (G | -3- (Z) -npon-1-eH-1-mi--3- cefem-4-car boxing at,
32.Acetaximethyl 7A- (Z) -2- (2-, -amino-thiazol-4-yl) -2-oxyiminoacetate-amido3 -3- (Z) -prop-1-ene-1-nl -3-cefe 4-carboxylate
33.7B- | (Z) -2- (2-aminothiazol-4- -yl) -2-oxides of the IsoJ-3- (E) - -prop-1-ei-1-yl-3-cephem 4-carbox carbide pulp acid,
34, acetoxymethyl 7p- (Z) 2- (2- -aminothiazol-4-yl) -2-oxyiminoace40
amidoZ-3-iE) -prop-1-en-1) yl 3-ceso P 1 (2;) - 2- (2-aminothiazol-4 fem-4-carboxylate; -2-methoxyimino acetamido 3- (E) fem-4-carboxylate,
35. 1-acetoxyethyl 7A- (Z) -2- (2 aminothiazol-4-yl) 2-hydroxy-amoacetate 6 -3- (E) prop-1-en-1-yl-3 tsefem-4-carboxylateJ
36 "pivaloyloxymethyl 7 (Z) -2. - (2-aminothiazol-4-1-t) - 2-oxyimino-acetamido-3 -, (E) -prop-1-en-1-yl-3-cephem 4-carboxylate;
Acetamido-3 C (E) -acetoxyprop-1-ene -1-yl3-3-cephem-4-carboxylate
45.7p - {(Z) -2- (2-aminothiazol-4-j.iji) -2-methoxyiminoacetamido | -3- -f (Z) -3-acetocciprop-1-en-1-yl-33-c fem-4 carboxylic acid
46. acetoxymethyl 7P | - (Z) -2- (2-amino-thiazol-4-B1) -methoxyiminoacetate-amido-3- (Z) -3 acetotoxypprop-1-en-1 or 3-cephem-4-carboxylate;
47.1-acetoxy from 1A- (Z) -2- (2- -aminothiol ol-4-nl) -2-methoxy-amino-acetamido-3- (Z) -acetoxyprop-1-ene-1 -yl-3-3-cephem-4 carboxyl at,
48. pivaloyloxymethyl 7A- (Z) -2- (2-aminothiazole 4-yl) -2-methoxyimino acetamido-3- (Z) -3-acetotoxypropro-1-ene 1 -yl3gZ-cephem-4-carboxy 1 J
49.7P (Z) -2- (2-aminothiazol-4-yl
45
3 acetoxyprop-1-en-sh1 3-cephem-4-k-ar lateral acid,
50. acetoxymethyl 7 | 5-t (Z) -2 - (- - amino-thiazol-4-yl) 2-methoxyimino-cetamido 1-3-CE) - 3-acetoxyprop-1-ene-1 -yl 3 -Z-cephem 4-carboxylate J
51.1-acetoxyethyl 7p- (Z) -2- (2- -amino-thiazole 4-sh1) 2-methoxyimino-3-acetoxyprop-1-ene-1-yl-3-cephem-4-carboxylic acid,
-.r, -j -, - - -,
-1-en-1-yl-3-cephem-4-carboxylate; - (Z) -2- (2-aminothiazole-45
38. aceto-xymethyl 76- (Z) -2- (2-amino-thiazol-4-yl) -2-oxy-amino acid-a fH-3- (Z) -3-aOtoxyciprop-1-en-1-yl3 -3- cephem-4-carboxylate,
39o 1-acetoxyethyl 7P) - (Z) -2- (2-a-rhinothiazol-4-yl) -2-hydroxyimoacetate - amido-3- (Z) -3-acetoxycpprop-1-en--1 nl -Z- cephem-4-carboxylate,
40. Pivaloyloxymethyl 7P) - (Z) -2- - (2-aminothiazol-4-yl) -2-oxyimino-acetamido-3- (Z) -3-acetothoxylprop Il) -2-oxynminoacetamido-3- (E)
-Z-acetoxyprop-T-en-T-yl -3-cephem- - 4-carboxylic acid,
42. acetox1-methyl 7gr- (Z) -2- (2--amino-thiazol-4-yl) -2-oxy-amino acid-amido-3- (E) -3-acetoxyprop-1-ena iaoJ-3- (E ) -3-acetothoxyprop-1-en--1-sh1 -3-cephem-4-carboxyl-0-pivaloyloxymethyl (Z) -2- (2-aminothiazol-4-yl) -2-oxyimino0
about R 1 (2;) - 2- (2-aminothiaz.ol-4 -2-methoxyiminoacetamido 3- (E) acetamido-3 C (E) -acetoxyprop-1--1 -1-yl3-3-cephem- 4-carboxylate
45.7p - {(Z) -2- (2-aminothiazol-4-j.iji) -2-methoxyiminoacetamido | -3- -f (Z) -3-acetocciprop-1-en-1-yl-33-cephem-4 carboxylic acid
46. acetoxymethyl 7P | - (Z) -2- (2-amino-thiazol-4-B1) -methoxyiminoacetate-amido-3- (Z) -3 acetotoxypprop-1-en-1 or 3-cephem-4-carboxylate;
47.1-acetoxy from 1A- (Z) -2- (2- -aminothiol ol-4-nl) -2-methoxy-amino-acetamido-3- (Z) -acetoxyprop-1-ene-1 -yl-3-3-cephem-4 carboxyl at,
48. pivaloyloxymethyl 7A- (Z) -2- (2-aminothiazole 4-yl) -2-methoxyimino-acetamido-3- (Z) -3-acetotoxypropro-1-ene 1 -yl3gZ-cephem-4-carboxy 1 J
49.7P (Z) -2- (2-aminotiazol-4-yl) 5
about R 1 (2;) - 2- (2-aminothiaz.ol-4 -2-methoxyiminoacetamido 3- (E) 3 acetoxyprop-1-en-sh1 3-cephem-4- -k ar latex acid,
50. acetoxymethyl 7 | 5-t (Z) -2 - (- - amino-thiazol-4-yl) 2-methoxyimino-cetamido 1-3-CE) - 3-acetoxyprop-1-ene-1 -yl 3 -Z-cephem 4-carboxylate J
51.1-acetoxyethyl 7p- (Z) -2- (2- -aminothiazole 4-sh1) 2-methoxyiminoacetamido-3- (E) -3-acetoxyprop-1-imino acetamido1-3- (2) -3-acetoxy-en -1-yl-3-cephem-4-carboxylate prop-1-en-yl-3-cephem-4-carboxylate; 53. 7P) - (g) -2- (2-aminothiazol-4-yl) -67. 5-methyl-2-oxo-1,3-dioxolene--2-acetoxymino-acetamido-3- (Z) - i-4-yl-methyl (Z) -2- (2-aHHOTHa3on "- 4ij, mii-imivyc4 .j, -i di-ui vj. - / w4-nji MtJiiui / j:) - Li / i. vz amlshlazi
-prop-1-en-1-yl3-3-cephem-4-carboxylic acid, h-4-W1) -2-a1; methoxyimino acetamido-3 acid, - (g) -3-acetoxyprop-1-en-1-yl - 3-ce54. acetoxymethyl 7p- (Z) -2- (2-fem-4-carboxylate,
-aminothiazol-4-yl) -2-acetoxyimino-68. 7p- (g) -2- (2-aminothiazol-4 acetamido-3- (E) -prop-1-en-1-yl3 - yl) -2-acetoxyiminoacetamido-3 acid,
54. acetoxymethyl 7p- (Z) -2- (2- -aminothiazol-4-yl) -2-acetoxyimine acetamido-3- (Z) -prop-1-En-1-yl3-3-cephem-4- carboxyl at,
55.1-acetoxyethyl 7B- (Z) -2- (2- -aminothiazol-4-Sh1) -2-acetoxyiminoacetamido-3- (Z) -npon-1-eH-1-Hn3-3-cephem-4 -karbokssh1at5
56. Pivaloyloxymethyl 7 | B-D (2) 2- - (2-amino-thiazol-4-yl) -2-acetoxyimino-acetamido-3- (Z) -pro-1-in-1-yl - -3-cep -4-cartridges
57.5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl 7p (Z) -2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamido | - -3- (Z) -propp-1-in-1-yl-3-cefem-4-carboxylate
58.7A- (E) -2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamido1-3- (E) -; -prop-1-en-1-yl-3-cefem-4-carbynova
15
20
- 25
acidi
59. acetoxymethyl 7 / 3- (Z) -2- (2- -aminothiazol-4-yl) 2-acetoxymino-acetamido-3- (E) -prop-1-ene-1-sh1 - -3-cephem- 4-carboxylate;
60.1-acetoxyatsh1 7 |} - (Z) -2- (2- -aminothiazol-4-yl) -2-acetoxyimino acetamido -3- (E) -prop-1-ene-1-yl - -3-cephem- 4-carboxylate J
61. Pivaloyloxymethyl 76-CZ) -2- (2-aminothiazol-4-yl) -2-acetoxymino-acetamido-3- (E) -prop-1-en-1-yl-3-cephem-4-carboxylate;
62.5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl-7p- (E) -2- (2-amino-thiazol-4-yl) -2-acetoxyiminoacetam- (E) -prop- 1-en-1-yl-3-cephem-4-carboxylate;
63.7A- (Z) -2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamido-3- -L (Z) -3-acetotociprop-1-in-1-yl | -3-cefe 4-carboxylic acid;
64. acetoxymethyl 7 | 5 -. (Z) -2- (2- -aminothiazol-4-yl) -2-acetoxymino-acetamido-3- (E) -3-acetoxy-1-ene-1-sh13- 3-cephem-4-carboxylah-,
65.1-acetoxyetch1 7A- (Z) -2- (2- -aminothiazol-4-yl) -2-acetoxyimino-yl) -2-acetoxyiminoacetamido3 -J- (E) -3-acetoxyprop-1-en-1-yl1 -3-cepheme-4-carboxylic acid -
69. acetoxymethyl 75- (Z) -2- (2- -amino-thiazol-4-yl) -2-acetoxyiminoacetamido3-3- (E) -3-acetoxyprop--1-en-1-yl-3-cephem -4-carboxylate
70.1-acetoxyethyl (Z) -2- (2-α-amino-thiazol-4-yl) -2-acetoxyimino-acetamido-3-G (E) -3-acetoxy-prop-1-en--1-yl 3 -3-cephem- 4-carboxylate;
71. Pivaloyloxymetip 7 / i- (Z) - 2- (2-aminothiazol-4-sh1) 2-acetoxyiminoacetamido-3- (E) -3-acetoxyprop--1-en-1-yl -Z- cephem-4-carboxylate;
72.5-methyl-2-oxo-1,3-dioxo-30 len-4-yl-metsh1 7 | 5- (Z) -2- (2-amino-thiazol-4-yl) -2-acetoxyiminoacetami- (E) - Z-acetoxyprop-1-ene-1-yl-Z-cephem-4-carboxylate}
73; (Z) -2- (2-aminothiazol-4- "with yl) -2-isopropyloxyiminoacetam- (Z) -prop-1-ene-1-yl3-3-cepheme-4-carboxylic acid;
74.1-acetoxyethyl 7 | i-C (Z) -2- (2- -aminothiazol-4-yl) -2-isopropyloxy-
4Q iminoacetamide-3- (Z) -npon-1-eH-1-yl-3-cephem-4-carboxylate
75. Pivaloyloxymethyl 7A- (Z) -2- - (2-aminothiazol-4-sh1) -2-isopropyloxyiminoacetamido-3- (Z) -prop-1-ene-
45 -1-ip3-3-cephem-4-carboxestat;
76. (Z) -2- (2-aminothiazol-4-yl) -2-allyloxy-amino acid-3- (Z) -propp-1-En-1-yl-3-cephem-4-carboxylic acid
5Q 77. 1-acetoxyethyl (Z) -2- (2- -amino-thiazol-4-yl) -2-All-l-oxoimino-acetamide d-3- (Z) -prop-1-en-1-l--3-cephem -4-carboxylate;
78, pivaloyloxymethyl 7fl-C (Z) -2-55 - (2-aminothiazol-4-yl) -2-allyloxyiminoacetamido-3-C (%) - prop-1-en-1-sh1 - -3-cephem- 4-carboxylate
79. (Z) -2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetamido-3- (Z) 68. 7p- (g) -2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamido -3
) -;
15
20
25

-
-yl) -2-acetoxyiminoacetamido3
69. acetoxymethyl 75- (Z) -2- (2- -amino-thiazol-4-yl) -2-acetoxyiminoacetamido3-3- (E) -3-acetoxyprop--1-en-1-yl-3-cephem -4-carboxylate
70.1-acetoxyethyl (Z) -2- (2-α-amino-thiazol-4-yl) -2-acetoxyimino-acetamido-3-G (E) -3-acetoxy-prop-1-en--1-yl 3 -3-cephem- 4-carboxylate;
71. Pivaloyloxymetip 7 / i- (Z) - 2- (2-aminothiazol-4-sh1) 2-acetoxyiminoacetamido-3- (E) -3-acetoxyprop--1-en-1-yl -Z- cephem-4-carboxylate;
72.5-methyl-2-oxo-1,3-dioxo-30 len-4-yl-metsh1 7 | 5- (Z) -2- (2-amino-thiazol-4-yl) -2-acetoxyiminoacetami- (E) - Z-acetoxyprop-1-ene-1-yl-Z-cephem-4-carboxylate}
73; (Z) -2- (2-aminothiazol-4- "with yl) -2-isopropyloxyiminoacetam- (Z) -prop-1-ene-1-yl3-3-cepheme-4-carboxylic acid;
74.1-acetoxyethyl 7 | i-C (Z) -2- (2- -aminothiazol-4-yl) -2-isopropyloxy-
4Q iminoacetamide-3- (Z) -npon-1-eH-1-yl-3-cephem-4-carboxylate
75. Pivaloyloxymethyl 7A- (Z) -2- - (2-aminothiazol-4-sh1) -2-isopropyloxyiminoacetamido-3- (Z) -prop-1-ene-
45 -1-ip3-3-cephem-4-carboxestat;
76. (Z) -2- (2-aminothiazol-4-yl) -2-allyloxy-amino acid-3- (Z) -propp-1-En-1-yl-3-cephem-4-carboxylic acid
5Q 77. 1-acetoxyethyl (Z) -2- (2- -amino-thiazol-4-yl) -2-All-l-oxoimino-acetamide d-3- (Z) -prop-1-en-1-l--3-cephem -4-carboxylate;
78, pivaloyloxymethyl 7fl-C (Z) -2-55 - (2-aminothiazol-4-yl) -2-allyloxyiminoacetamido-3-C (%) - prop-1-en-1-sh1 - -3-cephem- 4-carboxylate
79. (Z) -2- (2-aminothiazol-4- -yl) -2-ethoxyiminoacetamido-3- (Z) 142820466
-prop-1-en-1-yl-3-cephem-4-carboxy 89. 1- (ethoxycarboxy-1) ethyl
acid;
80. 1-acetoxyethyl 7ft- (Z) -2- (2- -aminothiazol-4- -sh) -2-ethoxyiminoacetate-amido-3- (Z) -prop-1-en-1-yl-3-ceBaK In vitro terrorist activity in free cephalosporanic acids
 (X.) - 2- (2-amyothiazol-4-yl) -2-oxioimoacetamido3-3- (Z) -prop-1-en- 1-yl-3-cephem-4-carboxylate.
fem-4-carboxes1,
81 pivaloyloxymethyl (Z) -2 :-( 2-aminothiazol-4-yl) -2-ethoxymyoacetamideo-3- (7.) - prop-1-en-1-yl - 3-cefem-4-carboxylate ,
82.7A- (g) -2- (2-aminothiazol-4; Il) -2-cyclopropylmethoxyiminoacet-- amido1-3-- (7) -prop - 1-en-1-yl -3-ce-: fem -4-carboxylic acid,
83.1-acetoxyethyl 7 | i- (Z) -2- (2-aminothiazol-4 III) -2-cyclopropyl labels of this 1 acetamido-3 (Z) -prop-1-ene-1-shG 3-cephem-4-carboxylate,
84. pivaloyloxymethyl 7 | i- (Z) -2- - (2-aminothiazol-4-Sh1) -2-cyclopropyl-methoxyiminoacetamido-3 (Z) npon--1-en-1 -yl 1-3-cephem -4-carboxylate;
85., 7j5) - (Z) -2- (2-aminothiazol-4 formulas I are presented in Table 1 in
ten
units of geometric mean minimum inhibitory concentration (MIC), which were determined using a double series of methods of diluting agar in Mueller-Hinton agar. against 25 strains of test &amp; oy organisms in six groups.
Tab. Figure 2 shows the levels of cefaposoric antibiotics as esters of the formula I in mouse blood, which were determined after oral administration.
Tab. 3 shows the activity of cephalosporin antibiotics in the form of esters of the formula I in vivo
20
-il) -2-propargyloxyiminoacetamido1-25 versus S. aureus smith, E. coli Juhl,
, lj-i4ITl-, - Af r f r T - fT- 1-.
-3-- (Z) -propan-1-in-1-yl-3-cefem-4-carboxylic acid;
86c 1-acetoxyethyl 7j3- (Z) -2- (2-aminothiazol-4-yl) -2 -products and hf-cells of FC; o 3 (Z) -npon-1--1-W-3 cephem-4 - karboks1-shat,
87. Pivaloyloxymethyl (Z) -2- - (2 Ashnothiazol-4-yl) -2-propargyloxyiminoacetamido3-3- (Z) -npon-l-eH- -1 -sht - 3-cephem-4-car6oxy1 1 ;
thirty
Pr, mirabilis A 9900, Pr. Vulgaris A9436 and Ser. marcescens A20019.
TaOl Figure 4 shows the levels of extraction of various complex zfir from urine.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives.
88 „5 methyl-2-oxo-1,3 - dioxolen-3-propene1-7- |: 2- (2-aminothiazolyl-4) -1 -1 yl Methyl 7po (Z) -2- (2 aminothiazop - 2-hydroxyiminoacetamido 3-cephem-) -2- (oxyimino) acetamido -3--4-carboxylic acid or its complex
™ (2) -prop 1-en-1-yl-3-cephem-4-car-ethers in the form of (Z) - or (E) -isomers
bauxyl; 40 mixtures of general formula I
D 1
scht
with II
t ok
.s
CONH - {- f
 CH-CH2-RS
COOK It
about
R, R.
hydrogen or trityl; hydrogen, straight or branched C, -C-alkyl, C-alkenyl. C-alkynyl, Cd-cycloalkyl, C-bc 10 Jyalkoxy or acetyl;
- hydrogen, Cj Cd-alkyl, methyroxy - or acetoxy group,
- hydrogen, acetoxymethyl,
acetoxyethyl, pivaloyloxymethyl, (tert-butyloxycarbonyl) -glycyloxnBenzo89. 1- (ethoxycarboxy-1) ethyl
 (X.) - 2- (2-amyothiazol-4-yl) -2-oxioimoacetamido3-3- (Z) -prop-1-en- 1-yl-3-cephem-4-carboxylate.
Formula I is presented in Table. 1 in
units of geometric mean minimum inhibitory cocentration (MIC), which were determined using a double series of methods of diluting agar in Mueller-Hinton agar against 25 strains of test organisms in six groups.
Tab. Figure 2 shows the levels of cefaposoric antibiotics as esters of the formula I in mouse blood, which were determined after oral administration.
Tab. 3 shows the activity of cephalosporin antibiotics in the form of esters of the formula I in vivo
five
Iloxymethyl, 4-glycyloxybenzoyloxymethyl, ethoxycarbonyloxyethyl or 5-methyl-2-OXO-1, 3-dioxolen-4-yl-methyl,
differing from the fact that a compound of the general formula II;
Ss
Ri
ABOUT
(SbN5) s
Yoosh (SbN5) o
five
67
benzylidene group or a group of the general formula
(SbN5) ZSSh
t-gs-ssht - oL
where Kj is trit, linear or branched C, -C-alkyl, Cd-alkenip, C, -alkinsh1, C-cycloalkyl, C-cycloalkylmethyl, or -acetyl,
subjected to interaction with the aldehyde of General formula III
R CHiCHO,
where R has the indicated values in an inert organic solvent selected from dichloromethane, dimethylformamide and isopropyl alcohol or a mixture thereof, possibly in the presence of lithium chloride, lithium bromide or lithium iodide at 0-25 ° C, and in the case when Rg benzylidene-amino group, in the resulting product the benzylidene group is removed by treatment with a mixture of Girard reagent and acetic acid or aqueous hydrochloric acid, followed by possible transformation of the resulting compound of general formula IV
Hon
,
J-N, xJ-CH2 CH-35
 COOCH CeEs)
where Rj has the indicated values, in the form of a 3 (g) isomer, to the compound of formula IV as a 3 (E) isomer by photochemical irradiation in methanol in the presence of benzophenone and
the compound of formula IV in the form of 3 (Z) -. . . .., or a 3 (E) -isomer or mixtures thereof, p-hydroxybenzoyloxymethyl.
pivaloyloxy - (tert-bucket cyloxy benzo ethoxycarbon 5-methyl-2-ok lex-4-yl-meth X - chlorine, bromine and in an inert organic medium with an organic product or compound R - 4-Gm- (tert-buto Cyloxy-benzoyl oxime acid hydrols of the target product,
42820468
acylated with total N-r-C-COOH
d
where r
R HNC- II
m
OR 2
and Rj are as defined.
-
, nd
ten
15
20
25
thirty
35
. . . .., - hydroxybenzoyloxymethyl.
in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide, or its ester with 1-hydroxybenzotriazole in an inert organic solvent at room temperature, or its acid chloride in medium: an inert organic solvent at a temperature from -20 ° C to room temperature and remove the ester iphenyl- a methyl protective group and, in the case of the presence of trityl groups protecting amino and / or hydroxy groups, by acid hydrolysis and the target product of general formula R is hydrogen, as a mixture of 3 (Z) - and 3 (E) isomers, or are it into separate 3 (Z) - and 3 (E) isomers, and the target product is isolated as free acid or converted into an alkali metal or ammonium salt, which is reacted with a compound of general formula VI
R4-X, acetoxymethyl, acetoxyethyl,
pivaloyloxymethyl, - (t-butoxycarbonyl) -glycyloxy benzoyloxymethyl, ethoxycarbonyloxyethyl or 5-methyl-2-oxo-1,3-dioxolen-4-yl-metsh1; X is chlorine, bromine or iodine, and in the medium of an inert organic solvent, the target product or compound, in which R is 4-Hm- (tert-butoxycarbonated 1) -glycyloxy-benzoyl-oxymethyl, is subjected to acid hydrolysis to obtain the desired product, where R is 4-glycylgde
Table The activity of cephalosporic acids in vitro
Gp-1a: penicillin (MS) - sensitive to S. aureus;
Gp-1b: PC - resistant to S. aureus;
Gn-las cephalosporin (CET) - sensitive to E. coli (2 strains)
K, pneuoonial (I) and R. tnirabilis (2)
Gn-1b: CET - resistant to E. coli (3) and K. Pneumonial (2) M. morganii (I), E. cloacal (2) and S. marcescens (2)
H
H-: rC-
OCHjCOOH
CO
sonn1-A sn
CHCHR,
soon
H
CONH-r- (8N |
th -l-sngsg
° COOH
71
Levels of cephalic acid antibiotics in the form of complex esters in the blood
PV - -CHsOCOC (CB,) j; VAM "i -CMjOODCR ,;
SCHYS i H: n (fn,), baseline ,,
""
GeK - CH OCOU28 .04
72 Tablvca2
73
Removing cephalosporin antibiotics from the urine of the mouse in the form of esters by oral administration
Standardized sample compound 7 (28154).
VNIIPI Order 4870/59 Circulation 370
Random polygons pr-tie, Uzhgorod, st. Project, 4
142820А74
Table3
TableA
Subscription

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法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US06/748,359|US4708955A|1985-06-24|1985-06-24|3-propenyl-7-aminothiazol-ylcephalosporanic acids and esters thereof|

---