前苏联专利SU1367858A3 Method of producing cephalosporin derivatives

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专利摘要:
7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(substituted)-iminoacetamido]-3 -[3-(quaternaryammonio)-1 - propen-1-yl]-3-cephem-4-carboxylates of the formula <IMAGE> in which R<1> and R<2> are as defined herein and <IMAGE> is a quaternary ammonio group as defined herein, and salts, solvates, hydrates and esters thereof, are potent antibacterial agents. Processes for their preparation and intermediates in such processes are described.
公开号:SU1367858A3
申请号:SU864023036
申请日:1986-02-06
公开日:1988-01-15
发明作者:Ока Масахиса；Ямасита Харухиро；Наито Такаюки；Окумура Юн
申请人:Бристоль-Мейерз Компани (Фирма)；
IPC主号:

专利说明:

one
The invention relates to a method for producing new cephalosporin derivatives, which are intermediates in the synthesis of new antibiotics of the cephalosporin series, possessing improved antibacterial properties against microorganisms, resistant to the well-known antibiotics of the cephalosporin and penicilpin series.
The purpose of the invention is to obtain new intermediates in the synthesis of new antibiotics of the cephalosporin series, which have improved antibacterial properties.
Example K Diphenylmethyl 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) oxyiminoacetamido) -3-chloromethyl-3-cem-4-carboxylate (IV-I).
To a stirred suspension of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-I) (2.1 g 10 mmol) in dry methylene chloride (50 ml) was added Phosphorus phosphorus (2.09 g, 10 mmol) is added at -30 ° C and the mixture is stirred for 20 minutes at a temperature of (-15) - (20) ° C. A solution of Diphenylmethyl-7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (11) (4.5 g, 10 mmol) is added to the above acid chloride solution. in methylene chloride (50 ml) containing N, O-bis- (trimethylsilyl). acetamide (10 g, 50 mmol), at -30 ° C. After stirring at -10 ° C for 1 h, the mixture is concentrated for remove methylene chloride and dilute with ethyl acetate (200 ml). The mixture was washed successively with 10% aqueous sodium bicarbonate (2 x 40 ml) with water (2 x 20 ml) and brine (10 ml) and dried over magnesium sulfate. The solvent is evaporated in vacuo and the resulting oily residue (10 g) is dissolved in chloroform (20 ml) and chromatographed on silica gel (C-200 Waco gel, 100 g containing 10 ml of 1 / 1.5 M pH 7 phosphate buffer) using one -
-
- -
ten
15
20
NMR ((/ (DMSO-d J, ppm): 3.53 (2H, ABq 2-H), 3.94 (3-H, singlet, qCHj), 4.42 (2H, singlet, H- CH)
5.22 (1H, doublet, 5 Hz-6-H),
5.92 (W, dd, H 4.5 and 6.7-H)
6.93 (1H, singlet, SNRp,), 7.36 (YUN, multiplet, Ph -), 8.1 (2H, shir, singlet, NHj), 9.58 (1H, doublet, J 6.7Sh) Example 2. Diphenylmethyl 7- (2- (5-amnno-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido) -3-iodomethyl-3-cephem-4-carboxylate (VI ).
A mixture of IV-I of Example 1 (5.7 g, 9.5 mmol) and sodium iodide - (4.3 g, 29 mmol) in dry acetone (50 ml): Stir for 5 minutes at room temperature. The mixture is concentrated under reduced pressure, and the resulting oil is shaken with a mixture of ethyl acetate (100 ml) and water (10 ml). The organic layer is separated and washed successively at 10% w / v. 25 sodium thiosulfate and saline. After drying, the ethyl acetate was removed in vacuo to give 6.1 g (93%) of the desired compound (V-I) as a yellow amorphous powder, melting at. 30 above (dec.),
IR,) „d, s (KVg) in cm-: 3300, 1780, 1725, 1680, 1620.
UV A d, KS (ethanol), nm (): 245., (17000), 282 (12000).
NMR: f (mCO - dg} ppm: 3.72 (2H, ABq 2-H), 3,: 94 (ZN, singlet, OCH),
4.23 (2H, singlet, W-CH), 5.21 (IH, doublet, D - 4.5 / 6-H), 4.89 (1H, dd, J 4.5 and 6, 7-H), 6.94 (1H, sing40 years, CHPh., 7.35 (YN) multiplet, Ph-H), 8.12 (2H, shir, singlet, NH), 9.65 (1, doublet J 6.7 -NH).
PRI me R 3. Diphenylmethyl iodide (5-amino, 2,4-thiadiazole)
45 3-yl) -2-methoxyiminoacetamido-3-triphenylphosphonio-methyl-3-cephem-4-carboxylate (IV-I).
A mixture of compound V-I from example 2 (690 mg, L mmol) and triphenylphosphine.
35
3% methanol / chloroform mixture. Frac-gg (786 mg, 3 mmol) in ethyl acetate
(20 ml) is stirred for n at room temperature. The solid is separated, collected by filtration, washed with gg and cetate (2x10 ml) and dried to a floor of 950 mg (100%) of phosphonium iodide (VI-I). M.p. 186 C (decomp.).
1 SAW containing the desired compound was evaporated, yielding 5.7 g (95%) of compound IV-I as a yellow amorphous powder. Tpd above 140 ° C (decomp.),
IR, „„ ,, (KVg), 3300, 1780, 1720, 1680, 1620.
UV, Lmsh (ethanol), nm (E): 245 (1800), 280 (9800).
gg (786 mg, 3 mmol) in ethyl acetate
(20 ml) stirred overnight at room temperature. The solid is separated, collected by filtration, washed with ethyl gg and cetate (2 x 10 ml) and dried, yielding 950 mg (100%) of phosphonium iodide (VI-I). M.p. 186 C (decomp.).
IR,
ffCKKC
(KBG), cm-: 3300, 1780,
1710, 1680, 1610.
31367858
UV A, s.x (ethanol), in nm (O: 268 IR, y „, s (KRr), cm: 3300, 1780,
1725, 1680, 1620.
UV “C, cs (ethanop), nm (E): 240 (20000), 286 (12000).
NMR with / (ZhSO-a +), NSJiH.flOJi. : 3.56 and 3.8 (multislett, 211), 3.94 pn. singlet, OCH), 4.16 (doublet, J 7.5 CHjCl), 5.26 (1-H, doublet, 10 J 4.5, 6-H), 5.87 (1-H, doublet, J 4.5 7-H), 6.28 (2 / 3N, doublet, 3-CH-cis-H), 6.72 (1) 3N, oak-. years old J 16.3-CH trans-H), 6.81 (2 / ZN) singlet, CHPhi), 6.91 (1), ZN, syn- 15 years,), 7.4 (UN, multiplet, Ph-H).
EXAMPLE 6 Diphenylmethyl (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido-3- (3-iodo-1-pro-20 pen-1-yl) -Z-cephem-4-carboxylate ().
A solution of VIII-I of example 5 (Z / E 2/1, 480 mg, 0.77 mmol) in dry acetone (10 ml) containing Nal
SRI. The resulting oil (346 mg, 2.3 mmol) was stirred and triturated with ethyl acetate to give 30 minutes at ambient temperature. The reaction mixture is evaporated under reduced pressure. The resulting oil is partitioned between ethyl acetate (50 ml) and water (10 ml). The upper layer is washed successively with 10% w / v aqueous solution of sodium thiosulfate (10 ml) and brine (10 ml)
PRI me R 5. Diphenylmethyl 7-C2- 35 and dried over magnesium sulfate. Upari (5-amino-1,2,4-thiadiazol-3-yl) -2-labeling of the solvent gives 540 mg (98%) of oxyiminoacetamido3-3- (3-chloro-1-protic compound () in the form of) -3-cephem-4-carboxylate, a reddish amorphous solid (VIII-I) substance melting at a temperature
To a solution of VII-I of Example 4 (6.9 g, O above 2Q ° C (decomp.). 8.4 mmol) in ethyl acetate is added
(15000), 275 (13000), 300 (7300).
NMR, (/ (DMSO-a), ppm: 3.52 (2H, broad singlet, 2H), 3.94 (GH, singlet, OSIe) 5.34 (1H, doublet, J i 4.5, 6-Н), 5.9 (1H, multiplet, 7-H), 6.3 (1H, singlet), 7.3 (10H, multiplet, Ph-H), 7.8 (15H , multiplet, Ph-H).
PRI me R 4. Diphenylmethyl.
(5-amino-, 2,4-thiadiazol-3-yl) 2-methoxnimoacetamido-3- (triphenylphosphoranylidene) methyl 1-3 cephem-4-carboxylate (VII-I)
A mixture of Compound VI-I from Example 3 (952 mg, 1 mmol), Amberlite IRA-410 (OH — form, 500 mg) and Norms, sodium hydroxide (4 ml) in methylene chloride (10 ml) was stirred for 1 h. at room temperature. The mixture is filtered and the separated organic layer is dried over magnesium sulphate and the yellow precipitate is concentrated under reduced pressure and collected by filtration, yielding 740 mg (90%) of title compound VII-I. M.p. higher than 180 ° C (decomp.).
F, (KBG), cm-: 3400, 1750, 1630.
UV l m «ks (ethanol), nm (): 268 (12000), 276 (10000), 384 (23000).
IR, (DVg cm-: 3300, 1780,
magnesium sulfate (3 g) and 40% chloroacetaldehyde (810 mg, 8.4 mmol). The mixture is stirred for 1.5 hours at a
IR, (DVg cm-: 3300, 1780,
.1720, 1680, 1620.
(ethanol), nm (E): 240
and then the filter 45 (21000), 290 (12000).
yut. The filtrate is eluted on NMR silica gel, J (DMSO +): 3.67
(2H, multiplet, 2-H), 5.29 Mon. doublet, 5, 6-Nt 5.95 (1H, doublet, 5, 7-H), 6.27 (1) 2H, oak (Bako C-200 gel, 100 g, containing 0 ml 1 / 1.5 M phosphate buffer) on
CHC1,
column using CHCl v.iiwj.j,
containing methanol. Fractions containing 50 years, J 11, 3-CH cis), 6.72 (1) 2H,
doublet, j .1 6 3 -CH trans, 6.87 and 6.96 (each 1-2H, singlet, CHPh), 7.4 (YUN, multiplet, Ph-H).
The desired product (0.5-1% methanol / chloroform) is evaporated in vacuo to give 1.6 g (30%) of the desired compound VIII-I as a yellow amorphous powder, which is a mixture of Z and E isomers relative to the chloropropenyl parts (according to NMR). M.p. higher
IR, (DVg cm-: 3300, 1780,
years, J 11, 3-CH cis), 6.72 (1) 2H,
doublet, j .1 6 3 -CH trans, 6.87 and 6.96 (each 1-2H, singlet, CHPh), 7.4 (YUN, multiplet, Ph-H).
EXAMPLE 7 Benzhydryl 7- 2- (5-amino-1,2, 4-thiadiazol-3-yl) -2-meth-hydroxyiminoacetamido) -3- (3-iodo-1-propene -1-yl) -3-cephem-4-carboxylate (E isomer).
A mixture of compound VIII-I (Z isomer) (28.5 g, 90% purity) and sodium iodide (19 g) in dry acetone (420 ml) was stirred for 10 minutes at room temperature and left to stand for 2 h. The mixture is concentrated under reduced pressure. Ethyl acetate (420 ml) and a 10% w / v aqueous solution of sodium thiosulfate (30 ml) were added to the residue, and the mixture was shaken. The organic layer is passed over with water (30 ml), dried over magnesium sulphate and evaporated to about 50 ml volume. The concentrate was diluted with n-heptane (200 ml) to obtain 30.6 g (95% purity) of the title compound (E isomer) as a yellow powder, melting with more (fold).
IR, l) „, KVg, cm-: 3400, 1780, 1725, 1680, 1620.
UV, ethanol, nm (): 306 (15000).
NMR, ppm (acetone d): 3.71 (2H, multiplet, 2-H), 3.97 (3N, synglet, OCH3), 4.0 2H, doublet. 8 Hz, CH1), 5.26 (W, doublet, J 4.5 Hz, 6-H), 6.03 (1H, dd, J 4.5 and 8 Hz, changed to doublet J 4, 5 Hz under the action of fljO, 7-H), 6.32 (1H, d-t, and 8 Hz,), 6.79 (W, doublet, J 15 Hz, 3-CH), 6.98 (W, singlet, CHPh 5), 7.35. (Yun, multiplet, Ph-H), 7.63 (2H, broad singlet, disappeared under the action, NH), 8.52 (1H, doublet, Z 8 Hz, disappeared under action, 7-Sh).

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of cellleporin formula
N o-surrendered-m-1
H, o4f CH CH-CHrB2
i coaxial (SbN5) g
where R is C, -C4 alkyl;
R1 is a chlorine or iodine atom, characterized in that the compound of the formula
H2N.-Y Q NY CH2C1
SOOCH (SbN5) 2 VNIIPI Order 6855/58
subjected to the interaction of the hydride acid of the formula
Ts n-COOH
H
L
ga N
OR
one
g 0
5 0 5
0
five
0
where R has the indicated meanings, in an anhydrous organic solvent environment at a temperature of (-30) - - (-10) C, a compound of the formula o is formed.
5 17 i-CONH-r-YS HzN S and. O- CHaCl:
ORi СООСН (СБН5) 2
where R has the indicated meanings, is reacted with sodium iodide or potassium in an anhydrous organic solvent at room temperature, forming a compound of the formula
ISj-jT-G-CONH-T-Y 1
SOVSNSbNz)
where R, has the indicated meanings, is reacted with triphenylphosphine in an organic solvent at room temperature, a compound of the formula
S
N 2 S
cj-afNH-T © r®
(C6H5) j
0
SOOCH (SbN5) 2
OR vuwvviivu6ii5; 2
where R has the indicated meanings, is reacted with an alkali metal hydroxide in an organic solvent at room temperature to form a compound. mules. (,
K fj-COl Hr-H and (CbH5) g ORiCOOCH (CbH5) 2
where R., has the indicated values, is reacted with chloroacetaldehyde in an organic solvent at room temperature and. The target product, where R is a chlorine atom, B7I, is reacted with sodium or potassium iodide in anhydrous organic solvent at room temperature to obtain the desired product, where RI is an iodine atom. Irage 370 Subscription
five

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引用文献:

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US5126336A|1990-08-23|1992-06-30|Bristol-Myers Squibb Company|Antibiotic c-3 catechol-substituted cephalosporin compounds, compositions and method of use thereof|

AT396108B|1991-08-21|1993-06-25|Biochemie Gmbh|NEW PROCESS AND NEW INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF 7-AMINOCEPHALOSPORANIC ACID DERIVATIVES|

KR100248851B1|1994-08-16|2000-04-01|이치로 키타사토|A novel cephem derivative|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

US59794184A| true| 1984-04-09|1984-04-09|

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