前苏联专利SU1380612A3 Method of producing active thio ether of (z)-2-(2-amino-4-thiazolyl)-2-alkoxycarbonylalkoxyiminoacet

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专利摘要:
The invention relates to the production of - .. d-nig thiazole (PTA), in particular the preparation of compounds of the general formula H NCrrN-CK-CH-S, where (0) RJ N-0-C (R,), - C (0) - OR 1- 2 3 RF, - 2-benzothiazolylthio, R 2 And or n. lower alkyl, R carboxyl protected by tert-butyl or p-nitrobenzyl,. which, as intermediates, can be used to obtain 1-sulfo-2-oxo-azetidine derivatives with antimicrobial and f-lactobazo-inhibitory properties. The goal is to find substances of the specified class, which are intermediate in the synthesis of valuable pharmacological products. PTA is synthesized from the corresponding acid (with R - OH) and 2,2-dithio-bis-benzothiazole in an inert organic solvent (acetonitrile) in the presence of N-methylmorpholine and phosphite (triethyl phosphite). 1 tab. ABOUT
公开号:SU1380612A3
申请号:SU853909204
申请日:1985-06-20
公开日:1988-03-07
发明作者:Кичимото Чойи；Матсуо Тайсуке；Осиаи Мисихико
申请人:Такеда Кемикал Индастриз,Лтд (Фирма)；
IPC主号:

专利说明:

OS
wasp
from about:
tc
The invention relates to the chemistry of heterocyclic compounds, in particular, to a process for the preparation of a novel active thioether of (Z) -2- - (2-amino-4-thiazolyl) -2-alkoxycarbonylalkoxyiminoacetic acid derivatives of the general formula
S
Tj
N-C-COR II
to
0
one
(I)
"2-1- 2
SOOKz
where R, is 2-benzothiazolylthio;
RJ is hydrogen or unbranched lower alkyl EZ is a carboxy-protecting group such as t-butyl or p-nitrobenzyl,
which are intermediates for the preparation of new 1-sulfo-2-oxo-azetidine derivatives, which have antimicrobial and -lactamaso-inhibiting properties.
The aim of the invention is to provide a method for producing new derivatives of general formula (I), which are intermediates in the synthesis of valuable biologically active compounds.
In all the examples given, elution was performed in the case of thin layer chromatography (TLC), unless otherwise indicated. TLC analysis was performed using Merck 60F 254 as a TLC plate, used as eluent in column chromatography, solvent was used as a developing solvent, and UV detectors were used for detection. As an auxiliary method for detecting the spot, a TLC plate is sprayed with 48% HB, hydrolyzed by heating, sprayed with ninhydrin reagent and reheated to determine the spot color (from red to reddish). The fractions thus confirmed for the content of the target compound are collected. A reference to two different solvents developing means that, unless otherwise indicated, the by-products are eluted with the first solvent and the target compound with the second. As regards cleaning procedures using
ten
15
20
25
thirty
35
40
45
50
55
Amberlite or Sephadex, then first pass water, and then aqueous ethanol with an increasing concentration gradient. When drying, anhydrous sodium sulfate is mainly used as a desiccant.
Amberlite, Dowex and Sephadex are products of Rom and Haas (USA), Dow Chemical and Farmacy Chemicals, respectively. 5IMP spectra are measured using tetramethylsilane as an internal or external reference and an EM390 (90 MHz) or 1 (60 MHz) spectrometer.
Example 1. A. After dissolving 191.2 g (1.25 mol) of p-nitrobenzyl alcohol in 250 ml of methylene chloride, 98.9 g of pyridine are added and the mixture is cooled to (-5) - 0 ° C. A solution of 193.75 g (1.25 mol) of chloroacetoacetylchlornd in 431 ml of methylene chloride is added over 1 hour, and the mixture is stirred for 30 minutes. The resulting pyridine hydrochloride is filtered off. The filtrate and washes were combined and washed with two 2-liter portions of water. The organic layer is dried over sodium sulfate and the solvent is then distilled off to obtain 354 g of p-nitrobenzyl-chloroacetoacetate as an oil. ,
NMR spectrum (HSCS) f, ppm: 3.80 (2H, singlet,) 4.30 (2H, singlet, ClCHjCO); 5.27 (2H, singlet, SOOSN C N); 7.50 (2H, doublet, 1 8 Hz, aromatic protons) i 8.15 (2H, doublet, I 8 Hz, aromatic protons).
B. In 100 ml of acetic acid, 50 g (0.184 mol, excluding purity) of the crude p-nitrobenzyl-y-chloroacetoacetate obtained in step A is dissolved, and the solution is cooled to or below, a solution of 12.7 is added. g (0.184 mol) of sodium nitrate in 50 ml of water for 1 hour. After that, the mixture is stirred for 30 minutes, poured into 600 ml of ice water and extracted with 300 and 200 ml portions of ethyl acetate. l The organic layers are combined and washed with acetic sodium chloride, dried over sodium sulfate and concentrate) rt to dryness to give 54.0 g of p-nitrobenzyl-c / -hydroxymino-chloroacetocetate as an oil.
NMR spectrum (CDClI) sc, ppm: 4.60 (2H, singlet, ClCHjCO), 5.40 (2H. Singlet, COOCHjC Hj; 7.52 (2H, doublet, Hz, aromatic protons), 8.12 (2H, doublet, Hz, aromatic protons),
at. In a mixture of 225 ml of ethanol and 225 m of water, 50 g (0.167 mol, excluding purity) of the crude p-nitroben zyl-c / -hydroxyimino-chloroacetoacetate obtained in step B are dissolved and 12.7 g ( 0.167 mol of thiourea and 22.7 g (0.167 mol) of sodium acetate trihydrate. The reaction is carried out at room temperature for 6 hours. After the addition of 900 ml of water, an oil-like product is separated. After stirring for 30 minutes, the oil is separated and 400 ml of ethyl acetate is added, after which crystals precipitate. After cooling, the crystals are filtered through, washed with a small amount of ether, and dried to obtain 14.9 g of p-nitrobenzyl-2- (2-amino-4-thiazolyl) -2-hydroxyimino acetate.
IR (KBG), cm: 3400, 3300, 3180, 31100, 1730, 1615, 1525, 1360.
NMR spectrum (d 4 - DMCO) f. ppm: 5.57 (2H, singlet, COOCH C HJi 6.95 (1H, singlet, thiazole. 5H), 7.22 (2H, singlet,); 7.80 (2H, doublet, Hz, aromatic protons) , 8.35 (2H, doublet, I 8 Hz, aromatic protons),
D. In 60 ml of acetonitrile, 3.0 g (9.3 mmol) of p-nitrobenzyl -2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetate obtained in Step B are suspended and 2.0 g ( 1.03 mmol) tert-butyl bromoacetate, 0.3 ml water and 5.14 g (37 mmol) of anhydrous potassium carbonate in the indicated order. The mixture was stirred at 40-41 ° C for 1 hour. After completion of the reaction, the mixture was poured into 300 ml of water and extracted with 300 ml of ethyl acetate. The organic layer is washed with three portions of 300 ml of 5% aqueous sodium chloride, dried over sodium sulfate and concentrated to 30 ml under reduced pressure. 100 ml of ether are added to the concentrate, and the mixture is cooled to 5 ° C or lower. The resulting crystalline precipitate is collected by filtration, washed with a small amount of ether, and dried in vacuo to give 2.7 p- -nitrobenzyl- (7) -2- (2-amino-4-thiazo)
0 5
ABOUT
Q with
five
0
five
lil) -2- (tert-butoxycarbonylmethoxy-imino) acetate.
IR spectrum l | (KBG). cm-: 3420, 3250, 3150, 1735, 1620, 1528, 1390, 1360.
NMR spectrum (ds - DMCO) f, ppm: 1.47 (9H, singlet, CH, x 3); 4.61 (2H, singlet, NOCH.jCOO); 5.50 (2H, singlet, COOCH C.HJ; 6.92 (1H, singlet, thiaool. 5H); 7.24 (2H, broad singlet, NH, ;-); (2H, doublet, Hz, aromatic protons), 8.26 (2H, doublet, Hz, aromatic protons).
D. In 1.2 l of tetrahydrofuran, 20 g (mmol) of p-nitrobenzyl- (Z) -2- (2-amine-4-thiazolyl) -2- (tert-butoxycarbonylmethoxyiminoimine) acetate is dissolved 20 g of 10% palladium-on-carbon hydrogen gas is passed through the solution. After completion of the reaction, the catalyst is filtered off and the filtrate is poured into 300 ml of water. The mixture is adjusted to pH 8 by the addition of 5% aqueous sodium bicarbonate and sold in three portions of 200 ml of ethyl acetate. The aqueous layer is adjusted to pH 2 by the addition of 10% HC1 and cooled to or below. The resulting crystalline precipitate is collected by filtration, washed with water and dried under reduced pressure to obtain 11.1 g (g) -2- (2-amino-4-thiazolyl) -2- - (tert-butoxycarbonylmethoxyimino) acetic acid .
IR spectrum (KBG), cm-: 3100, 3120, 1740, 1610, 1605, 1585.
NMR spectrum (dt-DMCO) (f, ppm: 1.50 (9H, singlet, 3); 4.78 (2H, singlet, NOCHjCOO), 6.86 (1H, singlet, thiazole. 5H).
E. In 140 ml of dry acetonitrile, 5.42 g (18 mmol) of (Z) - -2- (2-amino-4-thiazolyl) -2- (tert-butocarbonylmethoxyimimino) acetic acid are suspended, 2.96 g ml (27 mmol) of N-methylmorpholine, and then 7.2 g (21.6 mmol) of bis-benzothiazol-2-or-disulfide, and the mixture is cooled to 0 ° C. A solution of 5.38 ml (31.4 mmol) of triethyl phosphite in 35 ml of dry acetonitrile is added dropwise over 4.5 hours and the mixture is stirred at this temperature for 30 minutes and then cooled to. The resulting crystalline precipitate is collected by filtration, washed with a small amount of acetonitrile, and dried under reduced pressure to obtain 5.1 (g) -2- (2-amino-4-thiazolyl) -2- (tert-6-oxycarbonylmethoxyimino) acetic acid 2 -benzothiazolyl thiol ester.
IR spectrum (KBG), cm-: 3400, 3120 1738, 1710, 1620, 1540, 1450, 1415, 1370.
NMR spectrum (dj-DMCO) f, ppm -: 1.50 (9H, singlet, CH, x 3) 4.78 (singlet,); 7.10- (1H, singlet, thiazole; 1H); 7.4-7.65 (2H, multiplet, aromatic protons); 8.0-8.3 (2H, multiplet, aromatic protons).
Example 2. 43 g of 2- (2-bromo-2-) are treated with 43 g of 2- (2-amino-4-thiazolyl) -2- (Z) -hyroxyiminoacetic acid ethyl ester in 1.2 l of dimethylformamide. -methyl propionic acid of t-butyl ether and 110.6 g of powdered potassium carbonate. After stirring for 12 hours at 45 ° C, the reaction mixture is cooled to room temperature, 4 liters of water are added, the mixture is extracted with 3.5 liters of ethyl acetate. After washing the organic extract with water, drying with magnesium sulfate and evaporation to a dry residue, 2- (2-amino-4-thiazolyl) -2- (7.) - 1- (tert-butoxycarbonyl) -1- methylethoxy imino} acetic acid ethyl ester, which, after recrystallization from ether, is melted at. I
240 g of the ethyl ether thus obtained is stirred for 12 hours at 50 ° C with 1.3 liters of methanol and 1.34 liters of 1N. aqueous solution of caustic soda. After distillation of methanol, washing the aqueous phase with ethyl acetate and adding 1.34 l of 1N. the aqueous hydrochloric acid product crystallizes. The crystals are filtered off, washed successively with water, acetonitrile and ether and dried under vacuum at 40 ° C. After stirring for 2 hours in acetonitrile (to remove water of crystallization), filtering and drying under vacuum at 40 ° C, 2- (2-y 4-thiazolyl) -2- - C (g) -1- (tert-butoxycarbonyl) -1- -methyl-ethoxy immuno-acetic acid, t. Pl. 178-179 C.
28.8 g of the acetic acid derivative obtained in this way
,,
,, 0
., jn 25 35 dd. d5 50
55
poured into 360 ml of acetonitrile. 14.4 ml of N-α-methylmorpholine are added with stirring, and after 10 minutes, 34.6 g of 2,2-dithio-bis-benzothiazole are added. The suspension is cooled to 0 ° C, 20.2 ml of triethyl phosphite is slowly added over 2 hours and the suspension is stirred for another 12 hours at 0 ° C. The product is filtered, washed successively with cold acetonitrile, isopropyl ether and petroleum ether, and dried at room temperature under vacuum. The 2- (2-amino-4-thiazolyl) -2- {C (Z) - -1- (tert-butoxycarbonyl) -1-methyl-ethoxy-imino acetic acid, 2-benzothiazolptioether, m.p. 139-140 ° C.
Example 3. A 1.0 l flask was charged with 0.06 kg (0.2508 mol) of (3S, 48) -amino-4-carbamoyloxymethyl -2 -2 azetidinone-1-sulfonic acid and 0.9 g of methylene chloride to form a suspension, while stirring the suspension at 10-20 ° C, 0.070 kg (0.2508 X 2 mol) of triethylamine is added, and then 0.124 kg (0.2508 x 1.1 mol) of (Z) -2- (2-amino-4- thiazolyl-2-tert-butoxycarbonylmethoxyimino) acetic acid 2-benzothiaoolylthioether, the mixture is stirred at 25-27 ° C for 4 hours. The insoluble matter is filtered off and the filtrate is further stirred for 1 hour and extracted with 0.9 l of water. The aqueous layer was washed with 0.19 L of methylene chloride, 0.38 L of ethyl acetate and 0.19 L of methylene chloride in this order. After degassing, 0.45 L of concentrated hydrochloric acid was added and the mixture was stirred at 25 ° C for 2 hours. To the resulting suspension, 0.9 L of water was added and the mixture was stirred for 2 hours and then left to stand overnight at 0-2 ° s The resulting precipitates are collected by filtration and flush with 0.6 l of cold water to give 0.27 kg of (3S, 45) (2-amino-4-thiazolyl) - (Z) -2- (carboxymethoxyimino) acetamido-4-carbamoyloxymethyl -2-azetidinone-1-sulfonic acid in the form of wet crystals. I
Example 4. 1.62 g of sodium salt (3S, 45) -3-amino-4-carbamoyl-methyl-2-oxo-1-azetidine sulfonic acid in 180 ml of a mixture of acetone and water (2: 1) is mixed with 3, 87 g of (Z) -2- - (2-amino-4-thiazolyl) -2-G1- (tert-butoxycarbonyl) -1-methylethoxy-imino acetic acid 2-benzothiazolyl-thioether at room temperature for 15 h. After removing acetone in vacuo and adding 50 ml of water, crystals are obtained which are washed with water. The mother liquor is evaporated under reduced pressure at and chromatography (MS-gel, eluting with water). After lyophilization, the (3S, 4S) -3- (2-amino-4-thiazolyl) -2- (g) - (1-tert-butoxycarbonyl) -1-methyl-ethoxy) imino acetamido} -4 sodium salt is obtained. -carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid.
IR spectrum (KBG), cm-: 1766, 1723 1683, 1617, 1531, 1458, 1369.
NMR spectrum (d-DMCO), ppm: 1.35 (16H, singlet) 5, C-4.15 (3N, H and CHj-OCONH2) i 5.25 (1H, double doublet, HI) -, 6.5 (2H, broad SOMP); 6.7 (1H, singlet, N-thiazole); 7.25 (2H, singlet, NH); 8.9 (1H, CO-NH doublet).
Example 5. 2.28 g of sodium salt of (3S, 4S) -3 {(2-amino-4-thiazolyl) -2- (Z) - (1- (tert-butoxycarbonyl) -1- -methyl-toxy) imino acetamido - 4-Carbamoyloxymethyl-2-oxo-1-azetidine sulfonic acid is stirred at 0 ° C with 5 ml of trifluoroacetic acid. After further stirring at room temperature for 30 minutes, excess trifluoroacetic acid is removed in vacuo and the remaining oil is treated with 100 ml of ether. The resulting crystals are filtered, washed with ether and dried in vacuo. The product is purified by reverse phase chromatography and lyophilized. Receive (3S, 4S) -3- {(Z) -2- (2-amino-4-thiazolyl) -2- t (1 - -carboxy-1-methlethoxy) -imino acetamido -4-carbamohl-2-oxo - -1-azetidine sulfonic acid; el
+ 35.7 ° (with 0.3 in water).
Calculated,%: C 34.01; H 3.67; N 17.00.
C ,, H, 0 ,, 5g
Found,%: C 34.52; H 3.72 N, 16.63.
IR Spectrum (KBG), 1764, 1722 1680, 1637.
NMR spectrum (d (-DMCO), ppm 1.50 (6H, singlet 2xCHj), 4.00-4.20 (OOH, CH-CH); 5.35 (1H, double doublet, 4.5 and 9 Hz, nr, 6.50 (ZN, wide W or DREAM, CONH.,); 6.90 (1H
five
ginglet, triazolk. 5H); 9.15 (1H, doublet, 9 Hz, CONH).
Example 6. 6.1 g of 2- (2-amino-4-thiazolyl) -2 -2 (Z) -hydroxyiminoacetic acid tert-butyl ester in 250 ml of dry ap.etonitrile is stirred at room temperature with 13.7 g 4-nitrobenzyl ether
o bromoacetic acid and 12.9 ml of N- -ethyl diisopropylamine. After 5 minutes, 7.5 g of sodium iodide was added and the reaction mixture was stirred for an additional 3.5 hours under argon at room temperature. After distilling off the solvent, diluting with 500 ml of ethyl acetate, washing with water, drying over sodium sulfate, and evaporation to a dry residue, the 2- (2-amino-4-thiazolyl) 2-tert-butyl ester is obtained.
- (p-nitrobenzyloxycarbonyl) -methyl imino {acetic acid, which, after crystallization from ethyl acetate-n-hexane, melts at 146,
5 (different).
5.0 g of the tert-butyl ester thus obtained in 86 ml of acetic acid are mixed with 5.2 ml of boron trifluoride etherate. After stirring for 5 hours at room temperature and mixing with 260 ml of water, the precipitate obtained is filtered and dried under vacuum. 2- (2-amino-4-thiazolyl) -2- ((Z) - (p-nitrobenzyl-oxibarbonyl) - methoxy-imino} acetic acid is obtained, mp. 175 ° C (decomposition),
1.9 g of this acetic acid derivative in 30 ml of acetonitrile is mixed with 1.4 ml of N-methylmorpholine, 2.0 g of 2,2-dithio-bis-benzothiazole and 1.14 nl of triethylphosphite. After stirring for 1 hour at room temperature, the reaction mixture is cooled to and filtered. The filtrate is evaporated to dryness and it is crystallized from methyl chloride. A 2-benzothiazolyl thioester 2- - (2-amino-4-thiazolyl) -2- t (Z) - (n- -nitrobenzyloxycarbonyl) methoxy J-imino acetic acid is obtained, m.p. 124-1264.
Example 7. By analogy with Example 4, the reaction of 2-benzothiazolum-thioether 2- (2-amrto-4-thiazolyl) -2-5 - (g) - (p-nitrobenzyloxycarbonyl) - methoxyZimino} acetic acid with sodium salt (3S, 45) -3-amino-4- -carbamoyloxymethyl-2-oxo-1-azeti0
five
0
five
0
Dinsulfonic acid gives the sodium salt of (3S, 4S) -3- {(g) -2- (2-amino-4-thiazolyl) -2-G (p-nitrobenzylroxycarbonyl) methoxyimine Jatsetamide, j-4-carbamoylone, iyyyyyyyyyyyyyyyyyyyyvayyyyyyyykoziiminojatsetamido, j-4-karbeniloksikoarbonil) metoksiiminojatsetamido j-4-karbatomidomido j-4-karbatomido, iyyyyu 2-oco-1-acetyl acid phosphonic acid.
Calculated,%: C, 36.60; H 2.91; N 15.73; S 10.28.
С „Н ,, N, 0 ,, SjNa
Found,%: C 37.00; H 2.88, - N 15.74; S 10.45.
IR spectrum (KBG), 3353, 1761, 1729, 1524, 1348.
NMR spectrum (d -DMCO) o, 4.0-4.2 (3N, multiplet, CH - CHj); 4.7 (2H, singlet, 0-CH,); 5.30 (1H, double doublet, NH-CH-); 5.32 (2H, singlet, O-CH), 6.70 (2H, broad, NH,), 6.9 (1H, singlet, S-CH-); 7.10 (2H, broad, Wg) -, 7.70 and 8.2 (2x
x2H, 2 doublets, 2x3H, aromatics); 9.15 (1H, doublet, 9 Hz, NHCO).
The MIC value — the minimum inhibitory concentration — for each test compound is determined by the agar dilution method. Thus, an initial aqueous solution of each test compound is sequentially diluted and the resulting dilution series are applied to Petri dishes. Then, 9.0 ml of trypticose soybean agar per dish is added and mixed. Each of the agar plates is infected with a suspension of the experimental organism (about 10 C Pu / ml). After cultivation at 37 ° C overnight, the minimum concentration of the test compound, which provides complete inhibition of the growth of the organism, is taken as the MIC value.
The results of the analyzes are shown in the table.
Test compound
CNS-3- 2- (2-amino-4-thiazole1) -2- (Z) -methoxyiminoacetamido-4-carbamoyl-2-azetidinone-1-sodium sulfonate
Cys-3- 2- (2-amino-4-thiazolyl) -2- (g) - (1-carboxy-1-methylethoxyimino) acetamido-4-ureidomethyl-2-azetidinone-1-sulfonic acid
Monosodium-cis-3- 2- (2-amino-4-thiazolyl) -2- - (Z) - (1-carboxy-1-metsh1 toximimino) acetamido-3-pyridine-1-azetidinone-1-sulfonate
Cys-3- 2- (2-amino-4-thiazole1) -2- (g) - (1-carboxy-1-methylethoxyimino) acetamido-4-methoxymethyl-2-azetidinone-1-sulfonic acid
Cys-3- 2- (2-amino-4-thiazole1) -2- (g) - (1-carboxy-1-met1shethoxyimino) ac8tamidoJ-4-methylsulfoninylmethyl-azevdinon-1-sulfonic acid
Cys-3- 2- (2-amino-4-thiazolyl) -2- (g) -1-carboxy-1-methylethoxyimino) acetamido} -4-methylsulfonylmethyl-2-azetidinone-1-sulfonic acid
The value of MIC, µg / ml, using experimental organisms
E.coli 0-111
K. pneumoniae DT
0.39
3.13
12.5
0.2
0.78
1.56
Test compound
Cys-3- 2- (2-amino-A-thiazolyl) -2- (g) - (1-carboxy-1-methylethoxyamino) acetamido-4-(2-methoxy-carboxyl ethyl) 2-azetidinone-1- sulfonic acid
Sodium (3S, 45) -trans-3-f 2- (2-aminothiazol-4- -yl) -2- (7) -methoxyimino 1 azetamido-A- (2-hydroxypropyl) -2-azevdinon-1-sulfonate
Sodium (3S, 4S) (2-aminothiazol-4-yl) -2- - (Z) - (1-carboxy-1-methyl-ethoxyimino) acetami-1-4-propyl-2-azetidine-1-sulfonate
Cys-3- 2- (2-amino-A-thiazolyl) -2- (7) -carboxy-methoxyiminoacetamido1-4-methoxymethyl-2-azetidinone-1-sulfonic acid
Sodium (3S, 4S) (2-aminothiazol-4-yl) -2- - (Z) - (1-carboxy-1-methyl tylo current ci tmino) acetamido-4- (2-oxopropyl) -2-azetidinone- 1-sulfonate
Sodium (35, 4K) -Cis-3- (2-aminothiazol-4-yl) -2 -2 (g) methoxyimino acetamido-4- (2-oxopropyl) -aootgmtm t -1- / lgtt-Lch / and pgg
partrievj, chk-cis-j-L -2- (g) -methoxyimino ace j l -2-azetidinone-1-sulfonate
OOSN,
Known compound
ABOUT

权利要求:
Claims (1)
[1]
Thus, the proposed method allows to obtain compounds of general formula (I), which are intermediate in the synthesis of valuable biologically active compounds. Invention Formula
Method for preparing active thioate of (g) -2- (2-amino-4-β-thiazolyl) -2-al-coxycarbonylalkoxy-iminoacetic acid derivatives with the general formula
N-C-CORi and
N (I)
0
"2-4- 2
COOR
VNIIPI Order 994/59
The value of MIC, when using experimental organisms
E.coli 0-111
K.pneumoniae DT

6.25 6.25 12.5
3.13
12.5
3.13 1, OOP
3.13
0.78 0.1 3.13
3.13 1,000
Where R is 2-benzothiazolylthio,
R is hydrogen or unbranched lower alkyl
carboxyl group such as tert-buty.n or p -nitrobenzyl,
characterized by the fact that the corresponding general acid of formula (I), where K, is OH, is reacted with 2,2-dithio-bis-benzothiazole in an inert organic solvent that does not have hydroxyl groups in a molecule, such as acetonitrile in the presence of an organic base, such as N-methylmorpholine, and phosphite, such as triethyl phosphite.
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FR2496666A1|1982-06-25|NOVEL CEPHALOSPORINE DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME

FR2576596A1|1986-08-01|PROCESS FOR THE PREPARATION OF 4,4-DIALKYL-2-AZETIDINONES, AND NOVEL COMPOUNDS THUS PREPARED

FR2485016A1|1981-12-24|PHOSPHONIC ACID DERIVATIVES OF | OXIMINO) -7 CEPHALOSPORINS, PARTICULARLY USEFUL AS ANTIBACTERIAL MEDICINES

SE445350B|1986-06-16|OXIMO DERIVATIVES OF 3-AZIDOMETHYL-7-AMINO-THIAZOLYL-ACETAMIDO-CEPHALOSPORANIC ACID AND ITS USE AS ANTIBIOTICS

同族专利:

公开号 | 公开日

ZA832742B|1983-12-28|

CS520584A2|1990-02-12|

DD236930A5|1986-06-25|

DD232490A5|1986-01-29|

CS647985A2|1990-02-12|

JPS58189176A|1983-11-04|

JPS6334155B2|1988-07-08|

引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

FR2515182B1|1981-10-23|1986-05-09|Roussel Uclaf|NOVEL PRODUCTS DERIVED FROM 3-AMINO 2-OXO AZETIDINE 1-SULFAMIC ACID, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS AND THE INTERMEDIATE PRODUCTS NECESSARY FOR THEIR PREPARATION|

JPH0321542B2|1983-04-28|1991-03-22|Takeda Chemical Industries Ltd|

WO2015148379A1|2014-03-24|2015-10-01|Novartis Ag|Monobactam organic compounds for the treatment of bacterial infections|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

JP57073728A|JPS6334155B2|1982-04-30|1982-04-30|

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