CN104892674B - Preparation method of ceftaroline fosamil - Google Patents
Preparation method of ceftaroline fosamil Download PDFInfo
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- CN104892674B CN104892674B CN201510339882.9A CN201510339882A CN104892674B CN 104892674 B CN104892674 B CN 104892674B CN 201510339882 A CN201510339882 A CN 201510339882A CN 104892674 B CN104892674 B CN 104892674B
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Abstract
The invention provides a preparation method of ceftaroline fosamil. The method comprises steps as follows: adding a raw material, namely, 7beta-[(phenylacetyl)amino]-3-[4-pyridyl-2-thiazole thio]-3-cephem-4-carboxylic acid diphenylmethyl ester, to a PCl5/pyridine system, and performing hydrolysis on an amido bond to obtain an intermediate I; suspending the intermediate I in acetonitrile, slowly dropwise adding concentrated hydrochloric acid, performing hydrolysis on an ester group to obtain an intermediate II; dissolving the intermediate II in acetonitrile, adding 2-(5-dichlorophosphorylamino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetylchloride for a reaction to obtain an intermediate III; dissolving the intermediate III in DMF (dimethyl formamide), adding iodomethane for a reaction, adding methanol after the reaction, and obtaining a final product through crystallization. According to the preparation method of the ceftaroline fosamil, the intermediate obtained in each step of reaction and the final product can have higher purity without purification treatment, the production technology is simplified, the product yield is increased, and the production cost is reduced.
Description
Technical field
The present invention relates to a kind of preparation method of cephalosporins medicine is and in particular to a kind of preparation method of Ceftaroline Fosamil.
Background technology
CPT is the 5th generation cephalosporinses being derived from forth generation cephalosporin cefozopran, main
It is used for treating the acquired bacterial pneumonia in Adults Community and acute bacterial skin and skin structure infection, it is by Japan's force field
Pharmacy and forest laboratories company develop jointly, list in the U.S. in October, 2010.CPT is to many
The gram positive bacteria of weight drug resistance has good antibacterial activity, the effect of its mechanism of action and other beta-lactam antibacterials
Mechanism is the same, is also by acting on penicillin-binding protein, thus disturbing the synthesis of bacteria cell wall, playing antimicrobial and making
With.Experiment shows, Ceftaroline Fosamil is anti-with the appearance of other combination with medication short of money, can share with second antibacterials, have
Good development prospect.
A kind of method of synthesis Ceftaroline Fosamil is disclosed, it is with 7 β-[(benzene in the patent of grant number cn1189471c
Acetyl) amino] -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid benzhydryl ester be raw material, successively through methyl
Change, amido link hydrolysis, hydrolysis of ester group, draw side chain on 7, finally give 3- [4- (1- methyl -4- pyridine) -2- thiazole sulfur
Base] -7 β-[2-(5- phosphinylidyne amino -1,2,4- thiadiazoles -3- base) -2(z)-ethoxy imino acetylamino] -3- cephem -
4- carboxylic acid.The purity of the method gained intermediate and final products is all relatively low, generally requires substantial amounts of post processing and can be only achieved relatively
Good purity, this makes production operation become complicated, and production cost is greatly improved, and is unfavorable for industrialized production.
Content of the invention
It is an object of the invention to provide a kind of preparation method of Ceftaroline Fosamil, to solve to carry present in prior art
Pure complex operation and the high problem of production cost.
The object of the present invention is achieved like this:
A kind of preparation method of Ceftaroline Fosamil is it is characterised in that comprise the following steps:
A. by raw material 7 β-[(phenylacetyl) amino] -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid two
Benzyl esters are added to pcl5In/pyridine System, question response finishes, and reactant liquor is added in isobutanol, crystallize, obtains intermediate
ⅰ；
B. above-mentioned intermediate is suspended in acetonitrile, is slowly dropped into concentrated hydrochloric acid, question response finishes, add in reactant liquor
Ethyl acetate, crystallize, obtain intermediate；
C. above-mentioned intermediate is dissolved in acetonitrile, adds 2- (5- dichlor-phosphoryl amino -1,2,4- thiadiazoles -3- bases) -2
Z ()-ethoxy imino chloroacetic chloride is stirred at room temperature reaction, question response finishes, cooling, addition silylating reagent, stirring reaction, with
Afterwards reactant liquor is poured in frozen water, add oxolane, crystallize, obtain intermediate；
D. above-mentioned intermediate is dissolved in dmf, adds iodomethane, reaction, question response finishes, add methanol, crystallize, obtain
3- [4- (1- methyl -4- pyridine) -2- thiazole sulfenyl] -7 β-[2-(5- phosphinylidyne amino -1,2,4- thiadiazoles -3- base) -2(z) -
Ethoxy imino acetylamino] -3- cephem -4- carboxylic acid.
Preferably, 7 β-[(phenylacetyl) amino] -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem in described step a -
4- carboxylic acid benzhydryl ester and pcl5Mol ratio be 1:2 ~ 5, be 1:2 ~ 5. with the mol ratio of pyridine
Preferably, the intermediate in described step b and the mol ratio of concentrated hydrochloric acid are 1:20 ~ 80.
Preferably, the silylating reagent in described step c is n, double (trimethyl silane) acetamide of o- or trimethylchloro-silicane
Any one in alkane.
Preferably, the intermediate in described step d and the mol ratio of iodomethane are 1:2 ~ 5.
The reaction equation of the method is:
The preparation method of the Ceftaroline Fosamil that the present invention provides, every single step reaction gained intermediate and final products need not carry
Pure process can reach very high purity, thus enormously simplify production technology, reduces production cost, improves product and receives
Rate.
Specific embodiment
In the examples below, the various processes not described in detail and method are conventional methods as known in the art, institute
With reagent do not indicate source, specification be commercially available analysis pure or chemical pure.
The structure of intermediate and end-product is characterized by nuclear magnetic resoance spectrum.
Embodiment 1
Amido link hydrolyzes: weighs 7.37gpcl5It is added in reaction bulb, take 49ml dichloromethane to be added in reaction bulb, cooling
To 5 DEG C；Weigh 2.8g pyridine slowly to drip in reaction bulb, finish stirring 30min, weigh 7 β-[(phenylacetyl) amino] of 7.0g-
3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid benzhydryl ester, is added slowly in reaction bulb, after completion of the reaction
Reactant liquor instillation 100ml is cooled in -10 DEG C of isobutanol, after finishing stirring 10min, reaction bulb has been moved to and is stirred at room temperature
3h, sucking filtration, vacuum drying, obtain 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic acid two of 5.2g
Benzyl esters, yield 90%, purity 99%.
1h nmr (d6-dmso): δ 3.91(d, j = 6.0 hz, 2h), 5.33 (d, j = 6.0 hz, 1h),
5.44 (d, j = 6.0 hz, 1h), 8.99 (s, 1h), 7.23-7.25 (m, 1h), 7.27-7.30 (m, 3h),
7.32-7.34 (m, 2h), 7.38-7.42 (m, 4h), 8.38 (d, j = 6.0 hz, 1h), 8.91 (d, j =
6.0 hz, 1h).
The hydrolysis of ester group: weigh 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic acid of 5.0g
Benzhydryl ester is added in reaction bulb, adds 40ml acetonitrile, takes 42ml concentrated hydrochloric acid, be slowly dropped in reaction bulb, stirring while adding,
Finish, stirring reaction 0.5h, in reaction bulb, add 85ml ethyl acetate, stir 0.5h, sucking filtration, vacuum drying, obtain 2.6g
7 beta-amino -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid, yield 82%, purity 99%.
1h nmr (d6-dmso): δ 3.82 (d, j = 18.0 hz, 1h), 3.94 (d, j = 18.0 hz,
1h), 5.27 (d, j = 6.0 hz, 1h), 5.39 (d, j = 6.0 hz, 1h), 8.45 (d, j = 6.0 hz,
2h), 8.94 (d, j = 6.0 hz, 2h), 9.05 (s, 1h).
The introducing of side chain: weigh 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic acid of 1.5g
It is added in reaction bulb, adds 30ml acetonitrile, stirring makes it dissolve, weighs 2- (5- dichlor-phosphoryl amino -1,2, the 4- thiophenes of 2.56g
Diazole -3- base) -2 (z)-ethoxy imino chloroacetic chloride is added in reaction bulb, after reaction 45min is stirred at room temperature, reactant liquor dropped
Temperature, to 0 DEG C, weighs the n of 1.32g, and double (trimethylsilyl) acetamide of o- is dissolved in 8ml acetonitrile, and this solution is dripped to reaction bulb
In, stirring reaction 30min, question response finishes, and reactant liquor is poured in 30g ice, the thf of addition 15ml, 0 DEG C of stirring reaction 16h,
Sucking filtration, vacuum drying, obtain 3- [4-(pyridine radicals) -2- thiazole sulfenyl] -7 β-[2-(5- phosphinylidyne amino -1,2, the 4- thiophenes two of 1.99g
Azoles -3- base) -2(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid, yield 85%, purity 99%.
1h nmr (d6-dmso): δ 1.24 (t, j = 6.0 hz, 3h), 3.62 (d, j = 18.0 hz,
1h), 3.94 (d, j = 18.0 hz, 1h), 4.17-4.20 (q, j = 6.0 hz, 2h), 5.34 (d, j =
6.0 hz, 1h), 5.94-5.96 (m, 1h), 8.01 (d, j = 6.0 hz, 2h), 8.64 (s, 1h), 8.70
(s, 2h), 9.72 (d, j = 6.0 hz, 1h), 10.36 (d, j = 6.0 hz, 1h).
Methylate: weigh 3- [4-(pyridine radicals) -2- thiazole sulfenyl] -7 β-[2-(5- phosphinylidyne amino -1,2,4- thiophene of 0.5g
Diazole -3- base) -2(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid is added in reaction bulb, adds 5ml's
Dmf, stirring makes it dissolve, and weighs 0.32g iodomethane and instills to be stirred at room temperature in reaction bulb and react 3h, adds 20ml in reaction bulb
Methanol, sucking filtration after stirring 3h, vacuum drying, obtain 3- [4- (1- methyl -4- pyridine) -2- thiazole sulfenyl] -7 β-[2- of 0.47g
(5- phosphinylidyne amino -1,2,4- thiadiazoles -3- bases) -2(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid, receive
Rate: 75%, purity 98%.
1h nmr (d6-dmso): δ 1.22 (t, j = 6.0 hz, 3h), 3.45 (d, j = 18.0 hz,
1h), 3.82 (d, j = 18.0 hz, 1h), 4.21-4.24 (m, 2h), 4.24 (s, 3h), 5.28 (d, j =
6.0 hz, 1h), 5.79 (d, j = 6.0 hz, 1h), 8.19 (d, j = 6.0 hz, 2h), 8.37 (s,
1h), 8.62 (d, j = 6.0 hz, 2h).
Embodiment 2
Amido link hydrolyzes: weighs 4.31gpcl5It is added in reaction bulb, take 49ml dichloromethane to be added in reaction bulb, cooling
To 5 DEG C；Weigh 1.63g pyridine slowly to drip in reaction bulb, finish stirring 30min, weigh 7 β-[(phenylacetyl) ammonia of 7.0g
Base] -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid benzhydryl ester, it is added slowly in reaction bulb, reacted
After finishing, reactant liquor instillation 100ml is cooled in -10 DEG C of isobutanol, after finishing stirring 10min, reaction bulb has been moved to room temperature
Stirring 3h, sucking filtration, vacuum drying, obtain 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic of 5.2g
Sour benzhydryl ester, yield 90%, purity 98%.
The hydrolysis of ester group: weigh 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic acid of 5.0g
Benzhydryl ester is added in reaction bulb, adds 40ml acetonitrile, takes 14ml concentrated hydrochloric acid, be slowly dropped in reaction bulb, stirring while adding,
Finish, stirring reaction 0.5h, in reaction bulb, add 85ml ethyl acetate, stir 8h, sucking filtration, vacuum drying, obtain the 7 of 2.6g
Beta-amino -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid, yield 82%, purity 99%.
The introducing of side chain: weigh 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic acid of 1.5g
It is added in reaction bulb, adds 30ml acetonitrile, stirring makes it dissolve, weighs 2- (5- dichlor-phosphoryl amino -1,2, the 4- thiophenes two of 1g
Azoles -3- base) -2 (z)-ethoxy imino chloroacetic chloride is added in reaction bulb, after reaction 45min is stirred at room temperature, reactant liquor lowered the temperature
To 0 DEG C, the trim,ethylchlorosilane weighing 1.37g is dissolved in 8ml acetonitrile, this solution is dripped in reaction bulb, stirring reaction
30min, question response finishes, and reactant liquor is poured in 30g ice, adds the thf of 15ml, 0 DEG C of stirring reaction 16h, sucking filtration, vacuum is done
Dry, obtain 3- [4-(pyridine radicals) -2- thiazole sulfenyl] -7 β of 1.99g-[2-(5- phosphinylidyne amino -1,2,4- thiadiazoles -3- bases) -2
(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid, yield 85%, purity 98%.
Methylate: weigh 3- [4-(pyridine radicals) -2- thiazole sulfenyl] -7 β-[2-(5- phosphinylidyne amino -1,2,4- thiophene of 0.5g
Diazole -3- base) -2(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid is added in reaction bulb, adds 5ml's
Dmf, stirring makes it dissolve, and weighs 0.21g iodomethane and instills to be stirred at room temperature in reaction bulb and react 3h, adds 20ml in reaction bulb
Methanol, sucking filtration after stirring 3h, vacuum drying, obtain 3- [4- (1- methyl -4- pyridine) -2- thiazole sulfenyl] -7 β-[2- of 0.45g
(5- phosphinylidyne amino -1,2,4- thiadiazoles -3- bases) -2(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid, receive
Rate: 72%, purity 97%.
Embodiment 3
Amido link hydrolyzes: weighs 10.75gpcl5It is added in reaction bulb, take 49ml dichloromethane to be added in reaction bulb, cooling
To 5 DEG C；Weigh 4.08g pyridine slowly to drip in reaction bulb, finish stirring 30min, weigh 7 β-[(phenylacetyl) ammonia of 7.0g
Base] -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid benzhydryl ester, it is added slowly in reaction bulb, reacted
After finishing, reactant liquor instillation 100ml is cooled in -10 DEG C of isobutanol, after finishing stirring 10min, reaction bulb has been moved to room temperature
Stirring 3h, sucking filtration, vacuum drying, obtain 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic of 5.2g
Sour benzhydryl ester, yield 90%, purity 97%.
The hydrolysis of ester group: weigh 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic acid of 5.0g
Benzhydryl ester is added in reaction bulb, adds 40ml acetonitrile, takes 56ml concentrated hydrochloric acid, be slowly dropped in reaction bulb, stirring while adding,
Finish, stirring reaction 0.5h, in reaction bulb, add 85ml ethyl acetate, stir 0.5h, sucking filtration, vacuum drying, obtain 2.6g
7 beta-amino -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid, yield 82%, purity 99%.
The introducing of side chain: weigh 7 beta-amino -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- carboxylic acid of 1.5g
It is added in reaction bulb, adds 30ml acetonitrile, stirring makes it dissolve, weighs 2- (5- dichlor-phosphoryl amino -1,2, the 4- thiophenes two of 1g
Azoles -3- base) -2 (z)-ethoxy imino chloroacetic chloride is added in reaction bulb, after reaction 45min is stirred at room temperature, reactant liquor lowered the temperature
To 0 DEG C, the trim,ethylchlorosilane weighing 1.37g is dissolved in 8ml acetonitrile, this solution is dripped in reaction bulb, stirring reaction
30min, question response finishes, and reactant liquor is poured in 30g ice, adds the thf of 15ml, 0 DEG C of stirring reaction 16h, sucking filtration, vacuum is done
Dry, obtain 3- [4-(pyridine radicals) -2- thiazole sulfenyl] -7 β of 1.99g-[2-(5- phosphinylidyne amino -1,2,4- thiadiazoles -3- bases) -2
(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid, yield 85%, purity 98%.
Methylate: weigh 3- [4-(pyridine radicals) -2- thiazole sulfenyl] -7 β-[2-(5- phosphinylidyne amino -1,2,4- thiophene of 0.5g
Diazole -3- base) -2(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid is added in reaction bulb, adds 5ml's
Dmf, stirring makes it dissolve, and weighs 0.53g iodomethane and instills to be stirred at room temperature in reaction bulb and react 3h, adds 20ml in reaction bulb
Methanol, sucking filtration after stirring 3h, vacuum drying, obtain 3- [4- (1- methyl -4- pyridine) -2- thiazole sulfenyl] -7 β-[2- of 0.47g
(5- phosphinylidyne amino -1,2,4- thiadiazoles -3- bases) -2(z)-ethoxy imino acetylamino] -3- cephem -4- carboxylic acid, receive
Rate: 75%, purity 98%.
Comparative example
Methylate: weigh 7 β-[(phenylacetyl) amino] -3- [4- pyridine radicals -2- thiazole the sulfenyl] -3- cephem -4- of 12g
Carboxylic acid benzhydryl ester, is dissolved in 30mldmf, adds 7.54g iodomethane, 2h is stirred at room temperature, reaction finishes, and adds 10 times of volumes
Ethyl acetate, stirs 1h, has grease to adhere to bottle wall, clear liquid is poured out, add ethyl acetate, and stirring separates out yellow solid
Body, sucking filtration, it is dried, obtain product 12.32g, yield: 90%, purity: 90%.
Amido link hydrolyzes: weighs 6.32g phosphorus pentachloride, is suspended in the dcm of 70ml, is slowly added into 2.37g under the conditions of 0 DEG C
Pyridine, is warming up to 5 DEG C, stirs 1h, weighs 7 β-[(phenylacetyl) amino] -3- [4- (1- methyl -4- pyridine) -2- thiophene of 7.0g
Azoles sulfenyl] -3- cephem -4- carboxylic acid benzhydryl ester, take 140ml isobutanol, under the conditions of -10 DEG C, reactant liquor is dropped to
In isobutanol, 3h is stirred at room temperature, dcm is removed in rotation, has yellow solid to separate out, sucking filtration, use ethyl acetate and methyl tertiary butyl ether(MTBE) successively
Wash, be dried, obtain product 5.17g, yield: 89%, purity: 88%.
The hydrolysis of ester group: weigh 7 beta-amino -3- [4- (1- methyl -4- pyridine) -2- thiazole the sulfenyl] -3- cephalo of 5g
Alkene -4- carboxylic acid benzhydryl ester, is suspended in 30ml acetonitrile, Deca 14ml concentrated hydrochloric acid, and 8h is stirred at room temperature, and adds 60ml acetic acid second
Ester, is stirred at room temperature 10h, has solid to separate out, and sucking filtration is washed with acetonitrile, is dried, obtains product 1.53g, yield: 72%, purity: 84%.
The introducing of side chain: weigh 7 beta-amino -3- [4- (1- methyl -4- pyridine) -2- thiazole the sulfenyl] -3- head of 0.4g
Spore alkene -4- carboxylic acid, is suspended in 24ml water, under the conditions of 0 DEG C, adds the sodium acetate solution for 2m for the 5.5ml concentration, weighs 1.18g
2- (5- dichlor-phosphoryl amino -1,2,4- thiadiazoles -3- bases) -2 (z)-ethoxy imino chloroacetic chloride, be dissolved in 12ml acetonitrile,
This solution is added drop-wise in reactant liquor, -10 DEG C of stirring 2h, reaction finishes, and most of acetonitrile is removed in rotation, adds ethyl acetate, extracts,
Divide liquid, aqueous phase is evaporated to 1/6th volumes, add the ethanol of 2 volumes, 30min is stirred at room temperature, under the conditions of -10 DEG C
Stirring 30min, has yellow solid to separate out, and sucking filtration is used ethanol water (1/2) and washing with alcohol successively, is dried, obtains product
0.51g, yield: 75%, purity: 85%.
Claims (5)
1. a kind of preparation method of Ceftaroline Fosamil is it is characterised in that comprise the following steps:
A. by raw material 7 β-[(phenylacetyl) amino] -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid hexichol first
Base ester is added to pcl5In/pyridine System, question response finishes, and reactant liquor is added in isobutanol, crystallize, obtains intermediate；
B. above-mentioned intermediate is suspended in acetonitrile, is slowly dropped into concentrated hydrochloric acid, question response finishes, add acetic acid in reactant liquor
Ethyl ester, crystallize, obtain intermediate；
C. above-mentioned intermediate is dissolved in acetonitrile, add 2- (5- dichlor-phosphoryl amino -1,2,4- thiadiazoles -3- bases) -2 (z) -
Ethoxy imino chloroacetic chloride is stirred at room temperature reaction, and question response finishes, cooling, adds silylating reagent, stirring reaction, subsequently will
Reactant liquor is poured in frozen water, adds oxolane, crystallize, obtains intermediate；
D. above-mentioned intermediate is dissolved in dmf, adds iodomethane, reaction, question response finishes, add methanol, crystallize, obtain 3- [4-
(1- methyl -4- pyridine) -2- thiazole sulfenyl] -7 β-[2-(5- phosphinylidyne amino -1,2,4- thiadiazoles -3- base) -2(z)-ethoxy
Base imino group acetylamino] -3- cephem -4- carboxylic acid.
2. the preparation method of Ceftaroline Fosamil according to claim 1 is it is characterised in that 7 β-[(benzene second in described step a
Acyl) amino] -3- [4- pyridine radicals -2- thiazole sulfenyl] -3- cephem -4- carboxylic acid benzhydryl ester and pcl5Mol ratio be 1:2
~ 5, the mol ratio with pyridine is 1:2 ~ 5.
3. the preparation method of Ceftaroline Fosamil according to claim 1 is it is characterised in that intermediate in described step b
Mol ratio with concentrated hydrochloric acid is 1:20 ~ 80.
4. the preparation method of Ceftaroline Fosamil according to claim 1 is it is characterised in that silanization in described step c
Reagent is n, any one in double (trimethyl silane) acetamide of o- or trim,ethylchlorosilane.
5. the preparation method of Ceftaroline Fosamil according to claim 1 is it is characterised in that intermediate in described step d
Mol ratio with iodomethane is 1:2 ~ 5.
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| CN108341840A (en) * | 2017-01-21 | 2018-07-31 | 深圳华润九新药业有限公司 | The preparation method of Ceftaroline Fosamil |
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| CN102703559B (en) * | 2012-06-18 | 2013-09-11 | 山东诚创医药技术开发有限公司 | Preparation method for 7 beta-amino-3-[4-(1-methyl-4-pyridinium)-2-thiazole sulfenyl]-3-cephem-4-carboxylate acidification matter |
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