CN113024582A - Synthesis method of cefepime hydrochloride - Google Patents

Synthesis method of cefepime hydrochloride Download PDF

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CN113024582A
CN113024582A CN202110292741.1A CN202110292741A CN113024582A CN 113024582 A CN113024582 A CN 113024582A CN 202110292741 A CN202110292741 A CN 202110292741A CN 113024582 A CN113024582 A CN 113024582A
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刀鹏
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
    • C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The invention takes 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride as a raw material, uses di-tert-butyl dicarbonate to protect amino and then reacts with N-methylpyrrolidine, acid cuts off 4-position and 7-position protecting groups to obtain an intermediate 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP), and then performs acylation reaction with aminothiazoles mercaptobenzothiazole active ester (AE-active ester) of the thiaximic acid to obtain cefepime hydrochloride. The method has the advantages of simple reaction treatment, harsh reaction conditions, less isomer generation, high yield, high purity and simple process, and is suitable for industrial production.

Description

Synthesis method of cefepime hydrochloride
Technical Field
The invention belongs to the field of synthesis of cephalosporin raw material medicines, and particularly relates to a synthesis method of cefepime hydrochloride.
Background
Cefepime hydrochloride is a cephalosporin antibiotic for fourth generation injection, and is developed and marketed in 1993 by Bumai-Shi Guibao company in the United states. Compared with the common third-generation cephalosporin, the cephalosporin has wider antibacterial spectrum, stronger action on gram-positive bacteria and more stability on lactamase. The synthesis process of cefepime hydrochloride is studied. The cefepime hydrochloride has the structure of
Figure 588467DEST_PATH_IMAGE001
The former people have encountered the problem of 2, 3 position isomerism when connecting three side chains in the exploration of different routes for synthesizing cefepime hydrochloride. The mechanism of isomerism has been studied: n-methylpyrrolidine (NMP) has nucleophilicity and alkalinity, so that the N-methylpyrrolidine can participate in the reaction to obtain a product, and the N-methylpyrrolidine (NMP) can catalyze the cephalosporin nucleus to generate 2, 3-position isomerism by utilizing the alkalinity. Many attempts have been made to address this problem. Two more successful approaches are available:
1) walker et al reported that 7-ACA was used as a starting material, Freon was used as a reaction solvent, and a Trimethylsilicide intermediate was subjected to a one-pot method to obtain a key intermediate (7-ACP) of cefepime with a yield of 38% (based on 7-ACA). Carrying out 7-position acylation reaction on the refined product of the 7-ACP and benzotriazole active ester to obtain cefepime sulfate, wherein the yield of the step is 81%;
2) naito et al reported that ACLH is used as a starting material, firstly Schiff base is used for protecting 7-amino, after iodination activation, quaternary ammonium salt is generated in CCl4 with N-methylpyrrolidine (NMP), and then amino and carboxyl protecting groups are removed to obtain 7-ACP with the yield of 34% (based on the ACLH); 7-ACP and benzotriazole active ester are subjected to 7-position acylation reaction to prepare cefepime sulfate, and the yield of the step is 70%.
In order to reduce the generation of delta 2 isomer impurities, the Walker uses fluorine-containing polychlorinated hydrocarbon (Freon TF) as a reaction solvent, utilizes the low solubility of the fluorine-containing polychlorinated hydrocarbon to a product, enables the fluorine-containing polychlorinated hydrocarbon to exist in a reaction system in a precipitation form, reduces the chance of isomerization, and greatly reduces the generation of delta 2 isomers; the use of CCl4 as a solvent in the quaternization reaction by Naito et al is also based on the fact that the solvent has little solubility for the product. The main disadvantage of both processes is the use of polyhalogenated hydrocarbon solvents, which are strictly prohibited by environmental protection.
According to the process of patent CN107201391, it is well protected against the formation of isomers, but requires the removal of two protecting groups in two steps, making the process cumbersome and the yield reduced.
Disclosure of Invention
The invention aims to provide a synthesis method of cefepime hydrochloride, which is characterized in that 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride is used as a raw material to prepare cefepime hydrochloride through four-step reaction. The method has the advantages of economic and easily-obtained raw materials, recyclable solvent, greatly reduced generation of three wastes, greatly reduced production cost, reduced generation of isomer by-products by utilizing the principle that preferentially-obtained inner salt is easy to separate out, and improved yield and product purity.
The method takes 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride as a raw material to synthesize cefepime hydrochloride through the following reaction:
step one, controlling the temperature to be 25 ℃, adding triethylamine and 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into tetrahydrofuran, stirring and dissolving, then dripping di-tert-butyl dicarbonate (Boc2O), and adding water and dichloromethane for extraction after complete reaction to obtain a Boc protected product solution.
And step two, controlling the temperature to be 25 ℃, adding N-methylpyrrolidine into the dichloromethane solution protected by the Boc, stirring for 3 hours, then spin-drying the solvent, adding ether, stirring and crystallizing.
And step three, dissolving the crystal precipitated in the step two by using methanol and dilute hydrochloric acid and stirring at the temperature of-10 to 10 ℃, continuously adding the methanol after the reaction is finished, crystallizing at the temperature of 0 ℃, and filtering to obtain the 7-amino-3- (1-methyl pyrrolidine) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP).
And step four, adding AE-active ester into 7-ACP in methanol of triethylamine, reacting for 3 hours at 30 ℃, adding water and methyl tert-butyl ether for extraction, adding dilute hydrochloric acid into a water phase at 0 ℃ for crystallization, and assisting with the methyl tert-butyl ether to finally obtain the cefepime hydrochloride product.
Preferably, in the step one, the molar ratio of triethylamine, 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride and Boc2O is 2:1: 1.
Preferably, the solvent used in step one is tetrahydrofuran and the extractant is dichloromethane.
Preferably, in step two, the molar ratio of N-methylpyrrolidine is 1: 1.
Preferably, the hydrochloric acid used in step three is 2M-4M.
Preferably, the molar ratio of 7-ACP, AE-active ester in step four is 1: 1.
Preferably, in step four, methyl tert-butyl ether is used for crystallization with water.
Preferably, the temperature used for the crystallization in step four is 0 ℃.
Compared with patent CN107201391, the method has the advantages of low cost of used reagents, simpler treatment and higher yield.
Detailed Description
Example 1
1) Controlling the temperature to be 25 ℃, adding 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into 100ml of tetrahydrofuran, stirring and dissolving, then dripping 9.66g of di-tert-butyl dicarbonate, stirring at the controlled temperature for 3 hours, then adding water and dichloromethane for extraction, and obtaining the dichloromethane solution of the Boc protected product.
2) Adding 3.77g of N-methylpyrrolidine into a dichloromethane solution of the Boc protection product at 25 ℃, stirring at the controlled temperature for 3 hours, drying the solvent after the reaction is finished, stirring the crude product and ether for crystallization, and filtering to obtain an inner salt compound.
3) And (3) stirring the inner salt product obtained in the second step in 50ml of methanol and 3MHCl at the temperature of 0 ℃ to remove carboxyl and amino protecting groups, continuously adding 50ml of methanol after the reaction is finished, stirring and filtering to obtain 14g of 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP).
4) Dissolving 14g of 7-ACP in 8.95g of methanol containing triethylamine and 40ml of methanol, adding 15.4g of AE-active ester, reacting for three hours at 30 ℃, adding water and methyl tert-butyl ether for extraction, adding 4M Hcl into a water phase to form a salt, adding methyl tert-butyl ether to assist crystallization at 0 ℃, and filtering to obtain 22g of cefepime hydrochloride with the total yield of 93%.
Example 2
1) Controlling the temperature to be 25 ℃, adding 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into 100ml of tetrahydrofuran, stirring and dissolving, then dripping 9.66g of di-tert-butyl dicarbonate, stirring at the controlled temperature for 3 hours, then adding water and dichloromethane for extraction, and obtaining the dichloromethane solution of the Boc protected product.
2) Adding 3.77g of N-methylpyrrolidine into a dichloromethane solution of the Boc protection product at 25 ℃, stirring at the controlled temperature for 3 hours, drying the solvent after the reaction is finished, stirring the crude product and ether for crystallization, and filtering to obtain an inner salt compound.
3) And (3) stirring the inner salt product obtained in the second step in 50ml of methanol and 3MHCl at the temperature of-10 ℃ to remove carboxyl and amino protecting groups, continuously adding 50ml of methanol after the reaction is finished, stirring and filtering to obtain 10g of 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP).
4) Dissolving 10g of 7-ACP in 40ml of methanol containing 6g of triethylamine, adding 10.4g of AE-active ester, reacting for three hours at 30 ℃, adding water and methyl tert-butyl ether for extraction, adding 4M HCl into the water phase to form a salt, adding methyl tert-butyl ether to assist crystallization at 0 ℃, and filtering to obtain 15g of cefepime hydrochloride with the total yield of 63%.
Example 3
1) Controlling the temperature to be 25 ℃, adding 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into 100ml of tetrahydrofuran, stirring and dissolving, then dripping 9.66g of di-tert-butyl dicarbonate, stirring at the controlled temperature for 3 hours, then adding water and dichloromethane for extraction, and obtaining the dichloromethane solution of the Boc protected product.
2) Adding 3.77g of N-methylpyrrolidine into a dichloromethane solution of the Boc protection product at 25 ℃, stirring at the controlled temperature for 3 hours, drying the solvent after the reaction is finished, stirring the crude product and ether for crystallization, and filtering to obtain an inner salt compound.
3) And (3) stirring the inner salt product obtained in the second step in 50ml of methanol and 3MHCl at the temperature of 10 ℃ to remove carboxyl and amino protecting groups, continuously adding 50ml of methanol after the reaction is finished, stirring and filtering to obtain 13g of 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP).
4) Dissolving 7-ACP 13g in methanol 40ml of triethylamine 7.8g, adding AE-active ester 13.6g, reacting for three hours at 30 ℃, adding water and methyl tert-butyl ether for extraction, adding 4M HCl into the water phase to form a salt, adding methyl tert-butyl ether for assisting crystallization at 0 ℃, and filtering to obtain cefepime hydrochloride 20g with the total yield of 84.5%.
Example 4
1) Controlling the temperature to be 25 ℃, adding 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into 100ml of tetrahydrofuran, stirring and dissolving, then dripping 9.66g of di-tert-butyl dicarbonate, stirring at the controlled temperature for 3 hours, then adding water and dichloromethane for extraction, and obtaining the dichloromethane solution of the Boc protected product.
2) Adding 3.77g of N-methylpyrrolidine into a dichloromethane solution of the Boc protection product at 25 ℃, stirring at the controlled temperature for 3 hours, drying the solvent after the reaction is finished, stirring the crude product and ether for crystallization, and filtering to obtain an inner salt compound.
3) And (3) stirring the inner salt product obtained in the second step in 50ml of methanol and 2MHCl at the temperature of 0 ℃ to remove carboxyl and amino protecting groups, continuously adding 50ml of methanol after the reaction is finished, stirring and filtering to obtain 14g of 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP).
4) Dissolving 14g of 7-ACP in 8.95g of methanol containing triethylamine and 40ml of methanol, adding 15.4g of AE-active ester, reacting for three hours at 30 ℃, adding water and methyl tert-butyl ether for extraction, adding 4M Hcl into the water phase to form a salt, adding methyl tert-butyl ether to assist crystallization at 0 ℃, and filtering to obtain 21.8g of cefepime hydrochloride with the total yield of 92.1%.
Comparative example 1
1) Controlling the temperature to be 25 ℃, adding 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into 100ml of tetrahydrofuran, stirring and dissolving, then dripping 9.66g of di-tert-butyl dicarbonate, stirring at the controlled temperature for 3 hours, then adding water and dichloromethane for extraction, and obtaining the dichloromethane solution of the Boc protected product.
2) Adding 3.77g of N-methylpyrrolidine into a dichloromethane solution of the Boc protection product at 25 ℃, stirring at the controlled temperature for 3 hours, drying the solvent after the reaction is finished, stirring the crude product and ether for crystallization, and filtering to obtain an inner salt compound.
3) And (3) stirring the inner salt product obtained in the second step in 50ml of methanol and 3MHCl at the temperature of-20 ℃ to remove carboxyl and amino protecting groups, continuously adding 50ml of methanol after the reaction is finished, stirring and filtering to obtain 9g of 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP).
4) Dissolving 9g of 7-ACP in 5.4g of methanol containing triethylamine and 40ml of methanol, adding 9.42g of AE-active ester, reacting for three hours at 30 ℃, adding water and methyl tert-butyl ether for extraction, adding 4M Hcl into the water phase to form a salt, adding methyl tert-butyl ether to assist crystallization at 0 ℃, and filtering to obtain 8.67g of cefepime hydrochloride with the total yield of 60%.
Comparative example 2
1) Controlling the temperature to be 25 ℃, adding 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into 100ml of tetrahydrofuran, stirring and dissolving, then dripping 9.66g of di-tert-butyl dicarbonate, stirring at the controlled temperature for 3 hours, then adding water and dichloromethane for extraction, and obtaining the dichloromethane solution of the Boc protected product.
2) Adding 3.77g of N-methylpyrrolidine into a dichloromethane solution of the Boc protection product at 25 ℃, stirring at the controlled temperature for 3 hours, drying the solvent after the reaction is finished, stirring the crude product and ether for crystallization, and filtering to obtain an inner salt compound.
3) And (3) stirring the inner salt product obtained in the second step in 50ml of methanol and 5MHCl at the temperature of 0 ℃ to remove carboxyl and amino protecting groups, continuously adding 50ml of methanol after the reaction is finished, stirring and filtering to obtain 9g of 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP).
4) Dissolving 9g of 7-ACP in 5.4g of methanol containing triethylamine and 40ml of methanol, adding 9.42g of AE-active ester, reacting for three hours at 30 ℃, adding water and methyl tert-butyl ether for extraction, adding 4M Hcl into the water phase to form a salt, adding methyl tert-butyl ether to assist crystallization at 0 ℃, and filtering to obtain 8.7g of cefepime hydrochloride with the total yield of 60%.
Comparative example 3
1) Controlling the temperature to be 25 ℃, adding 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into 100ml of tetrahydrofuran, stirring and dissolving, then dripping 9.66g of di-tert-butyl dicarbonate, stirring at the controlled temperature for 3 hours, then adding water and dichloromethane for extraction, and obtaining the dichloromethane solution of the Boc protected product.
2) Adding 3.77g of N-methylpyrrolidine into a dichloromethane solution of the Boc protection product at 25 ℃, stirring at the controlled temperature for 3 hours, drying the solvent after the reaction is finished, stirring the crude product and ether for crystallization, and filtering to obtain an inner salt compound.
3) And (3) stirring the inner salt product obtained in the second step in 50ml of methanol and 3MHCl at the temperature of 20 ℃ to remove carboxyl and amino protecting groups, continuously adding 50ml of methanol after the reaction is finished, stirring and filtering to obtain 13g of 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP).
4) Dissolving 7-ACP 13g in methanol 40ml of triethylamine 7.8g, adding AE-active ester 13.6g, reacting for three hours at 30 ℃, adding water and methyl tert-butyl ether for extraction, adding 4M HCl into the water phase to form a salt, adding methyl tert-butyl ether for assisting crystallization at 0 ℃, and filtering to obtain cefepime hydrochloride 18.8g with the total yield of 90%.
Comparative example 4
Cefepime hydrochloride according to patent CN107201391, prepared as follows:
step 1: synthesis of 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid (DGCLE): 20g of GCLE was dissolved in 50ml of dichloromethane, and after the system was cooled to-25 ℃, 19.8ml of trifluoroacetic acid (molar ratio to GCLE: 6.5: 1) was added to the reaction mixture; the mixture is stirred and reacted for 16 hours at the temperature of minus 25 ℃; transferring the reaction solution to a rotary evaporator, evaporating 2/3 solvent under reduced pressure, and adding 200ml petroleum ether into the reaction solution to precipitate crystals; drying; 12.9g of compound I (DGCLE) are obtained with a molar yield of 85.6%. Step 2: synthesis of 7-phenylacetamido-3- [ (1-methyltetrahydropyrrole) methyl) ] -3-cephem-4-carboxylic acid (3-NMP-DGCLE): dissolving 12.0g of DGCLE obtained in the step 1 in 85ml of dichloromethane, stirring and reacting for half an hour at the temperature of minus 25 ℃, slowly dropwise adding 6.6ml of N-methylpyrrolidine (the molar ratio of the N-methylpyrrolidine to the DGCLE is 1.05: 1), stirring and reacting for 2 hours at the temperature of minus 25 ℃, and adding 480ml of diethyl ether into a reaction solution to separate out a product; filtration and drying gave 13.9g of Compound II (3-NMP-DGCLE) in 95.2% molar yield. And step 3: synthesis of 7-amino-3- [ (1-methyltetrahydropyrrole) methyl) ] -3-ceph-4-carboxylic acid hydrochloride (7-ACP): placing 14.0g of 3-NMP-DGCLE in a 500ml beaker, adding 140ml of water, adjusting the pH to 8.00 with 1% ammonia water, completely dissolving, placing the reaction solution in a water bath at 28 ℃, adding 5.9g of immobilized penicillin acylase (4.1%), continuously dropwise adding ammonia water under stirring to keep the pH of the solution at about 7.9 until the pH of the solution is kept at about 7.9 within 10 minutes, performing suction filtration, decolorizing the filtrate with 0.7g of activated carbon, rapidly dropwise adding 5% HCl aqueous solution at 0 ℃ to reach the pH of 2.00, precipitating a large amount of white precipitate, and then adding 200ml of ethanol to help to precipitate crystals; obtaining a product 7-ACP: 8.9 g, molar yield: 86.1 percent. And 4, step 4: synthesis of cefepime hydrochloride: dissolving 8.0 g of 7-ACP in 40ml of dichloromethane, adding 10ml of triethylamine, stirring for reaction for half an hour, adding 7.4g of AE-active ester (the molar ratio of 7-ACP to 7-ACP is 1.1:1, stirring for reaction for 2 hours at 28 ℃, pouring the reaction liquid into 200ml of water, washing the solution with 40ml of ethyl acetate for four times (10 ml each time), adding 5% dilute hydrochloric acid into the water phase to adjust the pH to 1.15, slowly dropwise adding 100ml of acetone into the reaction liquid, and separating out a large amount of white precipitates to obtain a product, namely cefepime hydrochloride, with the weight of 11.58 g, the molar yield of 86.9%, the purity of 99.62% and the melting point of 212.6-220.6 ℃.
Example 1 Example 2 Example 3 Example 4 Comparative example 1 Comparative example 2 Comparative example 3 Comparative example 4
Deprotection temperature deg.C 0 -10 10 0 -20 0 20
pH of the acid used for deprotection 3 3 3 2 3 5 3
The total yield is% 93 63 84.5 92.1 60 60 90 Single step condensation yield 86.9.
Compared with the comparative example, the method has the advantages of mild reaction conditions, recoverable solvent, low cost, green and environment-friendly route, simple treatment and suitability for industrial production.

Claims (1)

1. A method for synthesizing cefepime hydrochloride is characterized by comprising the following steps: the method comprises the steps of taking 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride as a raw material, using di-tert-butyl dicarbonate to protect amino, reacting with N-methylpyrrolidine, removing 4-and 7-protecting groups with acid to obtain an intermediate 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP), and performing acylation reaction with aminothiazoles mercaptobenzothiazole active ester (AE-active ester) of thiaximic acid to obtain cefepime hydrochloride; the method comprises the following steps:
1) controlling the temperature to be 25 ℃, adding 8.95g of triethylamine and 20g of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride into 100ml of tetrahydrofuran, stirring and dissolving, then dripping 9.66g of di-tert-butyl dicarbonate, stirring at the controlled temperature for 3 hours, then adding water and dichloromethane for extraction, and obtaining a dichloromethane solution of the Boc protection product;
2) adding 3.77g of N-methylpyrrolidine into a dichloromethane solution of the Boc protection product at 25 ℃, stirring at a controlled temperature for 3 hours, drying the solvent after the reaction is finished, stirring the crude product and ether for crystallization, and filtering to obtain an inner salt compound;
3) stirring the inner salt product obtained in the second step in 50ml of methanol and 3MHCl at the temperature of 0 ℃ to remove carboxyl and amino protecting groups, continuously adding 50ml of methanol after the reaction is finished, stirring and filtering to obtain 14g of 7-amino-3- (1-methyl tetrahydropyrrole) methyl) -3-cephem-4-carboxylic acid hydrochloride (7-ACP);
4) dissolving 7-ACP 14g in methanol containing triethylamine 8.95g and methanol 40ml, adding AE-active ester 15.4g, reacting at 30 deg.C for three hours, adding water and methyl tert-butyl ether, extracting, adding 4M HCl into water phase to form salt, adding methyl tert-butyl ether, and crystallizing at 0 deg.C.
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