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Synthesis method of cefepime hydrochloride

The technology of a kind of cefepime hydrochloride and synthetic method is applied in the field of synthesis of cefepime hydrochloride to achieve the effects of cost reduction, simple process and high yield

Active Publication Date: 2017-09-26
吉林省爱诺德生物工程有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main disadvantage of these two methods is the use of polyhalogenated hydrocarbon solvents that are strictly prohibited by environmental protection.

Method used

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  • Synthesis method of cefepime hydrochloride
  • Synthesis method of cefepime hydrochloride
  • Synthesis method of cefepime hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Step 1: Synthesis of 7-phenylacetamido-3-chloromethyl-3-cephalosporin-4-carboxylic acid (DGCLE)

[0033]Dissolve 20g of GCLE in 50ml of dichloromethane, and after cooling the system to -25°C, add 19.8ml of trifluoroacetic acid (the molar ratio to GCLE is 6.5:1) to the reaction solution; the mixture is stirred and reacted at -25°C for 16 hours; The reaction solution was transferred to a rotary evaporator to distill off 2 / 3 of the solvent under reduced pressure, and 200 ml of petroleum ether was added to the reaction solution to precipitate crystals; dried to obtain 12.9 g of compound I (DGCLE), with a molar yield of 85.6%.

[0034] 7-phenylacetamido-3-chloromethyl-3-cephalosporin-4-carboxylic acid (DGCLE) was analyzed and characterized by NMR.

[0035] NMR data: 1 HNMR (500MHz, CDCl 3 )δ3.52(s,2H,COCH 2 ); 3.71, 3.82 (d, J=7.5Hz, 2H, SCH 2 ); 4.05 (s,2H,ClCH 2 ); 4.19 (ABq, J=13.5Hz, 1H, N + CH 2 ), 4.61 (ABq, J=14.0Hz, 1H, N + CH 2 ), 5.13 (S, 1H, C-6, β-lactam...

Embodiment 2

[0049] Step 1: Synthesis of 7-phenylacetamido-3-chloromethyl-3-cephalosporin-4-carboxylic acid (DGCLE)

[0050] Dissolve 20g of GCLE in 50ml of ethyl acetate, and after cooling the system to -25°C, add 21.3ml of trifluoroacetic acid (the molar ratio to GCLE is 7.0:1) to the reaction solution. The mixture was stirred and reacted at -25°C for 16 hours; the reaction solution was transferred to a rotary evaporator to distill off 2 / 3 of the solvent under reduced pressure, and 200ml of n-hexane was added to the reaction solution to precipitate crystals; dried; to obtain compound I (DGCLE) 12.8 g, molar yield 85.3%.

[0051] 7-phenylacetamido-3-chloromethyl-3-cephalosporin-4-carboxylic acid (DGCLE) was analyzed and characterized by NMR.

[0052] NMR data: 1 HNMR (500MHz, CDCl 3 )δ3.52(s,2H,COCH 2 ); 3.71, 3.82 (d, J=7.5Hz, 2H, SCH 2 ); 4.05 (s,2H,ClCH 2 ); 4.19 (ABq, J=13.5Hz, 1H, N + CH 2 ), 4.61 (ABq, J=14.0Hz, 1H, N + CH 2 ), 5.13 (S, 1H, C-6, β-lactam); 5.42 (dd, J=4.0H...

Embodiment 3

[0066] Step 1: Synthesis of 7-phenylacetamido-3-chloromethyl-3-cephalosporin-4-carboxylic acid (DGCLE)

[0067] Dissolve 20g of GCLE in 50ml of chloroform, and after cooling the system to -30°C, add 14.2ml of formic acid (the molar ratio to GCLE is 7.5:1) to the reaction solution; the mixture is stirred and reacted at -30°C for 16 hours. The reaction solution was transferred to a rotary evaporator to distill off 2 / 3 of the solvent under reduced pressure, and 200 ml of cyclohexane was added to the reaction solution to precipitate crystals; dried to obtain 13.1 g of compound I (DGCLE), with a molar yield of 86.1%.

[0068] 7-phenylacetamido-3-chloromethyl-3-cephalosporin-4-carboxylic acid (DGCLE) was analyzed and characterized by NMR.

[0069] NMR data: 1 HNMR (500MHz, CDCl 3 )δ3.52(s,2H,COCH 2 ); 3.71, 3.82 (d, J=7.5Hz, 2H, SCH 2 ); 4.05 (s,2H,ClCH 2 ); 4.19 (ABq, J=13.5Hz, 1H, N + CH 2 ), 4.61 (ABq, J=14.0Hz, 1H, N + CH 2 ), 5.13 (S, 1H, C-6, β-lactam); 5.42 (dd, J=4....

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Abstract

The invention provides a synthesis method of cefepime hydrochloride. The synthesis method comprises the following steps: taking GCLE (7-phenylacetamide-3-chloromethyl-3-cepham-4-carboxylic acid p-methyl-oxybenzyl ester) as a raw material; cutting a 4-site protecting group (p-methoxybenzyl) and enabling the 4-site protecting group to react with N-methylpyrrolidine (NMP); then cutting a 7-site protecting group through an enzyme method to obtain an immediate 7-amino-3-(1-methylpyrrolidine)methyl)-3-cepham-4-carboxylic acid hydrochloride (7-ACP); taking cheap and available methoxyiminoacetic acid mercaptobenzothiazole active ester (AE-active ester) and the 7-ACP to be subjected to 7-site acylation reaction, so as to finally prepare the cefepime hydrochloride. A route provided by the invention can be used for obtaining the high-yield and high-quality cefepime hydrochloride without a delta2 isomer. The synthesis method provided by the invention has the advantages of simple process, no harsh reaction conditions and the like and is very suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of synthesis of cephalosporin raw materials, in particular to a synthesis method of cefepime hydrochloride. Background technique [0002] Cefepime hydrochloride is the fourth generation of cephalosporin antibiotics for injection, which was developed and marketed in 1993 by Boomer-Squibb Company of the United States. Compared with the commonly used third-generation cephalosporins, it has a wider antibacterial spectrum, stronger effect on Gram-positive bacteria, and more stable to lactamase. In this paper, the synthesis process of cefepime hydrochloride was studied. [0003] In the exploration of different routes for the synthesis of cefepime hydrochloride, the predecessors all encountered the problem of 2,3-position isomerism when the three-position side chain is connected. Its isomerization mechanism has been studied: since N-methylpyrrolidine (NMP) has both nucleophilicity and basicity, it can not only participate ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P35/04C07D501/46
CPCC07D501/46C12P35/04Y02P20/55
Inventor 宋立明杨琨许文革
Owner 吉林省爱诺德生物工程有限公司
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