Preparation method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid

A technology of aminocephalosporanic acid and methoxymethyl, which is applied in the field of preparation of pharmaceutical intermediates, can solve problems such as difficulties in the preparation of dicarbonium tetrafluoroborate, unsuitability for industrial production, and difficulty in product separation, and achieve low production costs , shorten the reaction time, the effect of easy to obtain raw materials

Active Publication Date: 2017-03-08
湖北凌晟药业股份有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The raw materials of the third preparation route are not easy to obtain, the reaction steps are long, and the impurities are too large, so it is not suitable for industrial production. The second route, the raw materials are easy to obtain, but the preparation of dicarbammonium tetrafluoroborate is difficult, and the separation of subsequent products is difficult, so it is not suitable. Industrial production, the first route, using 7-ACA as the starting material, the raw material is easy to get, using boron trifluoride solvent complex or trimethyl borate as the acid catalyst, the route of obtaining 7-AMCA through methylation is more suitable Industrial production
[0011] In summary, the known impurity control problems exist in the process of preparing 7-AMCA from 7-ACA raw materials. In order to overcome the problems in the process of preparing 7-AMCA from 7-ACA, it is necessary to conduct in-depth Research

Method used

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  • Preparation method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Under nitrogen protection, add 300ml dimethyl sulfoxide to the reaction flask, add 60g (0.22mol) 7-ACA, control the temperature at 30-35°C, add 0.8g of imidazole, add hexamethyldisilazane 17.75g (0.11 mol), stirred for 60 minutes after adding, vacuumed for 30 minutes to remove the generated ammonia, then cooled to 0-5°C, added 23.5g (0.23mol) of trimethyl borate, 8.3g (0.26mol) of methanol, and then added 317.1 g (3.3mol) methanesulfonic acid, slowly add dropwise a mixture of 23.5g (0.23mol) trimethyl borate and 8.3g (0.26mol) methanol, the feeding time is 60min; after the addition, the temperature is controlled at 0-5°C , react for 2-3 hours; take a sample after 2 hours, measure 7-ACA residue, HPLC peak area normalization method ≤0.5%, cool the system to -10°C; cool 90ml of cold water (0-3°C) drop into the system After the dropwise addition is completed, control the temperature at 0-5°C, stir for 30 minutes, filter, and transfer the filtrate to a crystallization bottle...

Embodiment 2

[0035]Under nitrogen protection, add 300ml of dioxane to the reaction flask, add 60g (0.22mol) 7-ACA, control the temperature at 30-35°C, add 0.8g of imidazole, add 17.75g (0.11mol) of hexamethyldisilazane ), stirred for 60 minutes after adding, vacuumed for 30 minutes to remove the generated ammonia gas, then cooled to 0-5°C, added 23.5g (0.23mol) trimethyl borate, 8.3g (0.26mol) methanol, and then added 317.1g (3.3mol) methanesulfonic acid, slowly add dropwise a mixture of 23.5g (0.23mol) trimethyl borate and 8.3g (0.26mol) methanol, the addition time is 60min; after the addition, the temperature is controlled at 0-5°C, React for 2 to 3 hours; take a sample after 2 hours, measure the 7-ACA residue, and the HPLC peak area normalization method is ≤0.5%; cool the system to -10°C; drop 90ml of cold water (0-5°C) into the system, After the dropwise addition is completed, control the temperature at 0-5°C and stir for 30 minutes; filter and transfer the filtrate to a crystallizatio...

Embodiment 3

[0037] Under nitrogen protection, add 300ml dimethyl sulfoxide to the reaction flask, add 60g (0.22mol) 7-ACA, control the temperature at 30-35°C, add 0.8g imidazole, add N, O-bistrimethylsilyl ethyl Amide 22.38g (0.11mol), add and stir for 60 minutes, then cool down to 0-5°C, add 23.5g (0.23mol) trimethyl borate, 8.3g (0.26mol) methanol, then add 317.1g (3.3mol) Methanesulfonic acid, slowly drop a mixture of 23.5g (0.23mol) trimethyl borate and 8.3g (0.26mol) methanol, the addition time is 60min; 3 hours; take a sample after 2 hours, measure 7-ACA residue, HPLC peak area normalization method ≤0.5%; cool down the system to -10°C; drop 90ml of cold water (0-5°C) into the system, and the addition is complete , control the temperature at 0-5°C, stir for 30min; filter, and transfer the filtrate to a crystallization bottle; Add ammonia solution to the system, adjust pH=3.0-3.5; grow crystals at 0-5°C for 60 minutes; wash with 100ml of cold water (0-5°C), wash with 100ml of cold me...

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Abstract

The invention discloses a preparation method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid, and relates to the technical field of preparation of pharmaceutical intermediates. The method includes the steps that under the protection of nitrogen, 7-aminocephalosporanic acid, a silane reagent and an imidazole catalyst are stirred for 0.5-2 h at 30-35 DEG C in a water-soluble organic solvent; then, the mixture is cooled to 0-5 DEG C, methanesulfonic acid, trimethyl borate and methyl alcohol are added, a methoxylation reaction is conducted with the temperature controlled to be 0-5 DEG C, and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid is obtained, wherein the silane reagent is hexamethyldisilazane or trimethylchlorosilane or N,O-bis(trimethylsilyl)acetamide or dimethoxydimethylsilane. According to the method, the product purity is high, the impurity content is low, operation is easy and convenient, refining steps are simplified, production cost is reduced, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates. Background technique [0002] 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA) is the mother nucleus for the production of cefpodoxime axetil. The preparation methods reported in the literature include: [0003] 1. Starting from 7-aminocephalosporanic acid (7-ACA), monomethyl sulfate as solvent, sulfuric acid as protonic acid or Lewis acid such as boron trifluoride as acidic medium, methanol, trimethoxyboron as methoxy Methanol and trimethyl borate can also be used as the methoxyl donor, or the 7-position protecting group can be used to remove the formyl group under alkaline conditions, and calcium chloride can be used as the methylation catalyst to prepare. [0004] 2. Starting from 7-amino-3-hydroxymethyl-4-cephalosporanic acid (D-7-ACA), it is prepared by selective methyl etherification with dicarbonium tetrafluoroborate. [0005] 3. Using 7-ph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/26C07D501/04
CPCC07D501/04C07D501/26
Inventor 门万辉金联明
Owner 湖北凌晟药业股份有限公司
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