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Cefetamet pivoxil hydrochloride preparation method

A technology of ceftametoxil hydrochloride and dilute hydrochloric acid, which is applied in the field of drug synthesis, can solve the problems of poor stability, easy deterioration, and low yield, and achieve the effects of mild reaction conditions, increased reactivity, and high product purity

Active Publication Date: 2018-09-28
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are following shortcomings and deficiencies in this synthesis process: the introduction and elimination conditions of the protecting group are very harsh, and the reaction requires absolute anhydrous operation; ceftamet sodium is not suitable for storage, has poor stability, and is easy to deteriorate when exposed to light and air; raw material pivaloyl bromide Methyl ester is not easy to obtain, and the raw material is more irritating
[0009] When these synthetic routes all use AE active ester as an acylating agent, a by-product of this reaction is the toxic compound 2-mercaptobenzothiazole (for example, Chemical Abstracts (Chemical Abstracts), 1989, 11, 19243), and the above-mentioned In the published literature, there is no description of the removal method of the by-product 2-mercaptobenzothiazole, and its content in the product ceftaxime acid
In addition, in the synthesis process of ceftazime pivoxil, excessive use of inorganic strong base and strong acid will cause damage to the skeleton of the cephem carboxylic acid mother nucleus.
[0010] In summary, most of the currently disclosed preparation methods of ceftamet pivoxil hydrochloride react with 7-ADCA and AE active ester, which easily produces the toxic compound 2-mercaptobenzothiazole, resulting in poor product purity. And the purification process is more difficult to handle, and the yield is low; And follow-up reaction, the condensate that makes will directly generate esterification reaction with iodomethyl pivalate under strong alkali, easily generates ceftazidime hydrochloride Δ 3 Isomer impurity (formula I), and the sodium salt of hemetexil should not be stored, poor stability

Method used

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Experimental program
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Embodiment 1

[0022] Step 1) Prepare a trimethylaluminum hexane solution with a concentration of 2M at 5°C for later use; prepare 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 ] oct-2-ene-2-carboxylic acid (7-ADCA) 4.71g was slowly added in 50mL of dichloromethane, fully stirred, then gradually added 12mL of a 2M trimethylaluminum hexane solution, stirred, in batches Add 4.59g of ethyl aminothioxamate, react at 35°C for 2 hours, monitor the completion of the reaction by TLC, cool to room temperature, slowly add 50mL of water to quench the reaction, let stand to separate layers; collect the water phase, adjust the pH to 2.0-2.5 with 6% hydrochloric acid , crystallized for 2.0 h, filtered, washed with 20 mL each of water and acetone successively, sucked dry, and dried in vacuum at 35°C to obtain 6.55 g of intermediate I, with an HPLC purity of 99.89% and a yield of 98.23%.

[0023] Step 2) Add 60mL of N-methylpyrrolidone and 3.33g of intermediate I to the reaction flask successively, stir,...

Embodiment 2

[0025] Step 1) Prepare a trimethylaluminum hexane solution with a concentration of 2M at 5°C for later use; prepare 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 ] 4.28 g of oct-2-ene-2-carboxylic acid (7-ADCA) was slowly added to 50 mL of dichloromethane, fully stirred, and then gradually added 10 mL of a hexane solution of 2M trimethylaluminum, stirred, and batchwise Add 4.59g of ethyl aminothioxamate, react at 35°C for 2 hours, monitor the completion of the reaction by TLC, cool to room temperature, slowly add 50mL of water to quench the reaction, let stand to separate layers; collect the water phase, adjust the pH to 2.0-2.5 with 4% hydrochloric acid , crystallized for 2.0 h, filtered, washed with 20 mL of water and 20 mL of acetone successively, sucked dry, and dried in vacuum at 35° C. to obtain 6.12 g of intermediate I. The HPLC purity was 99.21%, and the yield was 91.23%.

[0026]Step 2) Add 50mL of N-methylpyrrolidone and 3.33g of intermediate I to the reaction fla...

Embodiment 3

[0028] Step 1) Prepare a trimethylaluminum hexane solution with a concentration of 2M at 5°C for later use; prepare 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 ] Oct-2-ene-2-carboxylic acid (7-ADCA) 5.14g was slowly added to 50mL of dichloromethane, fully stirred, then gradually added 14mL of hexane solution of trimethylaluminum with a concentration of 2M, stirred, in batches Add 4.59g of ethyl aminothiaxamate, react at a temperature of 35°C for 2h, monitor the completion of the reaction by TLC, cool to room temperature, slowly add 50mL of water to quench the reaction, let stand to separate layers; collect the water phase, adjust the pH to 2.0-2.5 with 8% hydrochloric acid , crystallized for 2.0 h, filtered, washed with 20 mL of water and 20 mL of acetone in turn, sucked dry, and dried in vacuo at 35°C to obtain 6.44 g of Intermediate I with a HPLC purity of 99.74% and a yield of 96.37%.

[0029] Step 2) Add 60mL of N-methylpyrrolidone and 3.33g of intermediate I to the r...

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Abstract

The invention relates to a cefetamet pivoxil hydrochloride preparation method, which comprises: generating an intermediate I by using 7-ADCA and ethyl methylaminothiazolyloximate as starting raw materials under the catalysis of AlMe3; and carrying out an esterification reaction on the intermediate I and iodomethyl pivalate under the actions of a phase transfer catalyst and an acid adsorbent, carrying out salt formation on the esterified product, and crystallizing to obtain the target product cefetamet pivoxil hydrochloride. According to the present invention, the method has characteristics ofmild reaction conditions, high product purity, high yield and stable process, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of ceftazidime hydrochloride. Background technique [0002] Cefetamet Pivoxil, Hydrochloride, chemical name: (6R, 7R)-3-methyl-7-[(Z)-2-(2-amino-4-thiazolyl)-2-( Methoxyimino)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester hydrochloride , is an oral third-generation cephalosporin, developed and marketed by Takeda Pharmaceutical Company of Japan and Hoffmann-Roche Company of Switzerland in the late 1970s, with the trade name Globocef. As an oral anti-infection drug, it is characterized in that it is rapidly hydrolyzed by esterase in the body after oral administration to release active ingredients. It has significant curative effects on various infections such as upper and lower respiratory tracts and urinary tracts. Low toxicity, easy to take and so on. Its chemical structural formula is as follows: [0003] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/12C07D501/06
CPCC07B2200/13C07D501/06C07D501/12C07D501/22
Inventor 刘振腾李震侯善波孟凡娜
Owner SHANDONG YUXIN PHARMA CO LTD
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