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Preparation method of cefteram pivoxil

A technology for cefdram pivalate and methyl tetrazolium, which is applied in the field of preparation of cefdram pivoxil, can solve the problems of refining and removal, low product purity, easy generation of impurities and the like, and achieves mild reaction conditions, The effect of high product purity and stable process

Active Publication Date: 2018-07-20
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, cefditoren neopentyl is generally based on 7-ACA as raw material, after BF 3 gas or bf 3 Diethyl ether, dimethyl carbonate complex catalyzes the preparation of 7-MTCA, but the yield of 7-MTCA obtained by this method is low, and the content of impurity isomers is relatively large (as shown in formula 1), and cannot be refined through subsequent reactions Remove, and then the cefditoren neopentyl pivoxil of preparation does not meet pharmacopoeia standard; Neopentyl Δ 3 The generation of isomers (as shown in formula 2) affects product purity and is unfavorable for industrial production; in addition, when using AE active ester as an acylating agent, the reaction is likely to produce toxic compound 2-mercaptobenzothiazole; the last step reacts the amine group Without protection, the aminolysis of ester and iodine is easy to occur, and the reaction is easy to produce impurities, resulting in a decrease in product yield and low product purity.

Method used

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  • Preparation method of cefteram pivoxil
  • Preparation method of cefteram pivoxil
  • Preparation method of cefteram pivoxil

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Step 1) Slowly add 3.03g of 5-methyltetrazolium into 51mL of 60% H 2 SO 4 , stirred at room temperature for 20 minutes, 8.17 g of 7-ACA was added in three times, with an interval of 15 minutes between each addition, and the reaction was stirred at room temperature for 1 to 1.5 hours; ), and then the extract was washed with 40mL of water, 40mL (3%) Na 2 CO 3 Dissolved, washed with 40mL water, anhydrous Na 2 SO 4 After drying, the solvent was evaporated, and 7.87 g of 7-MTCA was obtained by vacuum drying, with a yield of 96.21%, a purity of 99.82%, and 7-MTCA isomer impurity of 0.02%.

[0034] Step 2) Prepare a trimethylaluminum hexane solution with a concentration of 2M at 5°C for subsequent use; 5.24g Boc 2 O. 4.58g of ethyl aminothiaxamate was slowly added to 50mL of dichloromethane, and stirred at room temperature for 2h. Gradually add 5.0mmol of N,N-dimethylethylenediamine, stir at room temperature for 30min, add 13mL of 2M trimethylaluminum hexane solution, st...

Embodiment 2

[0037] Step 1) Slowly add 2.52g of 5-methyltetrazolium into 40mL of 60% H 2 SO 4 , stirred at room temperature for 20 minutes, 8.17 g of 7-ACA was added in three times, with an interval of 15 minutes between each addition, and the reaction was stirred at room temperature for 1 to 1.5 hours; ), and then the extract was washed with 40mL of water, 40mL (3%) Na 2 CO 3 Dissolved, washed with 40mL water, anhydrous Na 2 SO 4 After drying, the solvent was evaporated, and 7.57 g of 7-MTCA was obtained by vacuum drying, with a yield of 91.84%, a purity of 99.05%, and 7-MTCA isomer impurities of 0.07%.

[0038] Step 2) Prepare a trimethylaluminum hexane solution with a concentration of 2M at 5°C for subsequent use; 4.80g Boc 2 O. 4.58g of ethyl aminothiaxamate was slowly added to 50mL of dichloromethane, and stirred at room temperature for 2h. Gradually add 5.0mmol of N,N-dimethylethylenediamine, stir at room temperature for 30min, add 10mL of a hexane solution of trimethylaluminum...

Embodiment 3

[0041] Step 1) Slowly add 3.28g of 5-methyltetrazolium into 59mL of 60% H 2 SO 4 , stirred at room temperature for 20 minutes, 8.17 g of 7-ACA was added in three times, with an interval of 15 minutes between each addition, and the reaction was stirred at room temperature for 1 to 1.5 hours; ), and then the extract was washed with 40mL of water, 40mL (3%) Na 2 CO 3 Dissolved, washed with 40mL water, anhydrous Na 2 SO 4 After drying, the solvent was evaporated, and 7.66 g of 7-MTCA was obtained by vacuum drying, with a yield of 93.22%, a purity of 99.37%, and 0.05% of 7-MTCA isomer impurity.

[0042] Step 2) Prepare a trimethylaluminum hexane solution with a concentration of 2M at 5°C for subsequent use; 5.67g Boc 2 O. 4.58g of ethyl aminothiaxamate was slowly added to 50mL of dichloromethane, and stirred at room temperature for 2h. Gradually add 5.0mmol of N,N-dimethylethylenediamine, stir at room temperature for 30min, add 16mL of 2M trimethylaluminum hexane solution, st...

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Abstract

The invention relates to a preparation method of cefteram pivoxil. The preparation method comprises following steps: taking 7-ACA and 5-methyltetrazole as starting raw materials, carrying out reactions in the presence of H2SO4 to generate 7-MTCA, protecting the amino groups of aminothiazol acetate, reacting aminothiazol acetate with 7-MTCA under the catalytic effect of AlMe3 to generate an intermediate (I); carrying out esterification reactions between the intermediate (I) and iodomethyl pivalate under the action of a phase transfer catalyst and an acid adsorbent, and removing the amino protection to obtain the target product (cefteram pivoxil). The reaction conditions are mild, the product purity and yield are high, and the technology is stable, is easy for amplification, and is suitablefor industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of cefditoren neopentyl ester. Background technique [0002] Cefteram pivoxil 1, chemical name: (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide ]-3-[(5-methyl-2H-tetrazol-2-yl)-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- 2,2-dimethylpropionyloxymethyl-ene-2-carboxylate is an oral third-generation cephalosporin developed and marketed by Toyama Chemical Co., Ltd. in Japan in the early 1990s under the trade name Tomirom. This product has high broad-spectrum antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and is highly stable against β-lactamase. Currently, common pathogenic bacteria are rarely resistant to it. Its chemical structural formula is as follows: [0003] [0004] Several preparation methods about the synthesis of cefditoren neopentyl ester have been reported at present, as follows: [0005] Route...

Claims

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Application Information

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IPC IPC(8): C07D501/46C07D501/04
CPCC07D501/04C07D501/46
Inventor 刘振腾董雪菊盛中丽田松
Owner SHANDONG YUXIN PHARMA CO LTD
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