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Refining method of side chain of tebipenem pivoxil

A technology of tipipenem ester and a purification method, applied in the field of organic drug synthesis, can solve the problems of low product purity and yield, difficult crystallization and the like, and achieve the effects of simple operation, reduced production cost and mild conditions

Active Publication Date: 2017-12-08
ZHEJIANG HISOAR CHUANNAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] We have referred to the report of the above-mentioned patent documents to refine the tipipenem ester side chain, and found that crystallization is difficult during refining, and the product purity and yield are low

Method used

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  • Refining method of side chain of tebipenem pivoxil
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  • Refining method of side chain of tebipenem pivoxil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 29.8g tipipenem ester side chain crude product and 0.1g potassium iodide into 60ml water, add saturated potassium iodate solution dropwise at 30°C, after TLC (thin layer chromatography) detects that the reaction is over, add 60ml dichloromethane, stir After 10 minutes, separate the liquid, discard the organic layer, adjust the pH value of the aqueous layer to 9-10 with 30% sodium hydroxide solution, filter, and dry to obtain 16.5 g of white solid, with a yield of 95.3%.

[0029] In a 250ml three-necked flask, add 13.9g (40mmol) of the white solid obtained in the previous step, 11.0g (42mmol) of triphenylphosphine, 8.5g of 36% hydrochloric acid (HCl84mmol) and 70ml of ethanol, stir and heat up to 30°C, heat preservation reaction, TLC The reaction was monitored until conversion of starting material was complete. The reaction solution was heated up to 50°C and concentrated to dryness under reduced pressure. After it was hot, 20ml of ethanol was added to dissolve it. Af...

Embodiment 2

[0031] Add 10.4g of tipipenem ester side chain crude product and 0.05g of potassium iodide into 30ml of water, add saturated potassium iodate solution dropwise at 30°C, after the reaction is detected by TLC, add 30ml of n-butanol, stir for 10min, separate the liquid, discard The organic layer and the aqueous layer were adjusted to pH 8-9 with sodium carbonate solution, filtered, and dried to obtain 7.8 g of white solid, with a yield of 90.0%.

[0032] In a 100ml three-necked flask, add 7.6g (22mmol) of the white solid obtained in the previous step, 6.0g (23mmol) of triphenylphosphine, 4.7g of 36% hydrochloric acid (HCl 46.2mmol) and 45ml of ethanol, stir and heat up to 30°C, and keep the temperature for reaction , TLC monitored the reaction until the conversion of the starting material was complete. The reaction solution was heated to 60°C and concentrated to dryness under reduced pressure. After it was hot, 13ml of n-butanol was added to dissolve it. After the temperature dro...

Embodiment 3

[0034] Add 44.3g of tipipenem ester side chain crude product and 0.1g of sodium iodide into 90ml of water, add saturated potassium iodate solution dropwise at 30°C, after the reaction is detected by TLC, add 90ml of ethyl acetate, stir for 10min, and separate the liquids , the organic layer was discarded, and the pH value of the aqueous layer was adjusted to 11-12 with sodium bicarbonate solution, filtered, and dried to obtain 25.1 g of a white solid, with a yield of 96.5%.

[0035]In the there-necked flask of 100ml, add 22.8g (66mmol) last step gained white solid, 18.0g (69mmol) triphenylphosphine, 2.4g (132mmol) water, 66ml ethanol and 2M HCl ethanolic solution 69ml (HCl 138mmol), stir The temperature was raised to 30° C., and the reaction was carried out with heat preservation, and the reaction was monitored by TLC until the conversion of the raw materials was complete. The reaction solution was heated up to 55°C and concentrated to dryness under reduced pressure. After it ...

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Abstract

The invention discloses a refining method of a side chain of tebipenem pivoxil. The refining method comprises the following steps: oxidizing a coarse side chain of tebipenem pivoxil into a disulphide; purifying the disulphide; and then reducing the disulphide into the side chain of tebipenem pivoxil to prepare a refined product of the side chain of tebipenem pivoxil. Compared with a method of physically refining the coarse side chain of tebipenem pivoxil, the refined side chain of tebipenem pivoxil prepared by the refining method is high in yield, high in purity and stable in chemical property, and the refining method disclosed by the invention has the advantages of being simple to operate, economical and practical, suitable for industrial production and the like.

Description

technical field [0001] The invention belongs to the technical field of organic medicine synthesis, and in particular relates to a method for refining tipipenem ester side chains, more precisely 3-mercapto-1-(1,3-thiazoline-2-yl)-azetidines Refining method of alkane hydrochloride. Background technique [0002] As a new member of carbapenem antibiotics, tipipenem ester has strong antibacterial activity against Gram-positive and negative bacteria. (Branhamella spp.) sensitive to penicillin-sensitive drug-resistant Streptococcus pneumoniae and Haemophilus influenzae have better curative effect. Tipipenem ester fine granule is the first carbapenem antibiotic administered orally in the world. It has strong clinical compliance, low antibacterial concentration, is not easy to lead to the emergence of bacterial resistance, and has few side effects. , High drug safety and other advantages, can be used for the treatment of ear, nose, throat and upper respiratory tract infections in p...

Claims

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Application Information

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IPC IPC(8): C07D417/04
CPCC07D417/04
Inventor 李洪明汪祝胜谢菊冲石岳崚陶敏杰赵思盛秀东唐鹤
Owner ZHEJIANG HISOAR CHUANNAN PHARMA
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