Preparation method of cefcapene pivoxil hydrochloride

A technology of cefcapene pivoxil hydrochloride and hydrochloric acid, which is applied in the field of medicine and chemical industry, can solve the problems of unsuitability for large-scale production, low yield, complicated operation, etc., and achieve the advantages of simple operation, high reaction yield, and high reaction yield Effect

Inactive Publication Date: 2015-12-30
马晓维 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is complicated to operate, and the cost is high, so it is not suitable for large-scale production
[0006] CN102775425A discloses a one-pot preparation method for the key intermediate of cefcapene axetil, cefcapene diisopropylamine salt. Although the operation is simple, the yield of the method is not high, and the two-step reaction product is only available when the purity is unknown. 67%

Method used

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  • Preparation method of cefcapene pivoxil hydrochloride
  • Preparation method of cefcapene pivoxil hydrochloride
  • Preparation method of cefcapene pivoxil hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0034] The preparation method of cefcapene pivoxil hydrochloride comprises the steps:

[0035] 1) 29.8 g (100 mmol) of the compound represented by formula I ((Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid)) was stirred and dissolved in 90 mL of pyridine, Add 16 g (140 mmol) of methanesulfonyl chloride at -10°C, stir and react for 2 hours, then filter to obtain a liquid containing the compound represented by formula (II), store it at -15°C, and set aside;

[0036]2) First mix 4.6g of proline, 12.1g (120mmol) of diisopropylamine and 23.1g (85mmol) of 7-ACA in 100ml of methanol and lower the temperature to 10°C, then mix the product obtained in step 1) containing the formula II The liquid of the compound was dripped into the reaction for 2h, naturally rose to room temperature, adjusted the pH of the solution to 4 with 2mol / L hydrochloric acid, extracted, combined the organic phases, concentrated under reduced pressure, recrystallized from methanol, and dried to o...

Embodiment 2

[0042] The preparation method of cefcapene pivoxil hydrochloride comprises the steps:

[0043] 1) 29.8 g (100 mmol) of the compound ((Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid) represented by formula I was dissolved in 80 ml of pyridine with stirring, Add methanesulfonyl chloride at -15°C, stir and react for 1-2 hours, then filter to obtain a liquid containing the compound represented by formula (II), store it at -10°C, and set aside;

[0044] 2) First, mix 4.4g of proline, 10.1g (100mmol) of diisopropylamine and 24.5g (90mmol) of 7-ACA in 100m methanol and cool down to 15°C, then mix the product obtained in step 1) containing the formula II The liquid of the compound was dropped into the reaction for 1 hour, and naturally rose to room temperature, and the pH of the solution was adjusted to 4 with 2mol / L hydrochloric acid, extracted with dichloromethane, the organic phases were combined, concentrated under reduced pressure, recrystallized from methanol, an...

Embodiment 3

[0050] The preparation method of cefcapene pivoxil hydrochloride comprises the steps:

[0051] 1) 29.8 g (100 mmol) of the compound represented by formula I ((Z)-2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid)) was stirred and dissolved in 120 ml of pyridine, Add 14.9 g (130 mmol) of methanesulfonyl chloride at 0°C, stir and react for 2 hours, then filter to obtain a liquid containing the compound represented by formula (II), store it at -15-0°C, and set aside;

[0052] 2) First, mix 3.3g of proline, 11.1g (110mmol) of diisopropylamine (110mmol) and 21.8g (80mmol) of 7-ACA in 100m methanol and cool down to 12°C. The liquid of the compound was dropped into the reaction for 2 hours, and naturally rose to room temperature, and the pH of the solution was adjusted to 4 with 2mol / L hydrochloric acid, extracted with dichloromethane, the organic phases were combined, concentrated under reduced pressure, recrystallized from methanol, and dried to obtain the compound shown ...

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Abstract

The invention discloses a preparation method of cefcapene pivoxil hydrochloride. The preparation method comprises the following steps: 1), a compound shown in the formula I is stirred and dissolved in pyridine, methanesulfonyl chloride is added and stirred for reaction, filtering is performed, and a liquid containing a compound shown in the formula II is obtained; 2), 7-ACA reacts with the liquid containing the compound shown in the formula II in the presence of proline and diisopropylamine, and a compound shown in the formula III is obtained; 3), the compound shown in the formula III reacts with potassium carbonate, and a compound shown in the formula IV is obtained; 4), the compound shown in the formula IV reacts with chlorosulfonyl isocyanate in the presence of diisopropylamine, and a compound shown in the formula V is obtained; 5), the compound shown in the formula V and obtained in the step 4) reacts with iodomethyl pivalate in DMF (dimethyl formamide) in the presence of potassium phosphate and copper acetate, a phosphate solution is added to end the reaction, and a compound shown in the formula VI is obtained; 6), cefcapene pivoxil hydrochloride is obtained after deprotection of the compound shown in the formula VI. The method increases product yield greatly and is particularly suitable for mass production, and few by-products are produced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a preparation method of cefcapene hydrochloride. Background technique [0002] Cefcapene pivoxil is the third-generation oral cephalosporin antibiotic. It is a new type of cephalosporin antibiotic developed by Shionogi Company in Japan. It has strong antibacterial activity against Gram-positive and Gram-negative bacteria. [0003] Cefcapene pivoxil hydrochloride, chemical name: (6R,7R)-3-((aminocarbonyl)oxy)methyl-7-(((Z)-2-(2-aminothiazol-4-yl)-2 -pentenoyl)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (2,2-dimethyloxypropoxy (methyl) ester hydrochloride monohydrate, there are many reports about its synthetic method at present, but there are various problems. [0004] IshikuraK et al. (TheJouralOfAntibiotics.1994,466-476) disclose a kind of synthetic method of cefcapene pivoxil, this method is raw material with 7-aminocephalosporanic acid, is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/04
CPCC07D501/04C07D501/34
Inventor 陈令浩
Owner 马晓维
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