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A kind of preparation method of cefcapene 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, complicated operation, and low yield, and achieve the effects of simple operation, increased reaction yield, and improved reaction yield

Active Publication Date: 2018-06-26
湖北凌晟药业股份有限公司
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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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  • A kind of preparation method of cefcapene hydrochloride
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  • A kind of preparation method of cefcapene hydrochloride

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Embodiment 1

[0032] A preparation method of cefcapene pivoxil hydrochloride, the method may further comprise the steps:

[0033] 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 80 mL of pyridine, Add 17.2 g (150 mmol) of methanesulfonyl chloride at -15°C, stir and react for 1 hour, then filter to obtain a liquid containing the compound represented by formula II, store it at -10°C, and set aside;

[0034]2) First mix 6.2g of proline, 10.1g (100mmol) of diisopropylamine and 20.7g (90mmol) of 7-HACA in 100mL of methanol and lower the temperature to 0°C, then mix the product containing formula II obtained in step 1) The liquid of the compound was dripped into the reaction for 1.5h, naturally rose to room temperature, adjusted the pH of the solution to 5 with 2mol / L hydrochloric acid, extracted with dichloromethane, combined the organic phases, concentrated under reduced pressure, recry...

Embodiment 2

[0039] A preparation method of cefcapene pivoxil hydrochloride, the method may further comprise the steps:

[0040] 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 100 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, put it at 0°C, and set aside;

[0041] 2) First mix 4.6g of proline, 11.1g (110mmol) of diisopropylamine (110mmol) and 18.4g (80mmol) of 7-HACA in methanol and lower the temperature to 5°C, then the 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 5 with 2mol / L hydrochloric acid, extracted with dichloromethane, the organic phases were combined, concentrated under reduced pressure, recrystallized from methanol, and dried t...

Embodiment 3

[0046] A preparation method of cefcapene pivoxil hydrochloride, the method may further comprise the steps:

[0047] 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 16 g (140 mmol) of methanesulfonyl chloride at -10°C, stir and react for 1 hour, then filter to obtain a liquid containing the compound represented by formula II, store it at -15°C, and set aside;

[0048] 2) First mix 5.5g of proline, 12.1g (120mmol) of diisopropylamine (120mmol) and 19.6g (85mmol) of 7-HACA in methanol and lower the temperature to 10°C, then the 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 5 with 2mol / L hydrochloric acid, extracted with dichloromethane, the organic phases were combined, concentrated under reduced pressure, recrystallized from methanol, and dri...

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Abstract

The invention discloses a preparation method for cefcapene pivoxil hydrochloride. The method comprises the following steps: (1) stirring and dissolving a compound which is shown as formula (I) in pyridine, adding methylsufonyl chloride to react to obtain a liquid which contains the compound shown as formula (II), placing the liquid at -15 DEG C to 0 DEG C for later use; (2) in the existence of proline and diisopropylamine, enabling 7-HACA and the liquid which contains the compound shown as the formula (II) to react in methyl alcohol to obtain the compound which is shown as formula (III); (3) adding diisopropylamine, enabling the compound which is shown as the formula (III) and chlorosulfonyl isocyanate to react, regulating the pH to 4 to 5, cooling the organic phase, and adding the diisopropylamine to obtain the compound which is shown as formula (IV); (4) in the existence of potassium phosphate and copper acetate, enabling the compound which is shown as the formula (IV) and iodomethyl pivalate to react in DMF (Dimethyl Formamide) to obtain the compound which is shown as formula (V); (5) removing protecting groups from the compound which is shown as the formula (V) in the methanol solution of hydrochloric acid to obtain the cefcapene pivoxil hydrochloride. According to the method, the product yield is greatly improved, and the method is suitable for industrial production.

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] Ishikura K et al. (The Journal Of Antibiotics.1994, 466-476) disclose a kind of synthetic method of cefcapene pivoxil, which uses 7-aminocephalosporanic acid as a raw material, a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/34C07D501/04
CPCY02P20/55
Inventor 门万辉金联明
Owner 湖北凌晟药业股份有限公司
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