Cefcapene pivoxil hydrochloride and method for preparing its intermediate

A technology of cefcapene pivoxil and cefcapene acid, which is applied in the field of preparation of cefcapene pivoxil hydrochloride and its intermediates, can solve the problems of long reaction steps and difficult availability of starting materials, and achieve few synthesis steps and cheap raw materials , the effect of simple operation

Active Publication Date: 2012-06-06
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The used starting raw material of this method is not easy to get, and reaction step is longer, just can obtain product cefcapene hydrochloride pivoxil hydrate through five-step reaction

Method used

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  • Cefcapene pivoxil hydrochloride and method for preparing its intermediate
  • Cefcapene pivoxil hydrochloride and method for preparing its intermediate
  • Cefcapene pivoxil hydrochloride and method for preparing its intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Embodiment 1: Preparation of tert-butoxycarbonyl cefcapene sodium salt (compound of formula vi)

[0051] Add 7-DACA (100 g, 0.43 mol), 500 mL of dichloromethane, and 55 ml of tetramethylguanidine into a 1 L reaction flask, and stir to dissolve. Cool down to -20°C and keep warm to prepare for the following condensation reaction.

[0052] Add cefcapine side-chain acid (130 g, 0.44 mol), 1.3 L of dichloromethane, and 90 ml of triethylamine into a 5 L reaction flask, and stir to dissolve. The temperature was lowered to -20°C, 60ml of methanesulfonyl chloride was added, and the reaction was stirred for 30min. Then add the prepared 7-DACA feed solution, and react at -20°C for 3 hours. Then chlorosulfonyl isocyanate (42ml, 0.48mol) was added, and the reaction was carried out at -20°C for 2 hours. Add 800 mL of tetrahydrofuran and water, 100 g of sodium bicarbonate, and stir for 30 min. The phases were separated, and the organic phase was washed once with water, and a sodium ...

Embodiment 2

[0053] Embodiment 2: Preparation of tert-butoxycarbonyl cefcapene sodium salt (compound of formula vi)

[0054] Add 7-DACA (100 g, 0.43 mol), 500 mL of dichloromethane, and 55 ml of tetramethylguanidine into a 1 L reaction flask, and stir to dissolve. Cool down to -15°C and keep warm to prepare for the following condensation reaction.

[0055] Add cefcapine side-chain acid (137 g, 0.46 mol), 1.3 L of dichloromethane, and 96 ml of diisopropylamine into a 5 L reaction flask, and stir to dissolve. Cool down to -15°C, add 67ml of methanesulfonyl chloride, stir for 30 minutes, add the prepared 7-DACA feed solution, and react at -15°C for 3 hours. Then trichloroacetyl isocyanate (63.2ml, 0.53mol) was added, and the temperature was controlled at -15°C for 2 hours. Add 800 mL each of tetrahydrofuran and water, add 139 g of sodium carbonate, and stir for 30 minutes. The phases were separated, the organic phase was washed once with water, a solution of sodium isooctanoate in tetrahyd...

Embodiment 3

[0056] Embodiment 3: the preparation of cefcapene acid (formula ii compound)

[0057] Add tert-butoxycarbonyl cefcapene sodium salt (100 g, 0.17 mol), 600 mL of methanol, and 600 mL of 1N HCl into a 2L reaction flask, and stir and react at -10°C for 8 hours. After the reaction was completed, the pH of the solution was adjusted to 7.5 with saturated sodium bicarbonate, and extracted with ethyl acetate. The resulting aqueous phase was adjusted to pH 3 with 3N HCl, and a solid was precipitated, filtered, washed, and dried to obtain 69.5 g of the title compound as a white solid, with a molar yield of 87% and an HPLC purity of 99.2%.

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Abstract

The invention relates to a cefcapene pivoxil hydrochloride and a method for preparing an intermediate of cefcapene pivoxil hydrochloride, the method is characterized in that 7-DACA (iii) is taken as a raw material, and is performed condensation reaction with cefcapene pivoxil hydrochloride side chain acid (iv) and a carbamylated reagent to obtain tertbutyloxycarbonyl cefcapene acid sodium salt (vi), an amino protective group is removed to obtain the cephalospene acid (ii), then performed esterification reaction with iodomethyl pivalate, salifying with hydrochloric acid to obtain the cefcapene pivoxil hydrochloride hydrate (i) (a flow chart is shown as follows). The preparation method has the advantages of cheap raw material, easy raw material acquisition, less reaction step, high yield and high purity of intermediate and product, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a kind of preparation method of cephalosporin, in particular to a kind of preparation method of cefcapene pivoxil hydrochloride and its intermediate. Background technique [0002] Cefcapene pivoxil hydrochloride (cefcapene pivoxil hydrochloride, structural formula shown in formula i), chemical name is (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-Dimethyloxypropoxymethyl) ester hydrochloride monohydrate is a broad-spectrum and β-lactam developed by Shionogi, Japan. An enzyme-stabilized oral antibiotic, which was launched in Japan under the trade name Flomox in July 1997, is used to treat respiratory and urinary system infections, ophthalmic and ENT infections, and skin and soft tissue infections. It has strong clinical application advantages. [0003] [0004] US4731361 first disclosed the cefcapene axetil c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/04
CPCY02P20/55
Inventor 张宏武龚登凰吕健马玉秀陈玉洁孙会谦武仙英
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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