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Preparation method for intermediate of tebipenem pivoxil

A technology of tipipenem and pivoxil is applied in the field of preparation of intermediates, and can solve the problems of difficult preparation and storage of raw materials and high production costs, and achieve the effects of simple operation, simple post-processing and high product yield.

Inactive Publication Date: 2012-11-14
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The technical problem to be solved by the present invention is to provide a tebipenem pivoxil intermediate in order to overcome the defects of high production cost, difficult raw material preparation and storage, etc. The preparation method of the intermediate I of voltaic acid ester

Method used

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  • Preparation method for intermediate of tebipenem pivoxil
  • Preparation method for intermediate of tebipenem pivoxil

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Under nitrogen protection, compound (IV) (33.8 g, 80.6 mmol), tributylphosphine (20 g) and water (1.45 g) were added to 600 mL of anhydrous acetonitrile, stirred at room temperature for 50 min, and MAP ( 87.2g, 146.5mmol), diisopropylethylamine (23.9g, 185mmol) was added dropwise, reacted for 1h after the dropwise addition at -10°C, added 360mL of water, stirred for 2h, filtered, washed with water, and dried to obtain the target compound (I) 74.7g, yield 98.2%, purity 99.2%.

Embodiment 2

[0040] Under argon protection, compound (IV) (33.8g, 80.6mmol), tributylphosphine (20g) and water (20.0g) were added to 1000mL of anhydrous acetonitrile, stirred at room temperature for 1.5h, and added at -10°C MAP (87.2g, 146.5mmol), N-methylmorpholine (15.5g, 163mmol) was added dropwise, reacted for 1h after the dropwise addition at -10°C, added 360mL of water, stirred for 2h, filtered, washed with water, and dried 68.1 g of the target compound (I) was obtained with a yield of 89.6% and a purity of 96.7%.

Embodiment 3

[0042]Under nitrogen protection, compound (IV) (33.8g, 80.6mmol), tributylphosphine (20g) and water (1.45g) were added to 1000mL acetonitrile, stirred at room temperature for 30min, and MAP (87.2g , 146.5mmol), dropwise added triethylamine (30.4g, 162.0mmol), reacted at -20°C for 3h after the dropwise addition, added 600mL of water, stirred for 2h, filtered, washed with water, and dried to obtain the target compound (I) 69.3 g, yield 91.1%, purity 99.4%.

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Abstract

The invention discloses a preparation method for an intermediate of tebipenem pivoxil shown as formula 1. The preparation method comprises the following step of performing the following reaction on a compound MAP and a compound IV in an organic solvent and water, with the action of (R1)3P and an organic base, under inert gas protection, wherein the volume ratio of the organic solvent and water is 1000 : 1-10 : 1; a reaction temperature is -40-50 DEG C; and R1 represents phenyl or C2-C8 alkyls. The preparation method is easy to operate, simple in post-treatment, with the product having high yield and high purity, and is suitable for industrialized production.

Description

technical field [0001] The present invention specifically relates to a preparation method of an intermediate of tipipenem pivoxil as shown in formula I. Background technique [0002] Tipipenem pivoxate is the world's first oral carbapenem antibiotic researched and developed by Japan's Meiji Seika Co., Ltd., and it was first launched in Japan on August 26, 2009. [0003] Tipipenem Pivolate is a prodrug of tipipenem. Tipipenem is a broad-spectrum antimicrobial that is effective against both Gram-positive and Gram-negative bacteria. Staphylococcus, Streptococcus, Pneumococcus (including PRSP), Moraxella (Branhamella) (including β-lactamase producing bacteria), Haemophilus influenzae (including ampicillin-resistant Haemophilus influenzae ) and so on have strong antibacterial effects, especially for bacteria that cause children's otitis media, sinusitis and pneumonia. For penicillin-resistant pneumococci, the antibacterial activity of macrolide-resistant pneumococci is stronge...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06
Inventor 罗颖刘相奎沈裕辉朱雪焱袁哲东
Owner SHANGHAI INST OF PHARMA IND
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