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Method for synthesizing novel meropenem chiral side chain

A technology of chiral side chains and synthetic methods, which is applied in the field of synthesis of meropenem intermediates, can solve the problems of difficult production safety, meropenem color difference, and low optical purity, and achieve low price, stable product quality, and optical purity high effect

Inactive Publication Date: 2018-03-27
SHANDONG RUIYING PIONEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The synthesis of side chain H uses p-nitrobenzyl chloroformate, potassium thioacetate, etc. as raw materials, and there are problems such as low optical purity and poor color grade.
When it is used to produce meropenem, it is necessary to use a precious metal catalyst to pressurize hydrogenation to remove the PNZ protecting group on the side chain H. The conditions are relatively harsh, and it is difficult to achieve safe production, and the color of the produced meropenem is poor.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The synthesis method of the novel chiral side chain of meropenem adopts the following steps:

[0025] a) Synthesis of compound (Ⅲ):

[0026] Dissolve 22.4 g of sodium hydroxide in 280 mL of water, cool down to 25°C, add 33g of (2S,4R)-4-hydroxyproline, and keep warm at 25°C. Dissolve 33.7mL of allyl chloroformate in 231 mL of dichloromethane, drop into the above solution, and stir at 25°C for 2h. After separation, the aqueous layer was washed with 100 mL of dichloromethane twice. The aqueous layer was adjusted to pH=1, extracted with 200 mL of ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain an oily substance. Add 280mL of toluene to the oil, stir and crystallize, and filter to obtain 48.9g of solid, yield 90%.

[0027] m.p.=90.8-91.8°C, [α]D25=-81.5° (c=1, MeOH).

[0028] 1H-NMR (300MHz, DMSO-d6)δ: 12.6 (s, 1H, COOH), 5.9 (m, 1H, =CH),5.05-5.35 (m, 2H, =CH2), 5....

Embodiment 2

[0043] The synthesis method of the novel chiral side chain of meropenem adopts the following steps:

[0044] a) Synthesis of compound (Ⅲ):

[0045] Dissolve 22.4g of sodium hydroxide in 280mL of water, cool down to 25°C, add 33g of (2S,4R)-4-hydroxyproline, and keep warm at 25°C. Dissolve 33.7mL of allyl chloroformate in 231mL of dichloromethane, drop into the above solution, and stir at 25°C for 2h. After the layers were separated, the aqueous layer was washed with 100 mL of dichloromethane twice. The aqueous layer was adjusted to about pH=1, extracted with 200 mL of ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. Filter and concentrate to dryness under reduced pressure to obtain an oil. Add 280mL toluene to the oil, stir and crystallize, filter to obtain 48.9g solid, yield 90%;

[0046] b) Synthesis of compound (IV):

[0047] Add 48.9g of compound (Ⅲ), 1000mL of dichloromethane, and 23.1mL of triethylamine into a 2000mL four-neck f...

Embodiment 3

[0054] The synthesis method of the novel chiral side chain of meropenem adopts the following steps:

[0055] a) Synthesis of compound (Ⅲ):

[0056] Dissolve 31.4g of potassium hydroxide in 280mL of water, cool down to 20°C, add 33g of (2S,4R)-4-hydroxyproline, and keep warm at 20°C. Dissolve 33.7 mL of allyl chloroformate in 231 mL of dichloromethane, drop into the above solution, and react with stirring at 20°C for 2 hours. After separation, the aqueous layer was washed with 100 mL of dichloromethane twice. Adjust the aqueous layer to about pH=1, extract with 200mL butyl acetate, and dry the butyl acetate layer with anhydrous magnesium sulfate. Concentrate under reduced pressure to dryness to obtain an oily substance, add 280mL toluene to the oily substance, stir and crystallize, filter to obtain 49.3g solid, yield 91%;

[0057] b) Synthesis of compound (IV):

[0058] Add 49.3g of compound (Ⅲ), 1000mL of dichloroethane, and 23.2mL of triethylamine into a 2000 mL four-neck...

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Abstract

The present invention relates to a synthesis method of a meropenem intermediate, in particular to a synthesis method of a novel chiral side chain of meropenem. The synthesis method of the novel chiral side chain of meropenem is characterized in that it comprises the following steps: a) using compound (I) and compound (II) as raw materials to synthesize compound (III); b) preparing compound from compound (III) (IV); c) synthesizing compound (V) from compound (IV); d) generating final product (VII) from compound (V) and compound (VI). The beneficial effects of the synthesis method of the novel chiral side chain of meropenem in the present invention are: the product has a novel structure, high optical purity, and good color grade; raw materials are cheap and easy to obtain, and the price of allyl chloroformate is lower than that of traditional p-nitrobenzyl chloroformate ; The reaction operation is simplified, and the reaction conditions are mild.

Description

technical field [0001] The present invention relates to a synthesis method of a meropenem intermediate, in particular to a synthesis method of a novel chiral side chain of meropenem. Background technique [0002] Meropenem (meropenem) is a fully synthetic carbapenem antibiotic, which was first successfully developed by Japan's Sumitomo Pharmaceutical Co., Ltd., and was first listed in Italy under the trade name "Merrem" (美平) in January 1995. [0003] As a new carbapenem antibiotic, meropenem has the outstanding advantages of broad antibacterial spectrum and strong antibacterial activity. It plays antibacterial and bactericidal effects by inhibiting the synthesis of bacterial cell walls. It is sensitive to Gram-positive bacteria and Gram-negative bacteria, especially has strong antibacterial activity against Gram-negative bacteria. It is currently one of the few medicines that can treat various diseases. Broad-spectrum antibiotic products for infectious diseases. [0004] M...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16C07B2200/07
Inventor 彭继先王辉尚中栋
Owner SHANDONG RUIYING PIONEER PHARMA
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