Improved manufacturing method of ertapenem side chain

A technology of ertapenem side chain and raw material is applied in the field of preparation of carbapenem antibiotic side chain, and can solve the problems of excessive waste water, high product cost, environmental pollution and the like

Inactive Publication Date: 2016-05-11
HANDAN KANGRUI BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The existing public preparation method of ertapenem side chain (1), such as patent US5872250, WO9802439, JP2009 / 007261 and CN1800162, etc., discloses the preparation method of N-protected ertapenem side chain, the reaction is in acetic acid, propane Carboxylic acid solvents such as acid; or halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane, nitrile solvents such as acetonitrile, ether solvents such as THF or ether, ethyl acetate, butyl acetate, etc. Carry out in the mixed solvent of the composition of aromatic hydrocarbon solvents such as ester solvent, benzene, toluene; The defective that prior art exists: (1) react with above-mentioned solvent, the product crystal character that obtains is fine and small, wraps a large amount of difficult volatile acetic acid etc. Solvent, the product is more difficult to dry, and the production cycle is long; (2) when the product is washed, a large amount of water is used to wash the acetic acid, resulting in excessive waste water and polluting the environment; (3) and the difficulty of solvent recycling, resulting in higher product costs

Method used

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  • Improved manufacturing method of ertapenem side chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Example 1: Preparation of Compound 1

[0015] At 60°C, to 200g of methanol solution containing meta-aminobenzoic acid (9.45g, 68.9mmol), add 1g of tributylphosphine and 400ml of 4MHCl / methanol solution, and then slowly add raw material I (19.8g, 64.28mmol) Then, the reaction mixture was stirred for 3h at the same temperature. The slurry reaction solution was cooled and filtered to obtain white crystals. The white crystals were washed with methanol and dried in vacuum to obtain 127.8 g of compound. The molar yield was 97% and the HPLC purity was 99.2. %

[0016] MS: 446.1[M+1], 444.3[M-1]

[0017] 1 H-NMR (400MHz, DMSO-d6): δ 1.85 (m, 1H), 2.70 (m, 1H), 3.27 (m, 2H), 3.97 (m, 1H), 4.35 (m, 1H), 5.13 ( m, 1H), 7.82 (m, 8H), 10.28 (d, J = 9.0 Hz, 1H).

Embodiment 2

[0018] Example 2: Preparation of Compound 2

[0019] At 70℃, to 120g of ethanol solution containing meta-aminobenzoic acid (5.59g, 40.8mmol), add 0.5g of tributylphosphine and 200ml of 4MHCl / 7 alcohol solution, and then slowly add raw material I (12.32g40mmol) 150g of ethanol solution, then stirred and reacted at the same temperature for 2.5h, the slurry reaction solution was cooled and filtered to obtain white crystals, which were washed with ethanol and dried in vacuum to obtain 116.8g of compound, molar yield 94.8%, HPLC purity 99.4 %

Embodiment 3

[0020] Example 3: Preparation of Compound 2

[0021] At 80°C, to 150 g of a propanol solution containing meta-aminobenzoic acid (11.18 g, 81.6 mmol), 1.2 g of tributyl phosphine and 140 g of acetic acid were added, and then slowly added the propylene of raw material I (24.64 g, 80 mmol). 400g of alcohol solution, then stirred and reacted at the same temperature for 2h. The slurry reaction solution was cooled and filtered to obtain white crystals. The white crystals were washed with propanol and dried in vacuum to obtain 134.25g of compound. The molar yield was 96% and the HPLC purity was 99.5. %.

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Abstract

The invention relates to an improved preparation method of a carbapenem compound ertapenem side chain (disclosed as Formula 1). The method comprises the following step: by using amino-protected thiolactone (disclosed as Formula I) as a raw material, carrying out reaction with 3-aminobenzoic acid under acidic conditions by using single saturated alcohol as a reaction solvent, thereby preparing the target compound. By using the single saturated alcohol as the reaction solvent, the crystal characters of the product are improved, and the production cycle is shortened. The method is economical, safe and environment-friendly, and is more suitable for the industrial production scale.

Description

Technical field [0001] The invention relates to a preparation method of carbapenem antibiotic side chains, in particular to an improved preparation method of N-protected ertapenem side chains. Background technique [0002] 3-[[(2S,4S)-4-mercapto-1-p-nitrobenzyloxycarbonyl-2-pyrrolidinyl]formyl]aminobenzoic acid is a new carbapenem antibiotic ertapenem Ertapenem (Ertapenem, MK-0826, L-749, trade name Invanztm) is a new broad-spectrum long-acting 1β-methyl carbapenem antibiotic developed by Merck in the United States, which was released in November 2001 and It was launched in the United States and Europe in April 2002. This product has good antibacterial activity and pharmacokinetic properties, and has significant effects on Gram-positive and negative aerobes and anaerobes. [0003] The existing public preparation methods for the side chain of ertapenem (1), such as patents US5872250, WO9802439, JP2009 / 007261 and CN1800162, etc., disclose the preparation methods of N-protected erta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 张艳玲秦玉君米国瑞
Owner HANDAN KANGRUI BIOTECH CO LTD
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