Carbpenem penicillin ertapenem intermediate, and preparation and use thereof

A technology of carbapenems and ertapenem, which is applied in the field of organic compound synthesis, can solve problems such as difficult industrial production, high equipment requirements, and harsh conditions, and achieve the effect of simple operation, simple experimental conditions, and mild reaction conditions

Inactive Publication Date: 2009-03-04
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to overcome that the synthesis method of ertapenem in the prior art is not easy to be applied to industrial production, and the industrial method needs to be car...

Method used

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  • Carbpenem penicillin ertapenem intermediate, and preparation and use thereof
  • Carbpenem penicillin ertapenem intermediate, and preparation and use thereof
  • Carbpenem penicillin ertapenem intermediate, and preparation and use thereof

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preparation example Construction

[0034] Reference Examples Preparation of Formula II Compounds

[0035] Formula I compound (26.5g, 157.9mmol) in CH 2 Cl 2 350ml, add NEt 3 (32g, 316.1mmol), 4-methoxybenzyl chloride (PMBCl) (44.4g, 283.6mmol) was added dropwise at room temperature, the temperature was raised to 45°C, and the reaction was carried out for 3 hours. use CH 2 Cl 2 and water extraction, combined CH 2 Cl 2 layer with anhydrous NaSO 4 Dry, filter, and concentrate the filtrate to obtain a light yellow solid (Formula II) (41.5 g, yield 91.5%, purity >99%).

Embodiment 1

[0036] The synthesis of embodiment 1 3-aminobenzoic acid 4-methoxybenzyl ester (formula III)

[0037] Compound shown in formula II (10.00g, 34.81mmol) in SnCl 2· 2H 2 O (39.33g, 174.05mmol) in 70ml of ethanol, heated up to 50°C, and reacted for 30min. Use 8wt% NaOH alcohol solution to adjust pH=9, filter, extract with ether and water, combine the ether layers, anhydrous NaSO 4 Dry, filter, and concentrate the filtrate to obtain a light yellow solid (Formula III) (8.10 g, 90.5%). Melting point: 45-47°C.

[0038] NMR (CDCl 3 )δ: 3.77(s, 3H); 5.25(s, 2H); 6.80(m, 1H); 6.89(m, 2H); 7.16(m, 1H); 7.33(m, 2H); ); 7.43 (m, 1H)

[0039] MS(CI): 258[M+H]

Embodiment 2

[0040] The synthesis of embodiment 2 3-aminobenzoic acid 4-methoxybenzyl ester (formula III)

[0041] Compound shown in formula II (40.93g, 142.47mmol) in SnCl 2· 2H 2 O (161.0g, 712.37mmol) in 300ml of ethanol, heated to 50°C, and reacted for 50min. Adjust the pH to 11 with 15% NaOH alcohol solution, extract with ether and water, combine the ether layers, anhydrous NaSO 4 Dry, filter, and concentrate the filtrate to obtain a light yellow solid (Formula III) (33.84 g, 92.3%). Melting point: 50-52°C.

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Abstract

The invention discloses an intermediate for synthesizing carbapenems penicillin etapenem having the formula of III, and a preparation method and application in the preparation of carbapenems penicillin etapenem thereof. The preparation method comprises the following steps: heating an intermediate having the formula of II under the action of stannous chloride dehydrate for reacting and regulating pH of reaction solution to greater than 7 with inorganic alkal, wherein PMB is the formula V. The intermediate can be used for preparing etapenem side chain, and further etapenem. The preparation method can be carried out at room temperature, with the advantages of mild reaction condition, low cost, simple operation, simple experiment condition, no requirement for expensive reagent, high yield, no requirement for refining, and easily applicable industrialized production.

Description

technical field [0001] The invention belongs to the field of organic compound synthesis, and in particular relates to an intermediate of the carbapenem penicillin ertapenem, a preparation method and application thereof. Background technique [0002] Ertapenem (ertapenem, MK-0826, L-749, 345, trade name Invanz) is a new type of broad-spectrum carbapenem antibiotic developed by Merck Pharmaceutical Company of the United States. Stability, excellent pharmacokinetic parameters, good clinical therapeutic effect, good tolerance, few adverse reactions and long half-life can be administered once a day. It is clinically used to treat infections caused by moderately to severely sensitive bacteria in adults. Satisfactory curative effect can be obtained for acquired mixed infection. This product was first launched in the United States in November 2001, and then successively launched in the United Kingdom, Ireland, Israel and the Philippines. [0003] US5478820 reports a synthetic meth...

Claims

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Application Information

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IPC IPC(8): C07C229/60C07C227/04C07D477/20
Inventor 陆洋单晓燕时惠麟
Owner SHANGHAI INST OF PHARMA IND
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