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Carbpenem penicillin ertapenem intermediate, and preparation and use thereof

A carbapenem and ertapenem technology, applied in the field of organic compound synthesis, can solve the problems of difficult industrialized production, high equipment requirements, harsh conditions, etc., and achieves the effects of simple operation, high purity and mild reaction conditions

Inactive Publication Date: 2011-08-10
SHANGHAI INST OF PHARMA IND CO LTD +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 carried out at a low temperature of -20°C, the conditions are relatively harsh, and the equipment requirements are relatively high. The problem of high cost, but provide a new intermediate compound and its preparation method and application

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Synthesis of 4-methoxybenzyl 3-nitrobenzoate (formula II)

[0023] Formula I compound (4.00g, 23.93mmol) in CH 2 Cl 2 50ml, add NEt 3 (4.84g, 47.91mmol), 4-methoxybenzyl chloride (PMBCl) (5.62g, 35.89mmol) 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) (6.29 g, yield 91.5%, purity >99%). Melting point: 82-84°C. The identification results are as follows:

[0024] NMR (CDCl 3 )δ: 3.81(s, 3H); 5.35(s, 2H); 6.93(m, 2H); 7.40(m, 2H); 7.63(m, 1H); )

[0025] MS (CI): 287

Embodiment 2

[0026] Example 2 Synthesis of 4-methoxybenzyl 3-nitrobenzoate (formula II)

[0027] Formula I compound (150.00g, 0.898mol) in ethyl acetate 100ml, add NEt 3 (181.89g, 1.797mol), PMBCl (251.49g, 1.605mol) was added dropwise at room temperature, the temperature was raised to 60°C, and the reaction was carried out for 5 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, which is recrystallized from ethanol to obtain white crystals (Formula II) (256.53 g, yield 99.5%, purity 100%). Melting point: 83-85°C. Identification result is the same as embodiment 1.

Embodiment 3

[0028] Example 3 Synthesis of 4-methoxybenzyl 3-nitrobenzoate (formula II)

[0029] Formula I compound (150.00g, 0.898mol) was added to 200ml of toluene, pyridine (106.41g, 1.35mol) was added, PMBCl (422.13g, 2.694mol) was added dropwise at room temperature, the temperature was raised to 40°C, and the reaction was carried out for 10 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, which is recrystallized from ethanol to obtain white crystals (Formula II) (256.00 g, yield 99.1%, purity >99%). Melting point: 83-85°C. Identification result is the same as embodiment 1.

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Abstract

The present invention discloses an intermediate shown as the formula II for synthesizing carbapenem penicillin ertapenem, and a preparation method thereof. The preparation method comprises the following steps: reacting a compound shown as a formula I with 4-methoxybenzyl chloride in the presence of an organic alkali reagent as a catalyst in a nonpolar solvent. The present invention also discloses the application of the intermediate on the preparation of the carbapenem penicillin ertapenem. In the formula I and formula II, PMB is the intermediate compound which can be prepared into ertapenem side chain and then further into ertapenem. The preparation method has the advantages that the conditions of each reaction are mild, the reaction can be carried out at the room temperature, the cost is low, the method is easily applied on an industrialized production, the operation is simple, the experimental condition is simple, no expensive reagent is required, the yield is high and reaches above 90%, and the purity is high.

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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Patent Type & Authority Patents(China)
IPC IPC(8): C07C205/57C07C201/12
Inventor 陆洋单晓燕时惠麟王朝东刘勇
Owner SHANGHAI INST OF PHARMA IND CO LTD