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Preparation of carbapenem penicillin ertapenem intermediate

An intermediate and time technology, applied in the field of organic compound synthesis, can solve the problems of harsh conditions, high cost and high equipment requirements, and achieve the effect of mild reaction conditions and low cost.

Inactive Publication Date: 2009-03-04
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 higher cost, and provide a kind of preparation method of carbapenem penicillin ertapenem intermediate with mild reaction conditions and lower cost

Method used

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  • Preparation of carbapenem penicillin ertapenem intermediate
  • Preparation of carbapenem penicillin ertapenem intermediate
  • Preparation of carbapenem penicillin ertapenem intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Synthesis of 4-methoxybenzyl 3-nitrobenzoate (formula II)

[0037] 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:

[0038] NMR (CDCl 3)δ: 3.81(s, 3H); 5.35(s, 2H); 6.93(m, 2H); 7.40(m, 2H); 7.63(m, 1H); )

[0039] MS (CI): 287

Embodiment 2

[0040] Example 2 Synthesis of 4-methoxybenzyl 3-nitrobenzoate (formula II)

[0041] 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.

Embodiment 3

[0042] Example 3 Synthesis of 4-methoxybenzyl 3-nitrobenzoate (formula II)

[0043] 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.

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Abstract

The invention discloses a preparation method of an intermediate for synthesizing carbapenems penicillin etapenem having the formula of VII. The preparation method comprises the following steps: allowing a compound having the formula of I and 4-methoxybenzyl chloride to react to obtain a product; reacting under the action of stannous chloride dehydrate, and regulating pH to 7; performing condensation reaction of above product and activated ester of PNZ L-hydroxyproline; reacting with methylsulfonyl chloride; reacting with potassium thioacetate; and hydrolyzing in acidic or alkaline condition, wherein PMB is shown in figure (1), PNZ is shown in figure (2), Ms is mesyl, and Ac is acetyl. The preparation method can be carried out at the room temperature, with the advantages of mild reaction condition, low cost, and easily realized industrial production.

Description

technical field [0001] The invention belongs to the field of organic compound synthesis, and in particular relates to a preparation method of an intermediate of carbapenem penicillin ertapenem. 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 method of ertapenem. The meth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16C07D477/20
Inventor 陆洋单晓燕时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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