A kind of preparation method of 7-chloro-2-(1-oxoethyl) ethyl heptanoate

Abstract

The invention provides a preparation method of 7-chlorin-(1-oxo ethyl) ethyl oenanthate. 1-bromine-5-chloropentane of a structural formula III and ethyl acetoacetate of a structural formula IV are adopted as starting materials, under the existence of a polar solvent, an acid binding agent and a phase transfer catalyst, normal pressure heating is performed till the polar solvent is boiling, a reaction is performed for 6-8 h, and 7-chlorin-(1-oxo ethyl) ethyl oenanthate of a structural formula V is obtained. The phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, tetrabutyl ammonium chloride, benzyl trimethyl ammonium chloride, benzyl trimethyl ammonium bromide, 18-crown-6, dibenzo-18-crown-6, polyethylene glycol-400, benzyltrimethylammonium chloride-400 and polyethylene glycol-600, and preferentially polyethylene glycol-400. The molar ratio of the phase transfer catalyst to ethyl acetoacetate is 0.2-1.0:1.0, and preferentially 0.2-0.3:1.0. The preparation method is short in reaction time, high in product yield and good in purity.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of ethyl 7-chloro-2-(1-oxoethyl)heptanoate, a key intermediate of Cilastatin Sodium. Background technique [0002] Cilastatin sodium, structural formula as shown in (I), is a kind of renal dehydrodipeptidase inhibitor developed by Merck of the United States when developing the β-carbapenem antibiotic imipenem (Imipenem) , used in combination with imipenem, can effectively inhibit the degradation of imipenem by renal dehydrodipeptidase, and can reduce the nephrotoxicity of imipenem. Imipenem / cilastatin sodium, which was approved by the FDA in 1985, has a trade name of "Primaxin" in the United States and is a widely used compound broad-spectrum antibacterial preparation. [0003] [0004] The preparation method of multiple cilastatin sodium (I) has occurred in the prior art, wherein the method reported by the patent US5147868 is the most commonl...

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Problems solved by technology

[0009] After in-depth study of the method, it was found that the first step reaction, that is, the condensation of 1-bromo-5-chloropentane (III) with ethyl acetoacetate (IV) under the action of an acid-binding agent gave 7-chloro-2-( In the process of 1-oxoethyl) ethyl heptanoate (V), there are following deficiencies: 1) when using alkali metal or alkaline earth metal carbonate, bicarbonate, hydroxide etc. as acid-binding agent, need compare Long reaction time (12~22 hours) and higher boiling point solvent (as methyl isobutyl ketone, normal heptane, toluene etc.), and yield is not high (the yield of patent US5268501 report method is 72~84 %, the yield of the patent US6348617 record method is 66%); such a long reaction time has increased energy consumption, and the solvent of high boiling point is difficult to recover, and these have all increased production cost, and environmental friendliness is not enough

2) When using sodium alkoxide or potassium alkoxide as the acid-binding agent, although the yield can reach 91.2% (patent US5268501 report), it requires anhydrous and oxygen-free operating conditions; anhydrous and anaerobic operating conditions are not suitable for industrial production, and There are major security risks

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