Method for preparing (3R,4R)-3-[(1R)tert-butyl-dimethyl-silyloxyethyl]-4-acetoxyl-2-azetidinone

Abstract

The invention relates to a method for preparing (3R,4R)-3-[(1R)tert-butyl-dimethyl-silyloxyethyl]-4-acetoxyl-2-azetidinone. The method comprises the following steps of: firstly, by using L-threonine as a raw material, preparing a key intermediate, namely (3S,4S)-1-para-methoxyphenyl-3-[(R)-1-hydroxyethyl]-4-acetyl-2-azetidinone by adopting a three-step one-pot method; secondly, introducing a silicon-based branched chain, and reacting acetyl into acetoxyl; and finally, removing methoxyphenyl to obtain a target product. The method is simple in raw material, mild in reaction, and environment-friendly, and facilitates industrial large-scale production.

Description

technical field [0001] The present invention relates to a synthesis process of a pharmaceutical intermediate, in particular to a (3R,4R)-3-[(1R)tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinine Process for the preparation of ketones. Background technique [0002] 4-AA is (3R,4R)-3-[(1R)tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone, which is the key to the synthesis of penem drugs intermediate. Penem drugs are a group of new-type β-lactam antibiotics. There are imipenem, meropenem and faropenem that have been marketed in China, and there are many varieties that are undergoing clinical trials. Therefore, it is of great significance to study the synthesis of penem drug intermediates. There are three chiral centers and a lactam ring in the 4-AA structure, which is the focus and difficulty of 4-AA synthesis. [0003] The synthesis process of this compound has been reported in the literature, such as the literature (Tetrahedron letter, 1986 27 (47): 5751) reporte...

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Problems solved by technology

[0003] The synthesis process of this compound has been reported in the literature, such as the literature (Tetrahedron letter, 1986 27 (47): 5751) reported that using S-ethyl lactate as a raw material to use the cycloaddition method, there is a problem that it is not easy to select a good catalyst or catalyst in China. The source is scarce, the yield is low, and chiral resolution is difficult, etc.; for example, the method reported by Sandor Karady (J.Am chem soc, 1981, 103 (22): 6765-6767) uses penicillin G as a raw material to utilize the properties of diazo compounds , the reaction requires diisopropylamine-borane and trifluoroacetate as a catalyst, but this catalyst is expensive; another example: Cainelli G et al. (Tetrahedron lett, 1998, 39 (42): 7779-7782) proposed A route for the synthesis of 4-acetoxy-2-azetidinone from (R)-methyl-3-hydroxybutyrate and hexahydrotriazine, but the purity of the product is not high; LeeMJ et al. (International Publication No. : WO9807690) reported a route of using L-threonine as a raw material to obtain 4-acetoxy-2-azetidinone through substitution, condensation, cyclization, substitution and other reactions. This route uses Pb 3 o 4 , relatively large environmental pollution; such as: Ohtake H et al. (J.O.C, 1999, 64 (11): 790-791) proposed a route for the synthesis of 4-acetoxy-2-azetidinone by nitric acid reagents, which Raw materials for this route are rare; for example: Laurent et al. (J.O.C, 2004, 64(9): 3194-3197) reported a new synthetic route in 2004, chiral epoxybutyrate was activated in situ by phosgene, and then combined with α-Bromoketone compound reaction, after two-step reaction and Baeyer-rilliger oxidative rearrangement reaction with m-chloroperoxybenzoic acid (MCPBA) to obtain β-lactam compound, the raw material of this route is easy to obtain, but phosgene is used, Phosgene is a highly toxic gas, which is harmful to the environment and is not conducive to industrial production

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