Preparation method of cyclopropylamine intermediate cyclopropanecarboxylic acid methyl ester

Abstract

The invention relates to a preparation method of a cyclopropylamine intermediate methyl cyclopropanecarboxylate, and solves the technical problems that an existing preparation method is unreasonable, high in requirements on reaction equipment, complicated to operate, low in yield and unsuitable for industrial production. With methyl acetate and 1,2-dihaloethane as raw materials, and under the action of potassium carbonate and a phase transfer catalyst, alkylation reaction is carried out to obtain methyl cyclopropanecarboxylate. The method can be widely applied to the technical field of synthesis of medical intermediates.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method for preparing a cyclopropylamine intermediate, methyl cyclopropanate. Background technique [0002] Cyclopropylamine, also known as aminocyclopropane, is a colorless and transparent liquid with volatility and ammonia odor, and is miscible with water, methanol, ethanol, benzene, toluene and other solvents. Cyproteramine is a pharmaceutical intermediate used as an intermediate of ciprofloxacin (ciprofloxacin), and also used in the synthesis of pesticides and plant protection agents. [0003] Cyclopropylamine preparation method (1) using 1,3-propanediol as raw material, references: Li Mei, Guo Huiyuan. Cyclopropylamine synthesis route diagram [J]. Chinese Journal of Pharmaceutical Industry, 1992, 023 (003): 141-141, via Bromination, cyanidation, cyclization, amidation, and Hoffman rearrangement degrade the product cyclopropylamine. This re...

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Problems solved by technology

[0003] Cyclopropylamine preparation method (1) using 1,3-propanediol as raw material, references: Li Mei, Guo Huiyuan. Cyclopropylamine synthesis route diagram [J]. Chinese Journal of Pharmaceutical Industry, 1992, 023 (003): 141-141, via Bromination, cyanidation, cyclization, amidation, and Hoffman rearrangement degrade the product cyclopropylamine. This reaction is simple to operate, but it is difficult to obtain starting materials, and highly toxic cyanide is used. The azide used High risk factor; (2) using ethyl acetoacetate as raw material, refer to this document: Wang Shuliang, Dai Guiyuan. Synthesis of Cyclopropylamine [J]. Chinese Journal of Pharmaceutical Industry, 1993, 024(011): 514-516. Oxyethane condensation and cyclization, ring opening and re-cyclization, oximation, rearrangement, and Hoffman degradation product cyclopropylamine; the main raw material of this process route, ethylene oxide, is flammable and explosive, and the operation is extremely dangerous, which increases unnecessary Safety factors require a special explosion-proof device, and the hydrolyzed product of the side reaction is a mixture of cyclopropylamine and methylamine, the product separation is difficult, and the route is lengthy; (3) using γ-butyrolactone as a raw material, reference: Wang Huirong. Ring Synthesis of Propylamine [D]. Nanjing University of Science and Technology, 2004, after high-pressure chlorination, esterification to 4-chlorobutyric acid methyl ester, cyclization to cyclopropyl carboxylate, ammonia solution to cyclopropyl carboxamide, Hofmann The product cyclopropylamine is degraded. This route is the current mainstream process for the synthesis of cyclopropylamine, and the synthesis yield is currently 87%. The characteristic of this route is that the raw materials are easy to obtain and cheap, but the acid gas treatment and reaction equipment requirements in the synthesis process are high, and the first One-step high-pressure device, high operating conditions and long reaction cycle

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