Preparation method of 4,4-difluorocyclohexylamine hydrochloride

Abstract

The invention discloses a preparation method of 4,4-difluorocyclohexylamine hydrochloride. The method comprises the following steps: carrying out direct one-step fluorination on ethyl 4-oxocyclohexanecarboxylate used as a raw material by using DAST to obtain an intermediate 3, hydrolyzing the intermediate 3 to obtain an intermediate 4, carrying out a rearrangement reaction on the intermediate 4 byusing an azide reagent to obtain an intermediate 5, and removing Boc from the intermediate 5 to obtain an intermediate 6. The method has the following advantages: the intermediate 3 avoids the use ofa dangerous raw material hydrogen fluoride as a solvent, so the raw materials are cheap and are easy to obtain, the reaction conditions are mild, the reaction steps are reduced, the operation is simplified, and the method is suitable for industrial production, is environmentally friendly and safe, and avoids toxic impurities in the product; and the intermediate 5 is used to replace sodium azide in the synthesis process, so the reaction conditions are mild, batch production conditions are avoided from being too harsh, and the method is suitable for industrial safety production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical intermediates, in particular to a method for preparing 4,4-difluorocyclohexylamine hydrochloride. Background technique [0002] It has been reported that the method of first chlorination and then fluorination has been used in the synthesis of intermediate 3. During the synthesis process, anhydrous hydrogen fluoride is used as a solvent, the reaction conditions are harsh, and there are relatively difficult and toxic chlorine-containing impurities in the synthesis process; 5. Explosive sodium azide is used in the process, which is not easy to ensure the safety of industrial production. Contents of the invention [0003] The object of the present invention is to provide a preparation method of 4,4-difluorocyclohexylamine hydrochloride to solve the problems raised in the above-mentioned background technology. [0004] In order to achieve the above object, the present invention provides the f...

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Problems solved by technology

[0002] It has been reported that the method of first chlorination and then fluorination has been used in the synthesis of intermediate 3. During the synthesis process, anhydrous hydrogen fluoride is used as a solvent, the reaction conditions are harsh, and there are relatively difficult and toxic chlorine-containing impurities in the synthesis process; 5 Explosive sodium azide is used in the process, which is not easy to ensure the safety of industrial production

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