Method for mildly preparing 2-azaspiro [3.3] heptane hydrochloride

Abstract

The invention relates to a method for mildly preparing 2-azaspiro [3.3] heptane hydrochloride, and solves the technical problem that in historical literatures, harsh conditions of strong base sodium are needed. The synthesis method comprises the following steps: (1) reducing cyclobutane-1,1-dicarboxylic acid into dimethyl alcohol; (2) reacting the 1, 1-cyclobutane dimethyl carbinol with methanesulfonyl chloride to generate 1,1-cyclobutane dimethyl carbinol dimethyl sulfonate; (3) carrying out ring closing on the 1,1-cyclobutane dimethyl carbinol dimethyl sulfonate and the 2-nitrobenzene sulfonamide to generate 2-(2-nitrobenzenesulfonyl)-2-azaspiro [3.3] heptane; (4) enabling the 2-(2-nitrobenzenesulfonyl)-2-azaspiro [3.3] heptane to react with dodecanethiol under the action of DBU to remove the 2-nitrobenzenesulfonyl so as to generate 2-azaspiro [3.3] heptane; and (5) reacting the 2-azaspiro [3.3] heptane with BOC anhydride to generate Boc-2-azaspiro [3.3] heptane, and then performing treatment with hydrochloric acid to obtain the 2-azaspiro [3.3] heptane hydrochloride. The method is mild and easy to operate, and avoids violent conditions of removing amino protecting groups by strong base at high temperature.

Description

technical field [0001] The invention relates to a synthesis method of 2-azaspiro[3.3]heptane hydrochloride. Background technique [0002] The traditional method for preparing 2-azaspiro[3.3]heptane and its hydrochloride is to reduce cyclobutane-1,1-dicarboxylic acid to dimethanol, and then react with methanesulfonyl chloride to form 1,1-cyclobutane Butane dimethanol dimesylate. The diester is cyclized with benzenesulfonamide or p-toluenesulfonamide, and finally deprotected by red aluminum or sodium to obtain 2-azaspiro[3.3]heptane and its hydrochloride. But the traditional preparation method has the following problems: [0003] 1. The direct reduction reaction of cyclobutane-1,1-dicarboxylic acid to dimethanol is relatively complicated, and purification is required for the next reaction; [0004] 2. The removal conditions of benzenesulfonyl and p-toluenesulfonyl groups are demanding, and metal sodium is required, and the operation is relatively dangerous, while the remo...

AI Technical Summary

Problems solved by technology

[0003] 1. The direct reduction reaction of cyclobutane-1,1-dicarboxylic acid to dimethanol is relatively complicated, and purification is required for the next reaction;

[0004] 2. The removal conditions of benzenesulfonyl and p-toluenesulfonyl groups are demanding, and metal sodium is required, and the operation is relatively dangerous, while the removal effect of red aluminum is poor;

[0005] 3. The final product is highly water-soluble, difficult to handle, and difficult to purify through the column

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