Yield:52-49-3 90.5%

Reaction Conditions:

Stage #1:cyclohexyl chloride with iodine;magnesium in 1,2-dimethoxyethane;tert-butyl methyl ether at 45 - 55; for 2 h;Sealed tube;Inert atmosphere;Large scale;
Stage #2:1-phenyl-3-piperidino-propan-1-one; hydrochloride in 1,2-dimethoxyethane;tert-butyl methyl ether at 5 - 10; for 2 h;Sealed tube;Inert atmosphere;Large scale;Solvent;

Steps:

1-3 Example 1
Pump 40L methyl tert-butyl ether and 3.0kg chlorocyclohexane into the reaction tank, start stirring, add 7.64kg magnesium powder and 0.13kg iodine, seal the mouth of the tank, vent nitrogen, and heat to about 55 °C to start , Add dropwise a mixed solution of 40.0kg of chlorocyclohexane and 40L of ethylene glycol dimethyl ether, and the addition is complete.Incubate at 45~55C for 2 hours. After the incubation is over, cool down to 0~10C. Add 26.90kg of phenacetone piperidine hydrochloride and keep at 5~10C for 2 hours.After the heat preservation is over, add dilute hydrochloric acid dropwise with stirring, control the temperature not to exceed 20C, and finish dropping. The reaction solution was reduced to 0~5C, stirred for 2 hours, and the temperature retention was over.Spin filtration, rinse with water to pH 3~4, and dry to obtain 32.5Kg crude trihexyphenid hydrochloride, yield 90.5%, purity 98.5%.

References:

Tianjin Lisheng Pharmaceutical Co., Ltd.;Jiang Genhua;Huo Zhijia;Shi Liangliang;Zhang Jing;Wang Hao;Yao Zhixiong;Zhang Yu;Zhang Jie CN111909115, 2020, A Location in patent:Paragraph 0015-0019

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