Preparation Of 4-Cyano-1-butyne By Acetone Cyanohydrin As Cyanogen Source

4-cyano-1-butyne is an important pharmaceutical intermediate,which is prepared by nucleophilic substitution reaction between sodium cyanide and 4-bromo-1-butyne.However,because sodium cyanide is a serious drug,its use is strictly restricted in our country.4-bromo-1-butyne is expensive and needs to be imported.Therefore,the main purpose of this study is to find cyanide reagents that can replace sodium cyanide and 4-bromo-1-butyne which is in short supply to prepare 4-cyano-1-butyne.In this paper,4-cyano-1-butyne was prepared by cyano substitution reaction with acetone cyanohydrin as cyaniding reagent and 3-butyne-1-alcohol as reaction substrate from the point of view of industrial production.The optimal process conditions for each step of reaction were determined,and the universality of the synthesis method was studied.The main research content is as follows:1.Preparation of 3-butyn-1-ol p-toluenesulfonate: 3-butyne-1-ol as the starting material,p-toluenesulfonyl chloride as the sulfonylation reagent,and methylene chloride as the solvent,The intermediates were prepared under the catalysis of triethylamine and DMAP at room temperature for 1.5-2 hours,the conversion rate was above 95% and the yield was >90%.2.Preparation of 4-cyano-1-butyne: Using 3-butyn-1-ol p-toluenesulfonate as a raw material and acetone cyanhydrin as a cyanogen source,an affinity substitution reaction occurs.The influence of the type of alkali,reaction solvent,type of catalyst,feed ratio,reaction temperature and other factors on the reaction conversion rate was investigated.The optimum process conditions were determined as follows: Lithium hydroxide monohydrate was used as a catalyst,NMP and dichloromethane were mixed at a ratio of 3:7 as a mixed solvent at 50° C,the target product was synthesized after 4-5 h of reaction,and the final conversion rate was 98%.3.4-Cyano-1-butyne Pilot Process Exploration: To increase raw material metering,4-cyano-1-butyne was prepared by esterification reaction and cyano substitution reaction in a 20 L reactor,and the final product was always pressed.In the rectification and decompression distillation method,the solvent was recovered,and at the same time,the purity was 98.9% of 4-cyano-1-butyne purified at a yield of 80%.4.Using the above conditions to investigate the universality of the reaction: Benzyl alcohol,phenyl ethyl alcohol,iso-octanol,and diheptanol were used as raw materials to prepare the corresponding p-toluene sulfonate.This intermediate was continued with acetone cyanohydrin.In the reaction,the target product was obtained in a high yield.In addition,the related structures in the synthesis were characterized by infrared spectroscopy,nuclear magnetic resonance spectroscopy and nuclear magnetic resonance spectroscopy.