Research On Synthesis Of The Key Intermediate Of Efavirenz

Efavirenz developed by Merck is an anti-HIV non-nucleoside reverse transcriptase inhibitor.It is the first-line choice of anti-HIV drug.?S?-1-?2-Amino-5-chlorophenyl?-1-tri-fluoromethyl-3-cyclopropyl-2-propyn-1-ol?1?is the key intermediate of efavirenz,and the molecule has a chiral center.Asymmetric synthesis is mostly used at present,but the yield and enantioselectivity of the resulting target chiral product are low.Therefore,the research and optimization of the synthesis process of this intermediate is an important prerequisite for the synthesis of Efaviren.This paper has made a new exploration of the traditional synthesis route and optimized the synthetic process parameters.The specific content is as follows:?1?.N-?4-chlorophenyl?-2,2-dimethylpropanamide?4?was obtained by nucleophilic substitution reaction of 2,2-dimethylpropionyl chloride with p-chloroaniline?2?.The preferred process conditions are as follows:,the molar ratio of p-chloroaniline to2,2-dimethylpropionyl to chloridesodium hydroxide is 1:1.1:1.3 with 4h of reaction time in the presence of sodium hydroxide as the base,and the yield of product?4?is up to 97.5%.?2?.The compound?4?was subjected to the Friedel-Crafts acylation reaction with trifluoroacetic anhydride under the action of aluminum trichloride,then hydrolyzed under acidic conditions to obtain 4-chloro-2-trifluoroacetylaniline hydrochloride?5?.The preferred process conditions are as follows:the solvent is dichloromethane,the aluminum trichloride is the catalyst,the addition temperature of the compound?4?is-20?,the feeding method is that the solids are added in three equal parts,the molar ratio of?4?to TFAA to aluminum chloride is 1:1.15:2.5,the temperature of reaction is 25?,the time of reaction is 3h,and the yield product?5?is up to 85%.This step used trifluoroacetic anhydride instead of the dangerous trifluoroacetyl chloride in the literature.?3?.The compound?5?was based with sodium hydroxide solution to obtain4-chloro-2-trifluoroacetylaniline?6?.The preferred process conditions are as follows:1mol/L sodium hydroxide is used as the base,the reaction time is 1h,the reaction temperature is 25?,and the yield of product?6?is up to 98%.The reaction time was shortened and the yield of product was improved in this step.?4?.?S?-l-?2-amino-5-chlorophenyl?-1-trifluoromethyl-3-cyclopropyl-2-propyne-1-ol?1?was obtained from the compound?6?reacting with chloromagnesium cyclopropylacet-ylide via a small amount of key intermediates being added into the catalytic system formed by zinc chloride reacting with?1R,2S?-phenyl-2-?1-pyrrolidinyl?-1-propanol?7?.The preferred process conditions are as follows:The Grignard reagent is cyclopropylacetylene magnesium chloride,non-chiral auxiliary is CF₃CH₂OH,sodium hydride is used as base,zinc chloride is used as metal reagent,the molar ratio?6?to?7?to?1?is 1:0.2:0.4,reaction temperature is 40?,reaction time is 12h,the yield of product is up to 85.7%with 85.6%of ee value.Zinc chloride was used instead of dangerous expensive diethyl zinc,and the use of expensive organic ligands was reduced in asymmetric autocatalytic reactions.?5?.After quenching the autocatalytic reaction,the aqueous phase was adjusted to basic by aqueous ammonia,extracted with toluene,concentrated to crystallization,and recrystallized from n-heptane to recover the organic ligand?7?.The best recovery conditions are:the pH of the aqueous solution was adjusted to 11 using aqueous ammonia,the extraction times of toluene is three times,and the recovery rate is up to 98.7%.The recovered organic ligand can be used for the next experiment,which greatly reduces the cost of raw materials.The single-factor test and orthogonal test were used to optimize the reaction conditions of each step.Finally,the total yield of key intermediate?1?of efavirenz reached69.5%,and the ee value reached 92.6%.The purity of intermediates?4?,?5?,?6?and?1?of efavirenz was determined by liquid chromatography,and the structure of?1?was confirmed by ¹H NMR,IR and MS.