Study On Synthetic Process Of Key Intermediates Of Efavirenz

Efavirenz is a non-nucleoside reverse transcriptase inhibitor,a first-line anti-HIV drug developed by Merck.Efavirenz has become the drug of choice in"cocktail therapy"due to its good efficacy,safety,well-tolerated tolerability,and long-lasting effect.（S）-2-（2-amino-5-chlorophenyl）-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol,an arylamine propargyl alcohol of S configuration is also a key intermediate in most of the existing synthetic processes of efavirenz.The current process route has high production costs,harsh synthesis conditions,and dangerous operation,and is not suitable for industrial production.In this paper,the synthesis of key intermediates of efavirenz was optimized.L-（-）-p-methyldibenzoyltartaric acid was used as the resolving agent,and p-chloroaniline was used as the starting material.The key intermediates of efavirenz were synthesized through the steps of fluoroacetylation,deamination protection,alkalization,nucleophilic addition and chemical resolution.The total yield was 24%.HPLC:the purity was 98.0%,and the ee value was 94.3%.Compared with the existing synthesis method,the synthesis process is simple in operation,raw materials cheap,environmentally friendly,good in product yield,and high in purity and ee value.The preferred synthetic process conditions are:1.Optimization of the synthesis conditions of N-（4-chlorophenyl）-2,2-dimethylpro-pionamide 3:the molar ratio of p-chloroaniline 2:sodium hydroxide:2,2-dimethylpr opionyl chloride is 1:1.3:1.15;acylation reaction occurs at 20-30°C;reaction time:3 h;Product yield:98.4%.2.Optimization of synthesis conditions for 4-chloro-2-trifluoroacetylaniline hydrochloride 4:the molar ratio of Intermediate 3:N,N-tetramethylethylenediamine:n-butyllithium:moles of ethyl trifluoroacetate is 1:1.15:2.3:1.3;Lithiation reaction occurs at 0°C,reaction time:2 h;Trifluoroacetylation reaction occurs at 5°C,reaction time:0.5 h;Acid hydrolysis reaction occurs at 65°C,the reaction time:5 h;Product yield:89.8%.3.Optimization of the synthesis conditions of 4-chloro-2-trifluoroacetylaniline 5:base:1 mol/L sodium hydroxide;the base reacts with intermediate 4 at room temperature;reaction time:2 h;recrystallization solvent:n-hexane;Product yield:97.1%.4.Optimization of synthesis conditions of 1-（2-amino-5-chlorophenyl）-1-trifluo romethyl-3-cyclopropyl-2-propyn-1-ol 7:the molar ratio of Intermediate 5:Cyclopropethyne:n-butylmagnesium chloride is 1:2.5:2.75;Grignard reaction occurs at10-15°C,reaction time:3 h;Nucleophilic addition reaction occurs at 0°C,reaction time:4 h,recrystallization solvent:n-heptane;Product yield:95.2%.5.Optimization of the synthesis conditions of L-（-）-p-methyldibenzoyl tartaric acid8:the molar ratio of L-tartaric acid:p-methylbenzoyl chloride:copper sulfate is 1:2.5:0.05;Esterification reaction occurs at 30°C;Hydrolysis reaction at 110℃for 5 h;reaction time:10 h;Product yield:95.0%.6.Optimization of synthesis conditions for（S）-1-（2-amino-5-chlorophenyl）-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol 1:Intermediate 7:The molar ratio of resolving agent 8 is 1:1;the reaction solvent:a mixture of methanol/acetone with a volume ratio of 1:4;solvent amount:60 m L（n（intermediate ₇）=0.01 mol）;occurs at 20°C Salt-forming reaction;Alkali hydrolysis reaction occurs at 30°C,base:triethylamine;recrystallization mode:n-heptane recrystallization twice;Product yield:31.4%.HPLC:purity:98.0%,ee value:94.3%.In this paper,the purity and enantioselectivity of the target product intermediate（1）were tested by HPLC,and the intermediate（1）was further characterized by ¹H NMR,IR and HR-MS,and the structures of other intermediates and resolving agents 8 were characterized by ¹H NMR.