Study On The Synthesis Of The Brexpiprazole

Objective To explore a new short environmental synthesis route of Brexpiprazole featured with low cost,high yield and easy operation.Methods Intermediate 4-1 was obtained from 3-Aminothiophenol via substitution,cyclization and substitution and intermediate 7-1 was synthesized from3-methoxyaniline in 3 steps,including ammonia hydrolysis,cyclization and substitution.The target product,brexpiprazole,was synthesized from intermediate 4-1and 7-1 through a substitution reaction.The structure of both the target product and intermediates was determinate by ¹H-NMR and ¹³C-NMR.Results According to the experimental data,we had obtained the best the reaction conditions for the new synthesis route to synthesis brexpiprazole.The optimized synthetic conditions for 3-??2,2-dimethoxyethyl?thio?aniline was:n?2-2?:n?2-3?:n?Potassium carbonate?=1:1:1.5 in DMF at 40?for 8 h with a yield 82.5%.The best reaction conditions for 4-aminobenzo[b]thiophene was:8 g PPA reacted at 120?for 6 h with a yield of 80.5%.4-?1-piperazinyl?benzo[b]thiophene was obtained with n?3-1?:n?4-2?=1:1 in n-butanol and Potassium carbonate at 120?for 24 h and the best yield was 75.0%.The best reaction condition of synthesis 3,3-Dimethoxy-N-?3-methoxyphenyl?propanamide was n?5-3?:n?5-2?=1:1 in Dichloromethane,Triethylamine as alkali,at 40?for 2 h,and yield was 89.0%.The optimized condition for 7-hydroxyquinoline-?1H?-2-one was in m-Dimethylbenzene at 130?for 12 h with a yield of 80.0%.The best reaction condition of synthesis 7-?4-Chlorobutoxy?-1H-quinolin-2-one,was n?7-3?:n?7-2?=1:1.2 in Methanol at 60?for 16 h and the best yield was 81.2%.The best reaction condition of synthesis brexpiprazole was n?7-1?:n?4-1?=1:1.05 in Methanol at 60?for 16h,which with a yield of 95.5%.Conclusions We had explored a new synthesis route of brexpiprazole and its intermediates,which was easily operated and with a higher total yield.It can provide a reference for the synthesis and application of brexpiprazole and its intermediates.