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.