Paper
LI Min, HONG Bibo, CHEN Yinbo, HU Liang, LIU Xiangkui
In this report, 4-nitrophenylacetic acid(5) reacted with acetic anhydride to give 1-(4-nitrophenyl)-
propan-2-one(6). Condensation of 6 with ethyl cyanoacetate followed by cyclization with sulfur afforded ethyl 2-amino-
4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate(7), which was acylated with butyl chloroformate to afford ethyl
2-[(butoxycarbonyl)amino]-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate(8). Then 8 was substituted with
2,6-difluorobenzyl chloride and the resulting product ethyl 2-[(butoxycarbonyl)(2,6-difluorobenzyl)amino]-4-methyl-
5-(4-nitrophenyl)thiophene-3-carboxylate(9) was reacted with N-bromosuccinimide and dimethylamine to generate
ethyl 2-[(butoxycarbonyl)(2,6-difluorobenzyl)amino]-4-[(dimethylamino)methyl]-5-(4-nitrophenyl)thiophene-
3-carboxylate(11). And then 2-[(butoxycarbonyl)(2,6-difluorobenzyl)amino]-4-[(dimethylamino)methyl]-5-(4-
nitrophenyl)thiophene-3-carboxylic acid(12) was obtained after hydrolysis of 11 with potassium hydroxide. Next, 12
was subjected to condensation with 3-amino-6-methoxypyridazine and cyclization with sodium methoxide to result in
1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-6-(4-nitrophenyl)thieno[2,3-d]-
pyrimidine-2,4(1H,3H)-dione(14). Then 14 reacted with hydrogen under catalysis of Pd/C to afford 6-(4-aminophenyl)-
1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-
dione(15). Finally, Substitution of 15 with phenyl chloroformate and methoxamine hydrochloride reduction to prepare
relugolix(1) with an overall yield of 22.9%(based on 5).