合成路线:Cyclization of 1-(4-nitrophenyl)acetone (I) with ethyl 2-cyanoacetate (II) by means of NH4OAc,HOAc,S and diethylamine gives 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (III),which is cyclized with phenyl isocyanate (IV) in pyridine to yield the thieno[2,3-d]pyrimidinedione derivative (V).Alkylation of compound (V) with 2,6-difluorobenzyl chloride (VI) by means of K2CO3 and KI in DMF affords the adduct (VII),which is brominated with NBS and AIBN in chlorobenzene to provide the bromomethyl derivative (VIII).Reaction of compound (VIII) with N-benzyl-N-methylamine (IX) by means of DIEA in DMF gives the tertiary amine (X),which by reduction of the nitro group with H2 over Pd/C in ethyl ether/formic acid yields the primary amine (XI).Finally,this compound is treated with CDI,O-methylhydroxylamine (XII) and TEA in dichloromethane.
参考文献标题:Processes for the production of thienopyrimidine derivs.
文献作者:Kimura,K.; Yamamoto,H.; Miki,S.; Kawakami,J.; Fukuoka,K.(Takeda Chemical Industries,Ltd.)
参考来源:EP 1266898; JP 2001316391; WO 0164683
合成路线:Cyclization of 1-(4-nitrophenyl)acetone (I) with ethyl 2-cyanoacetate (II) by means of NH4OAc,HOAc,S and diethylamine gives 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (III),which is cyclized with phenyl isocyanate (IV) in pyridine to yield the thieno[2,3-d]pyrimidinedione derivative (V).Alkylation of compound (V) with 2,6-difluorobenzyl chloride (VI) by means of K2CO3 and KI in DMF affords the adduct (VII),which is brominated with NBS and AIBN in chlorobenzene to provide the bromomethyl derivative (VIII).Reaction of compound (VIII) with N-benzyl-N-methylamine (IX) by means of DIEA in DMF gives the tertiary amine (X),which by reduction of the nitro group with H2 over Pd/C in ethyl ether/formic acid yields the primary amine (XI).Finally,this compound is treated with CDI,O-methylhydroxylamine (XII) and TEA in dichloromethane.
参考文献标题:Discovery of the thieno[2,3-d]pyrimidine-2,4-dione derivative TAK-013: Highly potent and orally active nonpeptide LHRH (GnRH) antagonist (II)
文献作者:Harada,M.; Nara,Y.; Endo,S.; Suzuki,N.; Cho,N.; Fujino,M.; Sasaki,S.; Furuya,S.
参考来源:224th ACS Natl Meet (Aug 18 2002,Boston) 2002,Abst MEDI 354
合成路线:Cyclization of 1-(4-nitrophenyl)acetone (I) with ethyl 2-cyanoacetate (II) by means of NH4OAc,HOAc,S and diethylamine gives 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (III),which is cyclized with phenyl isocyanate (IV) in pyridine to yield the thieno[2,3-d]pyrimidinedione derivative (V).Alkylation of compound (V) with 2,6-difluorobenzyl chloride (VI) by means of K2CO3 and KI in DMF affords the adduct (VII),which is brominated with NBS and AIBN in chlorobenzene to provide the bromomethyl derivative (VIII).Reaction of compound (VIII) with N-benzyl-N-methylamine (IX) by means of DIEA in DMF gives the tertiary amine (X),which by reduction of the nitro group with H2 over Pd/C in ethyl ether/formic acid yields the primary amine (XI).Finally,this compound is treated with CDI,O-methylhydroxylamine (XII) and TEA in dichloromethane.
参考文献标题:Synthesis of orally active nonpeptide LHRH (GnRH) antagonists [II]: Discovery of the thieno[2,3-b]pyrimidine-2,4-dione derivative TAK-013
文献作者:Sasaki,S.; Cho,N.; Nara,Y.; Harada,M.; Endo,S.; Furuya,S.; Fujino,M.; Suzuki,N.
参考来源:22nd Symp Med Chem (Nov 27 2002,Shizuoka) 2002,Abst 2P-26
合成路线:Cyclization of 1-(4-nitrophenyl)acetone (I) with ethyl 2-cyanoacetate (II) by means of NH4OAc,HOAc,S and diethylamine gives 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (III),which is cyclized with phenyl isocyanate (IV) in pyridine to yield the thieno[2,3-d]pyrimidinedione derivative (V).Alkylation of compound (V) with 2,6-difluorobenzyl chloride (VI) by means of K2CO3 and KI in DMF affords the adduct (VII),which is brominated with NBS and AIBN in chlorobenzene to provide the bromomethyl derivative (VIII).Reaction of compound (VIII) with N-benzyl-N-methylamine (IX) by means of DIEA in DMF gives the tertiary amine (X),which by reduction of the nitro group with H2 over Pd/C in ethyl ether/formic acid yields the primary amine (XI).Finally,this compound is treated with CDI,O-methylhydroxylamine (XII) and TEA in dichloromethane.
参考文献标题:Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: A highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor
文献作者:Sasaki,S.; Cho,N.; Nara,Y.; Harada,M.; Endo,S.; Suzuki,N.; Furuya,S.; Fujino,M.
参考来源:J Med Chem 2003,46(1),113
合成路线:Cyclization of 1-(4-nitrophenyl)acetone (I) with ethyl 2-cyanoacetate (II) by means of NH4OAc,HOAc,S and diethylamine gives 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (III),which is cyclized with phenyl isocyanate (IV) in pyridine to yield the thieno[2,3-d]pyrimidinedione derivative (V).Alkylation of compound (V) with 2,6-difluorobenzyl chloride (VI) by means of K2CO3 and KI in DMF affords the adduct (VII),which is brominated with NBS and AIBN in chlorobenzene to provide the bromomethyl derivative (VIII).Reaction of compound (VIII) with N-benzyl-N-methylamine (IX) by means of DIEA in DMF gives the tertiary amine (X),which by reduction of the nitro group with H2 over Pd/C in ethyl ether/formic acid yields the primary amine (XI).Finally,this compound is treated with CDI,O-methylhydroxylamine (XII) and TEA in dichloromethane.
参考文献标题:TAK-013
文献作者:Sorbera,L.A.; Castar,J.; Leeson,P.A.
参考来源:Drugs Fut 2003,28(2),121-124
产品链接: CAS No. 308831-61-0››