AS-5370(undefined isomer), AS-5820, DAT-582
1H-吚唑-3-羧酰胺,N-[(6R)-六氢-1-甲基-4-[(3-甲基苯基)甲基]-1H-1,4-地西泮-6-基]-,二盐酸盐(9CI)Chemical Name: (-)-(R)-N-[1-Methyl-4-(3-methylbenzyl)hexahydro-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide dihydrochloride
CAS No. 141034-42-6
项目整合开发状态: Phase II
项目研究机构: Dainippon Pharmaceutical (Originator), Taiho (Licensee)
合成路线:Condensation of N-benzyloxycarbonyl-D-serine (I) with 3-methylbenzylamine (II) in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.HCl (EDC) afforded amide (III).Reduction of this amide with borane gave amine (IV),which was then protected as the tert-butyl carbamate (V) with Boc2O.Subsequent treatment of (V) with methanesulfonyl chloride produced the corresponding mesylate (VI) which,without purification,was treated with methylamine in refluxing EtOH to provide triamine (VII).Alkylation of (VII) with methyl bromoacetate gave aminoacetate (VIII),and then,the tert-butoxycarbonyl protecting group was removed using HCl in EtOH.The resulting (IX) was treated with diisobutyl aluminum hydride in THF at -70 C to give aldehyde (X),and further reduction with NaBH4 of iminium salt (XI),derived from aldehyde (X),provided the optically active diazepine (XII).Deprotection of the benzyloxycarbonyl group,followed by coupling of the resulting amine (XIII) with indazole-3-carboxylic acid (XIV) in the presence of EDC gave the target amide,which was then converted to the dihydrochloride.
📌 参考资料/链接：
参考文献标题:Indazole-3-carboxylic acid derivs.
文献作者:Kon,T.; Kato,S.; Morie,T.; Karasawa,T.; Yoshida,N.(Dainippon Pharmaceutical Co.,Ltd.)
参考来源:EP 0358903; JP 1990256670; JP 1993092959; US 5017573
📄 详细内容
合成路线:Condensation of N-benzyloxycarbonyl-D-serine (I) with 3-methylbenzylamine (II) in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.HCl (EDC) afforded amide (III).Reduction of this amide with borane gave amine (IV),which was then protected as the tert-butyl carbamate (V) with Boc2O.Subsequent treatment of (V) with methanesulfonyl chloride produced the corresponding mesylate (VI) which,without purification,was treated with methylamine in refluxing EtOH to provide triamine (VII).Alkylation of (VII) with methyl bromoacetate gave aminoacetate (VIII),and then,the tert-butoxycarbonyl protecting group was removed using HCl in EtOH.The resulting (IX) was treated with diisobutyl aluminum hydride in THF at -70 C to give aldehyde (X),and further reduction with NaBH4 of iminium salt (XI),derived from aldehyde (X),provided the optically active diazepine (XII).Deprotection of the benzyloxycarbonyl group,followed by coupling of the resulting amine (XIII) with indazole-3-carboxylic acid (XIV) in the presence of EDC gave the target amide,which was then converted to the dihydrochloride.
参考文献标题:Efficient synthesis of (R)-6-benzyloxycarbonylamino-1-methyl-4-(3-methylbenzyl)hexahydro-1,4-diazepine.I
文献作者:Harada,H.; et al.
参考来源:Chem Pharm Bull 1998,46(7),1160
产品链接: CAS No. 141034-42-6››