|
【结 构 式】 
|
【分子编号】48437 【品名】2-Aminobenzimidazole; 2-Amino-1H-benzimidazol; 1H-Benzimidazol-2-amine; 2-Benzimidazolamine 【CA登记号】934-32-7 |
【 分 子 式 】C7H7N3 【 分 子 量 】133.1528 【元素组成】C 63.14% H 5.3% N 31.56% |
合成路线1
该中间体在本合成路线中的序号：(XII)Reduction of protected hydroxyproline (I) by means of borane dimethylsulfide complex (BH3-Me2S) in THF affords protected hydroxy prolinol (II), which is then treated with tert-butyldimethylsilyl chloride and Et3N in CH2Cl2 to provide hydroxypyrrolidine derivative (III). Swern oxidation of (III) by means of oxalyl chloride in DMSO/CH2Cl2 yields pyrrolidinone (IV), which is then converted into methylenepyrrolidine (V) by reaction with methyltriphenylphosphonium bromide and KOtBu in ether. Treatment of (V) with ethyl chlorooximidoacetate (VI) and Et3N in CH2Cl2 gives spiro compound (VII), which is then subjected to saponification by treatment with LiOH in MeOH to afford carboxylic acid (VIII). Coupling of (VIII) with amine (IX) by means of BOPCl and N-methylmorpholine (NMM) in DMF furnishes amide (X), which is then converted into aldehyde (XI) by first TBDMS removal by treatment with tetrabutylammonium fluoride (TBAF) in THF and oxidation with Dess-Martin periodinane. Reductive amination of aldehyde (XI) with amine (XII) by means of Na(AcO)3BH in benzene/1,2-dichloroethane followed by treatment with Boc2O provides compound (XIII), whose Cbz is selectively removed by hydrogenation over Pd/Ba2SO4 to give secondary amine (XIV). Finally, acylation of (XIV) with chloroformate (XV) followed by Boc removal by means of TFA allows to obtain the desired product.
| 【1】 Jadhav, P.K.; Smallheer, J.M. (DuPont Pharmaceuticals Co.); Spirocycle integrin inhibitors. EP 0888344; US 5760029; WO 9733887 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 36579 | (2S,4S)-1-[(benzyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid | 13504-85-3 | C13H15NO5 | 详情 | 详情 |
| (II) | 48432 | benzyl (2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C13H17NO4 | 详情 | 详情 | |
| (III) | 36580 | benzyl (2S,4S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-1-pyrrolidinecarboxylate | C19H31NO4Si | 详情 | 详情 | |
| (IV) | 36581 | benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-oxo-1-pyrrolidinecarboxylate | C19H29NO4Si | 详情 | 详情 | |
| (V) | 36582 | benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylene-1-pyrrolidinecarboxylate | C20H31NO3Si | 详情 | 详情 | |
| (VI) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (VII) | 48433 | 7-benzyl 3-ethyl (5R,8S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C24H36N2O6Si | 详情 | 详情 | |
| (VIII) | 48434 | (5R,8S)-7-[(benzyloxy)carbonyl]-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylic acid | C22H32N2O6Si | 详情 | 详情 | |
| (IX) | 36588 | tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate | C16H26N2O4S | 详情 | 详情 | |
| (X) | 48435 | benzyl (5R,8S)-3-[([(2S)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate | C38H56N4O9SSi | 详情 | 详情 | |
| (XI) | 48436 | benzyl (5R,8S)-3-[([(2S)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-8-formyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate | C32H40N4O9S | 详情 | 详情 | |
| (XII) | 48437 | 2-Aminobenzimidazole; 2-Amino-1H-benzimidazol; 1H-Benzimidazol-2-amine; 2-Benzimidazolamine | 934-32-7 | C7H7N3 | 详情 | 详情 |
| (XIII) | 48438 | benzyl (5R,8S)-8-[[1H-benzimidazol-2-yl(tert-butoxycarbonyl)amino]methyl]-3-[([(2S)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate | C44H55N7O10S | 详情 | 详情 | |
| (XIV) | 48439 | tert-butyl (2S)-3-[[((5R,8S)-8-[[1H-benzimidazol-2-yl(tert-butoxycarbonyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-en-3-yl)carbonyl]amino]-2-[(mesitylsulfonyl)amino]propanoate | C36H49N7O8S | 详情 | 详情 | |
| (XV) | 48440 | 1-[(chlorocarbonyl)oxy]butane | C5H9ClO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The title compound was synthesized within a combinatorial library on a Wang polystyrene resin. Attachment of N-Fmoc-(R)-beta-phenylalanine (I) to the solid support was achieved via activation with 2,6-dichlorobenzoyl chloride to afford the aminoacid-bound resin (II). After conventional Fmoc group deprotection with piperidine in DMF, the resultant amine resin (III) was acylated with 5-bromo-2-methoxybenzenesulfonyl chloride (IV) yielding sulfonamide (V). Mitsunobu coupling between aryl bromide (V) and 3-nitrobenzeneboronic acid (VI) gave rise to the biphenyl derivative (VII). Reduction of the nitro group of (VII) to the corresponding aniline (VIII) was then performed by treatment with stannous chloride in N-methylpyrrolidone. Alternatively, the aminobiphenyl resin (VIII) was directly prepared by coupling between aryl bromide (V) and 3-aminobenzeneboronic acid (IX). Reaction of amine (VIII) with p-nitrophenyl chloroformate (X) produced the nitrophenyl carbamate resin (IX), which was further reacted with 2-aminobenzimidazole (XII) to furnish urea (XIII). Final resin cleavage was effected by treatment with trifluoroacetic acid in CH2Cl2.
| 【1】 Gerdes, C.; Albers, M.; Schmidt, D.; Stelte-Ludwig, B.; Bruggemeier, U.; Vaupel, A.; Harter, M.; Urbahns, K.; Biphenyls as potent vitronectin receptor antagonists. Bioorg Med Chem Lett 2002, 12, 2, 205. |
| 【2】 Schmidt, D.; Urbahns, K.; Gerdes, C.; Keldenich, J.; Härter, M.; Stahl, E.; Albers, M.; Vaupel, A.; Stelte-Ludwig, B.; Brüggemeier, U.; Lustig, K. (Bayer AG); New biphenyl and biphenyl-analogous cpds. as integrin antagonists. EP 1140809; JP 2002532465; US 6420396; WO 0035864 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I),(II) | 56271 | Fmoc-(R)-3-amino-3-phenylpropionic acid | C24H21NO4 | 详情 | 详情 | |
| (III) | 56272 | (3R)-3-amino-3-phenylpropanoic acid | C9H11NO2 | 详情 | 详情 | |
| (IV) | 56273 | 5-Bromo-2-methoxybenzenesulfonyl chloride | 23095-05-8 | C7H6BrClO3S | 详情 | 详情 |
| (V) | 56274 | (3R)-3-{[(5-bromo-2-methoxyphenyl)sulfonyl]amino}-3-phenylpropanoic acid | C16H16BrNO5S | 详情 | 详情 | |
| (VI) | 40934 | 3-nitrophenylboronic acid | 13331-27-6 | C6H6BNO4 | 详情 | 详情 |
| (VII) | 56275 | (3R)-3-{[(4-methoxy-3'-nitro[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid | C22H20N2O7S | 详情 | 详情 | |
| (VIII) | 56276 | (3-Aminophenyl)dihydroxyborane; 3-Aminobenzeneboronic acid; 3-Aminophenylboronic acid | 30418-59-8 | C22H22N2O5S | 详情 | 详情 |
| (IX) | 56277 | 3-aminophenylboronic acid | C6H8BNO2 | 详情 | 详情 | |
| (X) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XI) | 56278 | (3R)-3-{[(4-methoxy-3'-{[(4-nitrophenoxy)carbonyl]amino}[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid | C29H25N3O9S | 详情 | 详情 | |
| (XII) | 48437 | 2-Aminobenzimidazole; 2-Amino-1H-benzimidazol; 1H-Benzimidazol-2-amine; 2-Benzimidazolamine | 934-32-7 | C7H7N3 | 详情 | 详情 |
| (XIII) | 56279 | (3R)-3-{[(3'-{[(1H-benzimidazol-2-ylamino)carbonyl]amino}-4-methoxy[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid | C30H27N5O6S | 详情 | 详情 |