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【结 构 式】 
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【分子编号】10173 【品名】(1R)-2-Amino-1-phenyl-1-ethanol 【CA登记号】2549-14-6 |
【 分 子 式 】C8H11NO 【 分 子 量 】137.18148 【元素组成】C 70.04% H 8.08% N 10.21% O 11.66% |
合成路线1
该中间体在本合成路线中的序号：(IX)The synthesis of [14C]-labeled BRL-26830A has been described: The reaction of copper sulfate (I) with sodium methabisulfite, followed by treatment with [14C]-labeled potassium cyanide (II) yields cuprous cyanide (III), which is condensed with methyl 4-bromobenzoate (IV) to afford methyl 4-cyanobenzoate (V). The reduction of (V) with Al/Ni and formic acid gives methyl 4-formylbenzoate (VI), which is condensed with nitroethane by means of butylamine and acetic acid in benzene to give methyl 4-(2-nitro-1-propenyl)benzoate (VII). The treatment of (VII) with Fe and HCl in refluxing methanol yields methyl 4-(acetonyl)benzoate (VIII), which is reductocondensed with (R*)-2-amino-1-phenylethanol (IX) by means of NaBH4 in refluxing benzene and crystallized in methanol to fractionate the optical diastereomers. Finally, the (R*,R*)-isomer (X) is treated with fumaric acid.
| 【1】 Freer, R.; Morecombe, D.J.; The synthesis of [14C]BRL 26830A, a novel beta-adrenoceptor agonist. J Label Compd Radiopharm 1992, 31, 9, 697. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 | |
| (IV) | 10168 | 4-Bromobenzoic acid methyl ester; methyl 4-bromobenzoate | 619-42-1 | C8H7BrO2 | 详情 | 详情 |
| (V) | 10169 | methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester | 1129-35-7 | C9H7NO2 | 详情 | 详情 |
| (V) | 44596 | methyl 4-cyanobenzoate | C9H7NO2 | 详情 | 详情 | |
| (VI) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (VI) | 44597 | methyl 4-formylbenzoate | C9H8O3 | 详情 | 详情 | |
| (VII) | 10171 | methyl 4-[(Z)-2-nitro-1-propenyl]benzoate | C11H11NO4 | 详情 | 详情 | |
| (VII) | 44598 | methyl 4-[(Z)-2-nitro-1-propenyl]benzoate | C11H11NO4 | 详情 | 详情 | |
| (VIII) | 10172 | methyl 4-(2-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (VIII) | 44599 | methyl 4-(2-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (IX) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (X) | 44595 | methyl 4-((2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate | C19H23NO3 | 详情 | 详情 | |
| (X) | 44600 | methyl 4-((2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate | C19H23NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of bromobenzene (I) with 14CO2 by means of Mg in ether gives the corresponding benzoic acid (II), which is treated with SOCl2 and DMAP to yield the benzoyl chloride (III). The homologation of (III) with diazomethane in ether affords the phenacyl chloride (IV), which is enantioselectively reduced with borane and a chiral borolidine catalyst in THF to give (R)-2-chloro-1-phenylethanol (V). The cyclization of (V) by means of NaOH in ethyl ether yields the oxirane (VI), which by reaction with ammonia is converted into the (R)-2-amino-1-phenylethanol (VII). The condensation of (VII) with 4'-chlorobiphenyl-4-carboxylic acid (VIII) by means of CDI in DMF provides the amide (IX), which is cyclized to the oxazoline (X) by means of methanesulfonic anhydride and TEA in THF. Finally, this compound is condensed with imidazole (XI) by heating at 125 C.
| 【1】 Moenius, T.; et al.; C-14 labelling of NVPVID400 - a specific vitamin D-3-hydroxylase inhibitor. J Label Compd Radiopharm 1999, 42, 11, 1053. |
| 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) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (II) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (III) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (IV) | 38669 | 2-chloro-1-phenyl-1-ethanone | 532-27-4 | C8H7ClO | 详情 | 详情 |
| (V) | 38670 | (1R)-2-chloro-1-phenyl-1-ethanol | 1674-30-2 | C8H9ClO | 详情 | 详情 |
| (VI) | 38671 | (2R)-2-phenyloxirane | C8H8O | 详情 | 详情 | |
| (VII) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (VIII) | 38672 | 4'-chloro[1,1'-biphenyl]-4-carboxylic acid | C13H9ClO2 | 详情 | 详情 | |
| (IX) | 38673 | 4'-chloro-N-[(2R)-2-hydroxy-2-phenylethyl][1,1'-biphenyl]-4-carboxamide | C21H18ClNO2 | 详情 | 详情 | |
| (X) | 38674 | (5S)-2-(4'-chloro[1,1'-biphenyl]-4-yl)-5-phenyl-4,5-dihydro-1,3-oxazole | C21H16ClNO | 详情 | 详情 | |
| (XI) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of (R)-2-phenyloxirane (I) with ammonia in ethanol gives 2-amino-1(R)-phenylethanol (II), which is condensed with 4'-chlorobiphenyl-4-carboxylic acid (III) by means of isobutyl chloroformate and TEA in DMF yielding the amide (IV). The cyclization of (IV) by means of methanesulfonic anhydride in pyridine affords the oxazoline (V), which is finally condensed with imidazole by heating at 120 C.
| 【1】 Schuster, I.; Egger, H. (Novartis AG; Novartis Deutschland GmbH); Acylated aminoalkanimidazoles and -triazoles. CA 2149459; EP 0683156; JP 1996053422; US 5622982 . |
| 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) | 38671 | (2R)-2-phenyloxirane | C8H8O | 详情 | 详情 | |
| (II) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (III) | 38672 | 4'-chloro[1,1'-biphenyl]-4-carboxylic acid | C13H9ClO2 | 详情 | 详情 | |
| (IV) | 38673 | 4'-chloro-N-[(2R)-2-hydroxy-2-phenylethyl][1,1'-biphenyl]-4-carboxamide | C21H18ClNO2 | 详情 | 详情 | |
| (V) | 38674 | (5S)-2-(4'-chloro[1,1'-biphenyl]-4-yl)-5-phenyl-4,5-dihydro-1,3-oxazole | C21H16ClNO | 详情 | 详情 | |
| (VI) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The condensation of 4-fluoro-3-nitrobenzoic acid (I) with 1-methylpiperazine (II) by means of oxalyl chloride in dichloromethane gives the expected acyl derivative (III), which is reduced with BH3/THF to yield the benzyl piperazine (IV). The condensation of (IV) with 2(R)-hydroxy-2-phenylethylamine (V) by means of DIEA in NMP affords the secondary amine (VI), which is reduced with H2 over Pd/C in ethanol, providing the phenylenediamine (VII). Finally, this compound is cyclized with 4-methoxybenzoyl isothiocyanate (VIII) by means of EDC in DMF to furnish the target benzimidazole.
| 【1】 Heyer, D.; et al.; 2-Aminobenzimidazoles: A class of orally bioavailable and brain permeable neuropeptide YY5 antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 284. |
| 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) | 46937 | 4-fluoro-3-nitrobenzoic acid | 453-71-4 | C7H4FNO4 | 详情 | 详情 |
| (II) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (III) | 54041 | (4-fluoro-3-nitrophenyl)(4-methyl-1-piperazinyl)methanone | C12H14FN3O3 | 详情 | 详情 | |
| (IV) | 54042 | 1-(4-fluoro-3-nitrobenzyl)-4-methylpiperazine | C12H16FN3O2 | 详情 | 详情 | |
| (V) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (VI) | 54043 | (1R)-2-{4-[(4-methyl-1-piperazinyl)methyl]-2-nitroanilino}-1-phenyl-1-ethanol | C20H26N4O3 | 详情 | 详情 | |
| (VII) | 54044 | (1R)-2-{2-amino-4-[(4-methyl-1-piperazinyl)methyl]anilino}-1-phenyl-1-ethanol | C20H28N4O | 详情 | 详情 | |
| (VIII) | 54045 | 4-Methoxybenzoyl isothiocyanate | 16778-84-0 | C9H7NO2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The reduction of 4-fluoro-3-nitrobenzoic acid (I) with BH3/THF gives the benzyl alcohol (IX), which is condensed with 2(R)-hydroxy-2-phenylethylamine (V) by means of DIEA in NMP to yield nitro compound (XI). Derivative (XI) is then converted into secondary amine (XII) by reduction either with H2 over Pd/C in EtOH or with Na2S·9H2O in dioxane/H2O or by treatment with Na2S2O4 in dioxane/NH4OH. Cyclization of (XI) with 4-methoxybenzoyl isothiocyanate (VIII) by means of EDC in DMF affords the benzimidazole (XIII), which is oxidized at the carbinol group by means of MnO2 in THF to provide the corresponding carbaldehyde (XIV). Finally, this compound is reductocondensed with 1-methylpiperazine (II) by means of NaBH(OAc)3 to furnish the target benzimidazole.
| 【1】 Heyer, D.; et al.; 2-Aminobenzimidazoles: A class of orally bioavailable and brain permeable neuropeptide YY5 antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 284. |
| 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) | 46937 | 4-fluoro-3-nitrobenzoic acid | 453-71-4 | C7H4FNO4 | 详情 | 详情 |
| (II) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (V) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (VIII) | 54045 | 4-Methoxybenzoyl isothiocyanate | 16778-84-0 | C9H7NO2S | 详情 | 详情 |
| (IX) | 54046 | (4-fluoro-3-nitrophenyl)methanol | C7H6FNO3 | 详情 | 详情 | |
| (XI) | 54047 | (1R)-2-[4-(hydroxymethyl)-2-nitroanilino]-1-phenyl-1-ethanol | C15H16N2O4 | 详情 | 详情 | |
| (XII) | 54048 | (1R)-2-[2-amino-4-(hydroxymethyl)anilino]-1-phenyl-1-ethanol | C15H18N2O2 | 详情 | 详情 | |
| (XIII) | 54049 | N-{5-(hydroxymethyl)-1-[(2R)-2-hydroxy-2-phenylethyl]-1H-benzimidazol-2-yl}-4-methoxybenzamide | C24H23N3O4 | 详情 | 详情 | |
| (XIV) | 54050 | N-{5-formyl-1-[(2R)-2-hydroxy-2-phenylethyl]-1H-benzimidazol-2-yl}-4-methoxybenzamide | C24H21N3O4 | 详情 | 详情 |