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【结 构 式】 
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【分子编号】10103 【品名】(2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol 【CA登记号】56755-20-5 (hydrochloride) |
【 分 子 式 】C17H21NO 【 分 子 量 】255.35988 【元素组成】C 79.96% H 8.29% N 5.49% O 6.27% |
合成路线1
该中间体在本合成路线中的序号：(IV)A new enantioselective synthesis for denopamine has been reported: The acylation of 1-(4-benzyloxyphenyl)-2-[2-(3,4-dimethoxyphenyl)ethylamino]ethanone (I) with benzyloxycarbonyl chloride (II) by means of NaHCO3 in dichloromethane gives the protected aminoketone (III), which is submitted to an asymmetric reduction with (R)-(+)-2-amino-3-methyl-1,1-diphenyl-1-butanol-borane complex in THF yielding the (R)-(-)-protected alcohol (V). Finally, the debenzylation of (V) by hydrogenolysis with H2 over Pd/C in methanol affords denopamine with 96% optical purity.
| 【1】 Takeda, M.; Saito, K.; Kawaguchi, T.; Matsuki, K.; Iwakuma, T.; Asymmetric reduction of aromatic ketones. I. Enantioselective synthesis of denopamine. Chem Pharm Bull 1993, 41, 4, 639. |
| 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) | 10100 | 1-[4-(Benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanone; N-(3,4-Dimethoxyphenylethyl)-4-benzyloxyphenacylamine | C25H27NO4 | 详情 | 详情 | |
| (II) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (III) | 10102 | Benzyl 2-[4-(benzyloxy)phenyl]-2-oxoethyl(3,4-dimethoxyphenethyl)carbamate; Benzyl (4-benzyloxy)phenacyl-(3,4-dimethoxyphenethyl)carbamate | C33H33NO6 | 详情 | 详情 | |
| (IV) | 10103 | (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol | 56755-20-5 (hydrochloride) | C17H21NO | 详情 | 详情 |
| (V) | 10104 | benzyl (2R)-2-[4-(benzyloxy)phenyl]-2-hydroxyethyl(3,4-dimethoxyphenethyl)carbamate | C33H35NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The regioselective reduction of 8-methyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (I) with borane-THF complex catalyzed by (R)-2-amino-3-methyl-1,1-diphenyl-1-butanol (II) in dichloromethane gives the 8(R)-methyl derivative (III), which is acetylated with acetic anhydride yielding the 7-acetyl-8(R)-methyl derivative (IV). Finally, the nitro group of (IV) is reduced with hydrazine and Ni-Raney in methanol.
| 【1】 Ling, I.; et al.; Asymmetric reduction of a carbon-nitrogen double bond: Enantioselective synthesis of 4,5-dihydro-3H-2,3-benzodiazepines. J Chem Soc - Perkins Trans I 1995, 11, 1423. |
| 【2】 Ling, I.; Hamori, T.; Botka, P.; Solyom, S.; Simay, A.; Moravcsik, I. (Gyogyszerkutato Intezet Kft.); Optically active 1-(4-nitrophenyl)-4-methyl-7, 8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and process for preparing same. WO 9501357 . |
| 【3】 Andrasi, F.; Berzsenyi, P.; Botka, P.; Farkas, S.; Goldschmidt, K.; Hamori, T.; Korosi, J.; Moravcsik, I.; Tarnawa, I. (Gyogyszerkutato Intezet Kft.); N-Acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0492485; JP 1993070463; US 5519019; US 5521174; US 5536832; US 5604223; US 5639751 . |
| 【4】 Berzsenyi, P.; Goldschmidt, K.; Moravcsik, I.; Kórösi, J.; Andrási, F.; Farkas, S.; Hámori, T.; Tarnawa, I.; Botka, P. (Gyogyszerkutato Intezet Kft.); N-Acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. US 5459137 . |
| 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) | 29266 | 8-methyl-5-(4-nitrophenyl)-9H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine | C17H13N3O4 | 详情 | 详情 | |
| (II) | 10103 | (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol | 56755-20-5 (hydrochloride) | C17H21NO | 详情 | 详情 |
| (III) | 29267 | (8R)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine | C17H15N3O4 | 详情 | 详情 | |
| (IV) | 29265 | 1-[(8R)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-7-yl]-1-ethanone | C19H17N3O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)An alternative procedure has been reported for the synthesis of the chiral (S)-amine (XXIV). Ketone (IX) was treated with O-methyl hydroxylamine to afford a geometric mixture of O-methyl oximes, from which isomer (XVII) was isolated by silica gel chromatography. Asymmetric reduction of the O-methyl oxime (XVII) with borane in the presence of the chiral auxiliary (XVIII) furnished the desired (S)-amine (XIX), which was further protected as the tert-butyl carbamate (XX) by treatment with Boc2O. Bromide (XXI), carboxylic acid (XXII) and amide (XXIII) were obtained following the same procedures as above. Then, acid cleavage of the Boc group of (XXIII) yielded the chiral amine (XXIV).
| 【1】 Bohacek, R.; Yang, M.; Shakespeare, W.; et al.; Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity. Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 17, 9373. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 43271 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H24O2 | 详情 | 详情 | |
| (XVII) | 43279 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one O-methyloxime | C19H27NO2 | 详情 | 详情 | |
| (XVIII) | 10103 | (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol | 56755-20-5 (hydrochloride) | C17H21NO | 详情 | 详情 |
| (XIX) | 43281 | (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylamine; (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-amine | C18H27NO | 详情 | 详情 | |
| (XX) | 43282 | tert-butyl (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H35NO3 | 详情 | 详情 | |
| (XXI) | 43283 | tert-butyl (5S)-3-bromo-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H34BrNO3 | 详情 | 详情 | |
| (XXII) | 43284 | (9S)-9-[(tert-butoxycarbonyl)amino]-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxylic acid | C24H35NO5 | 详情 | 详情 | |
| (XXIII) | 43285 | tert-butyl (5S)-3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C24H36N2O4 | 详情 | 详情 | |
| (XXIV) | 43286 | (9S)-9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)4-Bromo-3-fluorotoluene (I) is converted into the Grignard reagent (II) with magnesium in boiling Et2O, and subsequently added to cyclopropylacetonitrile (III) to produce ketone (IV). Condensation of (IV) with hydroxylamine affords oxime (V), which is further alkylated with benzyl bromide to yield the O-benzyl oxime (VI). Asymmetric reduction of oxime (VI) with borane in the presence of the aminoalcohol chiral auxiliary (VII) provides the (S)-amine (VIII). Reaction of amine (VIII) with ammonium thiocyanate and benzoyl chloride, followed by treatment with hydrazine hydrate, gives rise to the thiourea (IX). Friedel-Crafts acylation of 4-chloro-2-methoxytoluene (X) with 2-bromopropionyl bromide (XI) employing AlCl3 furnishes the bromo ketone (XII). Then, condensation of thiourea (IX) with bromo ketone (XII) in the presence of Et3N in boiling EtOH gives rise to the aminothiazole (XIII). Finally, alkylation of the amino group of (XIII) with propargyl bromide (XIV) and NaH furnishes the title compound
| 【1】 Roger, P.; Gully, D.; Pradines, A.; Fontaine, E.; Geslin, M. (Sanofi-Synthelabo); Aminothiazole derivs. and their use as CRF receptor ligands. EP 1200419; FR 2796380; JP 2003505380; WO 0105776 . |
| 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) | 60397 | 4-bromo-2-fluoro-1-methylbenzene | C7H6BrF | 详情 | 详情 | |
| (II) | 60398 | bromo(3-fluoro-4-methylphenyl)magnesium | C7H6BrFMg | 详情 | 详情 | |
| (III) | 16824 | 2-cyclopropylacetonitrile; Cyclopropylacetonitrile | 6542-60-5 | C5H7N | 详情 | 详情 |
| (IV) | 60399 | 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-1-ethanone | C12H13FO | 详情 | 详情 | |
| (V) | 60400 | 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-1-ethanone oxime | C12H14FNO | 详情 | 详情 | |
| (VI) | 60401 | 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-1-ethanone O-benzyloxime | C19H20FNO | 详情 | 详情 | |
| (VII) | 10103 | (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol | 56755-20-5 (hydrochloride) | C17H21NO | 详情 | 详情 |
| (VIII) | 60402 | (1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-1-ethanamine; (1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethylamine | C12H16FN | 详情 | 详情 | |
| (IX) | 60403 | N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]thiourea | C13H17FN2S | 详情 | 详情 | |
| (X) | 60405 | 5-chloro-2-methylphenyl methyl ether; 4-chloro-2-methoxy-1-methylbenzene | C8H9ClO | 详情 | 详情 | |
| (XI) | 13127 | 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide | 563-76-8 | C3H4Br2O | 详情 | 详情 |
| (XII) | 60404 | 2-bromo-1-(2-chloro-4-methoxy-5-methylphenyl)-1-propanone | C11H12BrClO2 | 详情 | 详情 | |
| (XIII) | 60406 | 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-1,3-thiazol-2-amine; N-[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl]-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]amine | C24H26ClFN2OS | 详情 | 详情 | |
| (XIV) | 23634 | acetylene | 74-86-2 | C2H2 | 详情 | 详情 |