【结 构 式】 |
【分子编号】17042 【品名】(2R)-3,4-dihydro-2H-chromen-2-ylmethanamine; (2R)-3,4-dihydro-2H-chromen-2-ylmethylamine 【CA登记号】 |
【 分 子 式 】C10H13NO 【 分 子 量 】163.21936 【元素组成】C 73.59% H 8.03% N 8.58% O 9.8% |
合成路线1
该中间体在本合成路线中的序号:(VI)The synthesis of BAY x 3702 was carried out as outlined: Chroman-2-carboxylic acid (I) was activated with thionyl chloride. The acid chloride (II) was treated with (S)-phenethylamine (III), affording a (1:1)-mixture of diastereomers. Fractional crystallization from ethanol gave the isomer (IV) in high diastereomerical purity; basic epimerization of the undesired diastereomer is feasible. The amide (IV) was reduced with diborane in THF, yielding the amine (V), which was submitted to catalytic hydrogenation over palladium-on-charcoal. The resulting optically pure (R)-2-aminomethyl chroman (VI) was alkylated with 4-bromobutyl saccharin (VII), which is easily available from saccharin sodium and 1,4-dibromobutane. BAY x 3702 was isolated as the hydrochloride salt. White, odorless crystals, m.p. 195 C, alpha(20,D) -42.2 (c 0.9, CHCl3). BAY x 3702 is soluble in water (2.1 g/100 ml), acetone (2.2 g/100 ml) and DMSO. The solid substance is heat-stable, nonhygroscopic and nonsensitive to light. It is unstable in alkaline medium (hydrolysis), sensitive to hydrolysis in aqueous dilute solutions/suspensions at weak acidic and neutral pH, but stable in acidic medium (pH less than or equal to 4). The UV spectrum shows maxima at 272 and 279 nm. BAY x 3702 can be assayed by HPLC.
【1】 Opitz, W.; Heine, H-G.; Mauler, F.; Schohe-Loop, R.; Maertins, T.; Jork, R.; Dietrich, H.; Glaser, T.; Horvath, E.; Scherling, D.; De Vry, J.; Bay-x-3702. Drugs Fut 1997, 22, 4, 341. |
【2】 Junge, B.; Schohe, R.; Seidel, P.-R.; Glaser, T.; Traber, J.; Benz, U.; Schuurman, T.; De Vry, J.-M.-V. (Bayer AG); Substd. amino methyl tetralines, and their heterocyclic analogous cpds. EP 0352613; JP 1990096552; US 5137901; US 5506246 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 | |
33704 | 1,1-Dioxide-1,2-benzisothiazol-3(2H)-one, sodium salt; 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt (1:1) | 38279-26-4 | C7H4NNaO3S | 详情 | 详情 | |
65068 | 2-(4-{[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C21H24N2O4S | 详情 | 详情 | ||
(I) | 17037 | 2-chromanecarboxylic acid | C10H10O3 | 详情 | 详情 | |
(II) | 17038 | 2-chromanecarbonyl chloride | C10H9ClO2 | 详情 | 详情 | |
(IV) | 17040 | (2R)-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide | C18H19NO2 | 详情 | 详情 | |
(V) | 17041 | (1S)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1S)-1-phenylethyl]amine | C18H21NO | 详情 | 详情 | |
(VI) | 17042 | (2R)-3,4-dihydro-2H-chromen-2-ylmethanamine; (2R)-3,4-dihydro-2H-chromen-2-ylmethylamine | C10H13NO | 详情 | 详情 | |
(VII) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(III)Addition of KCN to 3-(2-hydroxyphenyl)propanal (I) produced 2-cyanochromane (II), which was further reduced to the aminomethyl chromane rac-(III) by catalytic hydrogenation. Resolution of this racemic amine by recrystallization of the diastereomeric salts with N-tosyl-L-proline furnished the required (R)-enantiomer (III). Alkylation of amine (III) with 3-(chloromethyl)-5-(4-fluorophenyl)pyridine (IV) in the presence of N-methylmorpholine yielded the target secondary amine.
【1】 Bottcher, H.; Devant, R.; Greiner, H.; Bartoszyk, G.; Berthelon, J.-J.; Noblet, M.; Zeiller, J.-J.; Brunet, M. (Merck Patent GmbH); Amino(thio)ether derivs. as CNS active agents. CA 2160447; EP 0707007; EP 1123933; JP 1996225501; US 5767132 . |
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) | 56036 | 3-(2-hydroxyphenyl)propanal | 53580-62-4 | C9H10O2 | 详情 | 详情 |
(II) | 56037 | 2-chromanecarbonitrile | C10H9NO | 详情 | 详情 | |
(III) | 17042 | (2R)-3,4-dihydro-2H-chromen-2-ylmethanamine; (2R)-3,4-dihydro-2H-chromen-2-ylmethylamine | C10H13NO | 详情 | 详情 | |
(IV) | 56038 | 3-(chloromethyl)-5-(4-fluorophenyl)pyridine | 177976-33-9 | C12H9ClFN | 详情 | 详情 |