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【结 构 式】 
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【分子编号】26381 【品名】(3R)-N,N-dicyclobutyl-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; N,N-dicyclobutyl-N-[(3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-yl]amine 【CA登记号】 |
【 分 子 式 】C18H24FNO2 【 分 子 量 】305.3925032 【元素组成】C 70.79% H 7.92% F 6.22% N 4.59% O 10.48% |
合成路线1
该中间体在本合成路线中的序号：(XX)2) The bromination of 3(R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran (XV) with Br2 in acetic acid gives the 8-bromo compound (XVI), which is protected with benzyl bromide and K2CO3 in acetonitrile, yielding the dibenzylamino compound (XVII). The reaction of (XVII) with N-fluorobenzenesulfonimide and BuLi in THF provides the corresponding 8-fluoro derivative (XVIII), which is deprotected with H2 over Pd/C in methanol/THF, giving 3(R)-amino-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (XIX). The alkylation of (XIX) with cyclobutanone (XII) and sodium cyanoborohydride in methanol gives the dicyclobutylamino compound (XX), which is demethylated by means of boron tribromide in dichloromethane to afford the 5-hydroxy compound (XXI). The triflation of (XXI) with trifluoromethanesulfonic anhydride and collidine in dichloromethane yields the triflate (XXII), which is treated with carbon monoxide, palladium acetate and methanol to give methyl 3(R)-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (XXIII). The hydrolysis of (XXIII) with refluxing 6M aqueous HCl yields the free acid (XXIV), which by reaction with SOCl2 is converted into the acyl chloride (XXV). Finally, this compound is treated with ammonia in dichloromethane to give robalzotan (XIII).
| 【1】 Leeson, P.; Castañer, J.; Sorbera, L.A.; Robalzotan Tartrate Hydrate. Drugs Fut 1999, 24, 7, 740. |
| 【2】 Evenden, J.L.; Hammarberg, E.M.; Hansson, H.S.; Hellberg, S.E.; Johansson, L.G.; Lundkvist, J.R.M.; Ross, S.B.; Sohn, D.D.; Thorberg, S.O. (AstraZeneca plc); Novel (R)-5-carbamoyl-8-fluoro-3,-N, N-disubstd.-amino-3,4-dihydro-2H-1-benzopyranes. EP 0725779; JP 1997504287; WO 9511891 . |
| 【3】 Hammarberg, E.M.; Johansson, L.G.; Ross, S.B.; Thorberg, S.O. (AstraZeneca plc); 3-(N-Isopropyl-N-n-propylamino)-5-(N-isopropyl)carbamoylchroman as a selective 5-hydroxytryptamine receptor stimulant. EP 0538222; EP 0607274; JP 1995500320; US 5616610; WO 9307135 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 26374 | cyclobutanone | 1191-95-3 | C4H6O | 详情 | 详情 |
| (XIII) | 26375 | (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxamide | C18H23FN2O2 | 详情 | 详情 | |
| (XV) | 26376 | (3R)-5-methoxy-3,4-dihydro-2H-chromen-3-ylamine; (3R)-5-methoxy-3,4-dihydro-2H-chromen-3-amine | C10H13NO2 | 详情 | 详情 | |
| (XVI) | 26377 | (3R)-8-bromo-5-methoxy-3,4-dihydro-2H-chromen-3-amine; (3R)-8-bromo-5-methoxy-3,4-dihydro-2H-chromen-3-ylamine | C10H12BrNO2 | 详情 | 详情 | |
| (XVII) | 26378 | N,N-dibenzyl-N-[(3R)-8-bromo-5-methoxy-3,4-dihydro-2H-chromen-3-yl]amine; (3R)-N,N-dibenzyl-8-bromo-5-methoxy-3,4-dihydro-2H-chromen-3-amine | C24H24BrNO2 | 详情 | 详情 | |
| (XVIII) | 26379 | (3R)-N,N-dibenzyl-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; N,N-dibenzyl-N-[(3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-yl]amine | C24H24FNO2 | 详情 | 详情 | |
| (XIX) | 26380 | (3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; (3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-ylamine | C10H12FNO2 | 详情 | 详情 | |
| (XX) | 26381 | (3R)-N,N-dicyclobutyl-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; N,N-dicyclobutyl-N-[(3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-yl]amine | C18H24FNO2 | 详情 | 详情 | |
| (XXI) | 26382 | (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromen-5-ol | C17H22FNO2 | 详情 | 详情 | |
| (XXII) | 26383 | (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate | C18H21F4NO4S | 详情 | 详情 | |
| (XXIII) | 26384 | methyl (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylate | C19H24FNO3 | 详情 | 详情 | |
| (XXIV) | 26385 | (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylic acid | C18H22FNO3 | 详情 | 详情 | |
| (XXV) | 26386 | (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carbonyl chloride | C18H21ClFNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The synthesis of [3H]-labeled robalzotan has been described: The bromination of 3(R)-(dicyclobutylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-benzopyran (I), a previously described intermediate in the synthesis of robalzotan, with Br2 in ethanol affords the 6-bromo-8-fluorobenzopyran derivative (II), which is first demethylated with refluxing conc. HBr yielding the 5-hydroxy compound (III) and then treated with Tf2O in dichloromethane providing triflate (IV). The carbonylation of (IV) with CO and Pd(OAc)2 in DMF/methanol gives the methyl ester (V), which is hydrolyzed with refluxing HCl to yield the carboxylic acid (VI). The reaction of (VI) with SOCl2 affords the corresponding acyl chloride (VII), which is treated with ammonia to provide the carboxamide (VIII). Finally, this compound is hydrogenated with 3H2 catalyzed by PdO in DMF.
| 【1】 Werner, T.F.; et al.; Radiosynthesis of [C-14]- and [H-3]-robalzotan a selective 5-HT1A antagonist. J Label Compd Radiopharm 2000, 43, 5, 437. |
| 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) | 26381 | (3R)-N,N-dicyclobutyl-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; N,N-dicyclobutyl-N-[(3R)-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-yl]amine | C18H24FNO2 | 详情 | 详情 | |
| (II) | 37663 | (3R)-6-bromo-N,N-dicyclobutyl-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-amine; N-[(3R)-6-bromo-8-fluoro-5-methoxy-3,4-dihydro-2H-chromen-3-yl]-N,N-dicyclobutylamine | C18H23BrFNO2 | 详情 | 详情 | |
| (III) | 37664 | (3R)-6-bromo-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromen-5-ol | C17H21BrFNO2 | 详情 | 详情 | |
| (IV) | 37665 | (3R)-6-bromo-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate | C18H20BrF4NO4S | 详情 | 详情 | |
| (V) | 37666 | methyl (3R)-6-bromo-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylate | C19H23BrFNO3 | 详情 | 详情 | |
| (VI) | 37667 | (3R)-6-bromo-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxylic acid | C18H21BrFNO3 | 详情 | 详情 | |
| (VII) | 37668 | (3R)-6-bromo-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carbonyl chloride | C18H20BrClFNO2 | 详情 | 详情 | |
| (VIII) | 37669 | (3R)-6-bromo-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxamide | C18H22BrFN2O2 | 详情 | 详情 |