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【结 构 式】 
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【分子编号】26375 【品名】(3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxamide 【CA登记号】 |
【 分 子 式 】C18H23FN2O2 【 分 子 量 】318.3913032 【元素组成】C 67.9% H 7.28% F 5.97% N 8.8% O 10.05% |
合成路线1
该中间体在本合成路线中的序号：(XIII)1) The esterification of 4-fluoro-3-hydroxybenzoic acid (I) with trimethyl orthoformate and sulfuric acid gives the methyl ester (II), which is condensed with propargyl bromide (III) by means of K2CO3 in acetone, yielding the corresponding ether (IV). The cyclization of (IV) by heating at 220 C in N,N-diethylaniline affords 8-fluoro-2H-1-benzopyran-5-carboxylic acid methyl ester (V), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (VI). The reaction of (VI) with thionyl chloride and then with ammonia affords the carboxamide (VII), which is nitrated with NaNO2 and iodine, giving the 8-fluoro-3-nitro-2H-1-benzopyran-5-carboxamide (VIII). The hydrogenation of the double bond of (VIII) with NaBH4 in isopropanol yields the 3,4-dihydro compound (IX), which is then further reduced at the nitro group with H2 and RaNi in ethanol/THF, providing racemic 3-amino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (X). Optical resolution of (X) with L-(+)-tartaric acid gives the 3(R)-amino derivative (XI), which is alkylated with cyclobutanone (XII) and sodium cyanoborohydride in methanol/acetic acid to afford robalzotan (XIII). Finally, this compound is treated with L-(+)-tartaric acid (XIV) in THF/ethyl ether.
| 【1】 Leeson, P.; Castañer, J.; Sorbera, L.A.; Robalzotan Tartrate Hydrate. Drugs Fut 1999, 24, 7, 740. |
| 【2】 Muroi, M.; Tobita, T.; Nozaki, Y. (Takeda Chemical Industries, Ltd.); Physiologically active substances TAN-1323, their preparation method and use. JP 1991290193 . |
| 【3】 Sohn, D.D.; Johansson, L.; Hanson, S. (AstraZeneca plc); A new process. WO 9846586 . |
| 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) | 26364 | 4-fluoro-3-hydroxybenzoic acid | 51446-31-2 | C7H5FO3 | 详情 | 详情 |
| (II) | 26365 | methyl 4-fluoro-3-hydroxybenzoate | C8H7FO3 | 详情 | 详情 | |
| (III) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (IV) | 26366 | methyl 4-fluoro-3-(2-propynyloxy)benzoate | C11H9FO3 | 详情 | 详情 | |
| (V) | 26367 | methyl 8-fluoro-2H-chromene-5-carboxylate | C11H9FO3 | 详情 | 详情 | |
| (VI) | 26368 | 8-fluoro-2H-chromene-5-carboxylic acid | C10H7FO3 | 详情 | 详情 | |
| (VII) | 26369 | 8-fluoro-2H-chromene-5-carboxamide | C10H8FNO2 | 详情 | 详情 | |
| (VIII) | 26370 | 8-fluoro-3-nitro-2H-chromene-5-carboxamide | C10H7FN2O4 | 详情 | 详情 | |
| (IX) | 26371 | 8-fluoro-3-nitro-5-chromanecarboxamide | C10H9FN2O4 | 详情 | 详情 | |
| (X) | 26372 | 3-amino-8-fluoro-5-chromanecarboxamide | C10H11FN2O2 | 详情 | 详情 | |
| (XI) | 26373 | (3R)-3-amino-8-fluoro-3,4-dihydro-2H-chromene-5-carboxamide | C10H11FN2O2 | 详情 | 详情 | |
| (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 | |
| (XIV) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)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 |