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【结 构 式】 
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【分子编号】12412 【品名】(1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine 【CA登记号】 |
【 分 子 式 】C8H16N2 【 分 子 量 】140.22852 【元素组成】C 68.52% H 11.5% N 19.98% |
合成路线1
该中间体在本合成路线中的序号：(II)The target compound has been obtained by condensation of 3.3-dimethylindoline-1-carbonyl chloride (IV) with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (II) by means of triethylamine followed by salification with HCl. The intermediates (II) and (IV) have been obtained as follows: A) The metthylation of 3-methylindole (III) with methylmagnesium iodid / methyl iodid, followed by hydrogenation with H2/Pt in acetic acid gives 3,3-dimethylindoline (I), which is then treated with phosghene / Et3N to afford intermediate (IV). B) The reductocondensation of 8-methyl-para-bicyclo[3.2.1]octan-3-one (V) with benzylamine and H2/Pt gives the secondary benzylamine (VI), which is finally deprotected by hydrogenation over Pd/C to give intermediate (II).
| 【1】 Archer, S.; Lewis, T.R.; Unser, M.J.; 3alpha-(2-Diethylaminoethyl)-aminotropane and related compounds. J Am Chem Soc 1957, 79, 4194-8. |
| 【2】 Miyasaka, T.; Mutai, M.; Nokata, K.; Sawada, S.; Sugino, E. (Yakult Honsha Co., Ltd.); New camptothecin derivs. and process for preparing same. EP 0137145; JP 1985019790 . |
| 【3】 Joiner, K.A.; King, F.D. (SmithKline Beecham plc); Certain 2,3-dihydro-indole-1-carboxamido-N-[8-azabicyclo(3.2.1)octan-3-yl] derivatives having 5-HT-antagonist activity. EP 0363466; JP 1990503569; US 4871744; US 5049556; WO 8909217 . |
| 【4】 Blackburn, T.; King, F.; BRL46470A. Drugs Fut 1992, 17, 11, 987. |
| 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) | 12411 | 3,3-Dimethylindoline | C10H13N | 详情 | 详情 | |
| (II) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 | |
| (III) | 63428 | 3-methyl-1H-indole | C9H9N | 详情 | 详情 | |
| (IV) | 12414 | 3,3-Dimethyl-1-indolinecarbonyl chloride | C11H12ClNO | 详情 | 详情 | |
| (V) | 16443 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one | C8H13NO | 详情 | 详情 | |
| (VI) | 12413 | N-Benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amine; (1R,5S)-N-Benzyl-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C15H22N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)1) The esterification of 5-chloro-2-hydroxybenzoic acid (I) with methanol - HCl gives the corresponding methyl ester (II), which is alkylated with 3-chloro-2-methylpropene (III) to afford methyl 5-chloro-2-(2-methyl-2-propenyloxy)benzoate (IV). The rearrangement of (IV) by heating with N-methylpyrrolidine yields methyl 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoate (V). The cyclization of (V) in formic acid followed by hydrolysis with NaOH gives 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (VI), which is finally treated with SOCl2, condensed with 3alpha-aminotropane (VII) and treated with maleic acid.
| 【1】 Cohen, M.L.; Lacefield, W.B. (Eli Lilly and Company); Improvements in or relating to specific 5-HT3 antagonists. AU 8821916; EP 0307172; JP 1989110684 . |
| 【2】 Robertson, D.W.; Bloomquist, W.; Pfiefer, W.; Cohen, M.L.; Simon, R.L.; Lacefield, W.B.; Zatosetron, a potent, selective, and long-acting 5-HT3 receptor antagonist: Synthesis and structure-activity relationships. J Med Chem 1992, 35, 2, 310-9. |
| 【3】 Graul, A.; Castaner, J.; Prous, J.; Zatosetron Maleate. Drugs Fut 1994, 19, 9, 850. |
| 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) | 13895 | 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid | 321-14-2 | C7H5ClO3 | 详情 | 详情 |
| (II) | 13714 | Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate | 4068-78-4 | C8H7ClO3 | 详情 | 详情 |
| (III) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (IV) | 13898 | methyl 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoate | C12H13ClO3 | 详情 | 详情 | |
| (V) | 13899 | methyl 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoate | C12H13ClO3 | 详情 | 详情 | |
| (VI) | 13900 | 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C11H11ClO3 | 详情 | 详情 | |
| (VII) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)2) The title compound, with or without [14C]-radiolabeling at the carboxamide group, is synthesized as follows: The alkylation of 2-bromo-4-chlorophenol (VIII) with 2-methylallyl chloride (III) by means of cesium carbonate in acetone gives the corresponding allyl ether (IX), which is submitted to an allylic transposition to the ortho allyl phenol (X); the latter, without isolation, is thermically cyclized to 7-bromo-5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran (XI). The reaction of (XI) with KCN (with or without [14C]-radiolabel) by means of CuCN yields 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carbonitrile (XII), which is hydrolyzed with methanolic KOH to the corresponding acid (XIII). The reaction of (XIII) with oxalyl chloride in toluene affords the corresponding acyl chloride (XIV), which is finally condensed with endo-3-amino-8-methyl-8-azabicyclo[3.2.1]octane (3alpha-aminotropane) (VII) in toluene as solvent.
| 【1】 O'Bannon, D.D.; Wheeler, W.J.; The synthesis of the carbonyl-14C analog of zatosetron maleate, a potent, long-acting, orally effective 5-HT3 receptor antagonist. J Label Compd Radiopharm 1991, 29, 6, 625-32. |
| 【2】 Graul, A.; Castaner, J.; Prous, J.; Zatosetron Maleate. Drugs Fut 1994, 19, 9, 850. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (VII) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 | |
| (VIII) | 13902 | 2-Bromo-4-chlorophenol | 695-96-5 | C6H4BrClO | 详情 | 详情 |
| (IX) | 13903 | 2-Bromo-4-chlorophenyl 2-methyl-2-propenyl ether; 2-Bromo-4-chloro-1-[(2-methyl-2-propenyl)oxy]benzene | C10H10BrClO | 详情 | 详情 | |
| (X) | 13904 | 2-Bromo-4-chloro-6-(2-methyl-2-propenyl)phenol | C10H10BrClO | 详情 | 详情 | |
| (XI) | 13905 | 7-Bromo-5-chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran | C10H10BrClO | 详情 | 详情 | |
| (XII) | 13906 | 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonitrile | C11H10ClNO | 详情 | 详情 | |
| (XII) | 45187 | 5-chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C11H11ClO3 | 详情 | 详情 | |
| (XIII) | 13900 | 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C11H11ClO3 | 详情 | 详情 | |
| (XIII) | 45188 | 5-chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonitrile | C11H10ClNO | 详情 | 详情 | |
| (XIV) | 13908 | 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonyl chloride | C11H10Cl2O2 | 详情 | 详情 | |
| (XIV) | 45189 | 5-chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonyl chloride | C11H10Cl2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The reaction of 5-chloro-2-hydroxybenzoic acid (I) with 2-methyl-2-propenyl chloride (II) by means of K2CO3 and KI in hot DMF gives 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid 2-methyl-2-propenyl ester (III), which is rearranged by heating at 190 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid 2-methyl-2-propenyl ester (IV). The cyclization of (IV) with refluxing 90% formic acid affords 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (V), which is treated with SOCl2 in DMF and condensed with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI). The acid intermediate (V) can also be obtained by hydrolysis of the ester (III) with NaOH and tetrabutylammonium bisulfate in refluxing water to give 5-chloro-2-(2-methyl-2-propenyloxy)benzoic acid (VII), which is rearranged by heating at 170 C yielding 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid (VIII). Finally, (VIII) is cyclized to acid intermediate (V) by a treatment with aqueous refluxing 2.7N HCl. The intermediate endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (VI) has been obtained as follows: 2,5-dihydroxytetrahydrofuran (IX) or 2,5-dimethoxytetra-hydrofuran (X) with HCl give butanedialdehyde (XI), which, without isolation, is cyclized with 3-oxoglutaric acid (XII) and methylamine by means of NaOAc and HCl in hot water yielding 8-methyl-8-azabicyclo[3.2.1]octan-3-one (XIII). The reductocondensation of (XIII) with benzylamine by means of NaBH(OAc)3, followed by hydrogenolysis with H2 over Pd/C in basic water gives directly the amine (VI). The intermediate amine (VI) can also be obtained by condensation of bicyclooctanone (XIII) with benzylamine(A) to give the imine (XIV), which is reduced to the benzylamine (XV) with H2 over PtO2 in ethanol. Finally, this compound is debenzylated by hydrogenation over Pd/C in the same solvent yielding amine (VI).
| 【1】 Burks, J.E.; et al.; Development of a manufacturing process for zatosetron maleate. Org Process Res Dev 1997, 1, 3, 198. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (I) | 13895 | 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid | 321-14-2 | C7H5ClO3 | 详情 | 详情 |
| (II) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (III) | 36355 | 2-methyl-2-propenyl 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoate | C15H17ClO3 | 详情 | 详情 | |
| (IV) | 36356 | 2-methyl-2-propenyl 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoate | C15H17ClO3 | 详情 | 详情 | |
| (V) | 13900 | 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C11H11ClO3 | 详情 | 详情 | |
| (VI) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 | |
| (VII) | 36357 | 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoic acid | C11H11ClO3 | 详情 | 详情 | |
| (VIII) | 36358 | 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid | C11H11ClO3 | 详情 | 详情 | |
| (IX) | 36359 | tetrahydro-2,5-furandiol | C4H8O3 | 详情 | 详情 | |
| (X) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (XI) | 36360 | succinaldehyde | C4H6O2 | 详情 | 详情 | |
| (XII) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XIII) | 16443 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one | C8H13NO | 详情 | 详情 | |
| (XIV) | 36361 | N-benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene]amine; N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene](phenyl)methanamine | C15H20N2 | 详情 | 详情 | |
| (XV) | 12413 | N-Benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amine; (1R,5S)-N-Benzyl-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C15H22N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Coupling of methyl 4-acetamido-5-chlorosalicylate (I) with 3-penty-2-ol (II) under Mitsunobu conditions furnished the propargyl ether (III). Acetamide hydrolysis en (III) using H2SO in methanol gave aminoester (IV), whih was further hydrolyzed with NaOH to the carboxylic acid (V). Condensation of racemic acid (V) with the aminopropane (VI) in the presence of DCC afforded the corresponding amide, which was resolved into the enantiomers by means of preparative, chiral HPLC.
| 【1】 Miyazawa, S.; Hibi, S.; Yoshimura, H.; Mori, T.; Hoshino, Y.; Nagai, M.; Kikuchi, K.; Shibata, H.; Hirota, K.; Yamanaka, T.; Yamatsu, I.; Mizuno, M. (Eisai Co., Ltd.); Aminobenzoic acid derivs.. EP 0554794; JP 1994128254; JP 1998007674; US 5389643; US 5578603 . |
| 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) | 59800 | methyl 4-(acetylamino)-5-chloro-2-hydroxybenzoate | C10H10ClNO4 | 详情 | 详情 | |
| (II) | 59801 | 3-pentyn-2-ol | C5H8O | 详情 | 详情 | |
| (III) | 59802 | methyl 4-(acetylamino)-5-chloro-2-[(1-methyl-2-butynyl)oxy]benzoate | C15H16ClNO4 | 详情 | 详情 | |
| (IV) | 59803 | methyl 4-amino-5-chloro-2-[(1-methyl-2-butynyl)oxy]benzoate | C13H14ClNO3 | 详情 | 详情 | |
| (V) | 59804 | 4-amino-5-chloro-2-[(1-methyl-2-butynyl)oxy]benzoic acid | C12H12ClNO3 | 详情 | 详情 | |
| (VI) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)Condensation of acid chloride (VIII) 3-aminotropane (IX) provided amide (X). N-Demethylation of (X) was then achieved by treatment with 1-chloroethyl chloroformate, followed by hydrolysis and decarboxylation of the intermediate carbamate (XI) with MeOH. The resulting secondary amine (XII) was then alkylated with 3-bromopropanol (XIII) to afford the target hydroxypropyl derivative.
| 【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29. |
| 【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 22014 | 1-chloro-1-[(chlorocarbonyl)oxy]ethane | 50893-53-3 | C3H4Cl2O2 | 详情 | 详情 | |
| (VIII) | 36336 | 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride | C13H12ClNO2 | 详情 | 详情 | |
| (IX) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 | |
| (X) | 36337 | 1-isopropyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-1,2-dihydro-3-quinolinecarboxamide | C21H27N3O2 | 详情 | 详情 | |
| (XI) | 36338 | 1-chloroethyl (1R,5S)-3-[[(1-isopropyl-2-oxo-1,2-dihydro-3-quinolinyl)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate | C23H28ClN3O4 | 详情 | 详情 | |
| (XII) | 36339 | N-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide | C20H25N3O2 | 详情 | 详情 | |
| (XIII) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |