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【结 构 式】 
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【药物名称】Frovatriptan, SB-209509AX(succinate), VML-251, SB-209509, Allegro, Frova, Frovelan(former Brand Name), Miguard, Migard 【化学名称】(R)-(+)-3-(Methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide 【CA登记号】158747-02-5, 158930-18-8 ((S)-isomer), 158747-09-2 (racemate), 158930-17-7 (succinate), 147009-08-3 (undefined stereoch.) 【 分 子 式 】C14H17N3O 【 分 子 量 】243.31109 |
【开发单位】GlaxoSmithKline (Originator), Menarini (Licensee), Vernalis (Licensee), UCB Pharma (Comarketer) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 5-HT1B Agonists, 5-HT1D Agonists |
合成路线1
1) The cyclization of 4-hydrazinobenzonitrile (I) with 4-(benzoyloxy)cyclohexanone (II) in refluxing acetic acid gives 3-(benzoyloxy)-1,2,3,4-tetrahydro-9H-carbazole-6-carbonitrile (III), which is hydrolyzed with aqueous KOH to the corresponding alcohol (IV). The tosylation of (IV) with tosyl chloride in pyridine yields the tosylate (V), which by treatment with methylamine in hot ethanol is converted into 3-(methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carbonitrile (VI). The partial hydrolysis of the nitrile group with NaOH/H2O2, with previous protection of the amino group with di-tert-butyl dicarbonate, affords 3-(methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide (VII) as a racemic mixture. The reaction of (VII) with di-tert-butyl dicarbonate gives the carbamate (VIII), which is submitted to chiral HPLC in hexane/ethanol giving the (R)-isomer (IX). Finally, this carbamate is hydrolyzed with aqueous HCl/methanol. 2) The optical resolution can also be performed with the benzoyloxycarbonyl derivative of (VII) in a similar way. 3) The optical resolution of (VII) can also be performed directly with (1S)-(+)-camphorsulfonic acid in methanol. 4) The reaction of cyclohexane-1,4-dione mono 2,2-dimethyltrimethylene ketal (X) with methylamine in toluene gives the corresponding methylimine (XI), which is reduced with H2 over Pd/C in ethanol to the expected methylamine (XII). Finally, this compound is cyclized with 4-aminobenzamide (XIII) by treatment first with NaNO2/HCl and then with sodium dithionite affording the racemic mixture (VII) already described.
| 【1】 Graul, A.; Leeson, P.; Castañer, J.; SB-209509/VML-251. Drugs Fut 1997, 22, 7, 725. |
| 【2】 King, F.D.; Gaster, L.M.; Kaumann, A.J.; Young, R.C. (SmithKline Beecham plc); Use of tetrahydrocarbazole derivs. as 5HT1 receptor agonists. EP 0591280; JP 1994508827; US 5464864; US 5827871; WO 9300086 . |
| 【3】 Borrett, G.T.; Kitteringham, J.; Porter, R.A.; Shipton, M.R.; Vimal, M.; Young, R.C. (SmithKline Beecham plc); Enantiomers of carbazole derivs. as 5-HT1-like agonists. EP 0674621; JP 1996504790; US 5650426; US 5962501; WO 9414772 . |
| 【4】 King, F.D.; Gaster, L.M.; Kuamann, A.J.; Young, R.C. (SmithKline Beecham plc); Tetrahydrocarbazole derivs. for the manufacture of a medicament for the treatment of a disease where a 5-HT1-like agonist is indicated. EP 0603432 . |
| 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) | 16766 | 4-hydrazinobenzonitrile | C7H7N3 | 详情 | 详情 | |
| (II) | 16767 | 4-oxocyclohexyl benzoate | C13H14O3 | 详情 | 详情 | |
| (III) | 16768 | 6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl benzoate | C20H16N2O2 | 详情 | 详情 | |
| (IV) | 16769 | 3-hydroxy-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile | C13H12N2O | 详情 | 详情 | |
| (V) | 16770 | 6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl 4-methylbenzenesulfonate | C20H18N2O3S | 详情 | 详情 | |
| (VI) | 16771 | 3-(methylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile | C14H15N3 | 详情 | 详情 | |
| (VII) | 16772 | 3-(methylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide | C14H17N3O | 详情 | 详情 | |
| (VIII) | 16773 | tert-butyl N-[6-(aminocarbonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-methylcarbamate | C19H25N3O3 | 详情 | 详情 | |
| (IX) | 16774 | tert-butyl N-[(3R)-6-(aminocarbonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-methylcarbamate | C19H25N3O3 | 详情 | 详情 | |
| (X) | 16775 | 3,3-Dimethyl-1,5-dioxaspiro[5.5]undecan-9-one; 1,4-Cyclohexanedione mono-2,2-dimethyltrimethylene ketal | 69225-59-8 | C11H18O3 | 详情 | 详情 |
| (XI) | 16776 | N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-ylidene)-N-methylamine; N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-ylidene)methanamine | C12H21NO2 | 详情 | 详情 | |
| (XII) | 16777 | N,3,3-trimethyl-1,5-dioxaspiro[5.5]undecan-9-amine; N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-N-methylamine | C12H23NO2 | 详情 | 详情 | |
| (XIII) | 16778 | 4-aminobenzamide; p-aminobenzamide | 2835-68-9 | C7H8N2O | 详情 | 详情 |
合成路线2
5) The cyclization of 4-phthalimidocyclohexanone (XIV) with 4-hydrazinobenzamide (XV) in relfuxing acetic acid gives 3-phthalimido-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide (XVI), which is treated with hydrazine in methanol yielding 3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide (XVII) as a racemic mixture. Reaction of (XVII) with di-tert-butyl dicarbonate gives the corresponding carbamate that is resolved by chiral HPLC in hexane/ethanol to give (XVIII). The hydrolysis of (XVIII) with HCl in dioxane affords the enantiomerically pure (R)-amine (XIX) (1-3). The reductoalkylation of (XIX) with benzaldehyde and NaBH3CN yields the corresponding benzylamine (XX), which is methylated with formaldehyde and NaBH3CN to the N-benzyl-N-methylamine (XXI). Finally, this compound is debenzylated by hydrogenation as usual. 6) The monomethylation of (XIX) can also be performed by its reaction with carbon disulfide and dicyclohexylcarbodiimide (DCC) in pyridine to give the expected isothiocyanato (XXII), which is finally reduced with NaBH4 in ethanol.
| 【1】 Graul, A.; Leeson, P.; Castañer, J.; SB-209509/VML-251. Drugs Fut 1997, 22, 7, 725. |
| 【2】 Borrett, G.T.; Kitteringham, J.; Porter, R.A.; Shipton, M.R.; Vimal, M.; Young, R.C. (SmithKline Beecham plc); Enantiomers of carbazole derivs. as 5-HT1-like agonists. EP 0674621; JP 1996504790; US 5650426; US 5962501; WO 9414772 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 16779 | 2-(4-oxocyclohexyl)-1H-isoindole-1,3(2H)-dione | C14H13NO3 | 详情 | 详情 | |
| (XV) | 16780 | 4-Hydrazinobenzamide | C7H9N3O | 详情 | 详情 | |
| (XVI) | 16781 | 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide | C21H17N3O3 | 详情 | 详情 | |
| (XVII) | 16782 | 3-amino-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide | C13H15N3O | 详情 | 详情 | |
| (XVIII) | 16783 | tert-butyl N-[(3R)-6-(aminocarbonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbamate | C18H23N3O3 | 详情 | 详情 | |
| (XIX) | 16784 | (3R)-3-amino-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide | C13H15N3O | 详情 | 详情 | |
| (XX) | 16785 | (3R)-3-(benzylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide | C20H21N3O | 详情 | 详情 | |
| (XXI) | 16786 | (3R)-3-[benzyl(methyl)amino]-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide | C21H23N3O | 详情 | 详情 | |
| (XXII) | 16787 | (3R)-3-isothiocyanato-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide | C14H13N3OS | 详情 | 详情 |