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【结 构 式】

【药物名称】Sumatriptan succinate, SN-308, GR-43175C, Imigrane, Suminat, Imitrex, Imigran

【化学名称】3-[2-(Dimethylamino)ethyl]-N-methyl-1H-indole-5-ylmethylsulfonamide succinate

【CA登记号】103628-48-4 ((1:1) salt), 103628-47-3 ((2:1) salt), 103628-46-2 (free base)

【 分 子 式 】C18H27N3O6S

【 分 子 量 】413.49639

【开发单位】GlaxoSmithKline (Originator), Atrix (Formulation), Nastech (Formulation)

【药理作用】Acute Attacks of Migraine, Treatment of, ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 5-HT1B Agonists, 5-HT1D Agonists

合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

1) The diazotation of 4-amino-N-methylbenzenemethanesulfonamide (I) with NaNO2-HCl followed by reduction with SnCl2 gives the 4-hydrazino compound (II), which is condensed with (phenylthio)acetaldehyde (III) in ethanol yielding the ethylideneamino compound (IV). The cyclization of (IV) with HCl in ethanol affords N-methyl-3-(phenylthio)-1H-indole-5-methansulfonamide (V), which is desulfurized with RaNi in refluxing ethanol-water to give N-methyl-1H-indole-5-methanesulfonamide (VI). The reaction of (VI) with oxalyl chloride and dimethylamine yields the oxalyl derivative (VII), which is finally reduced with LiAlH4 in refluxing THF.

参考文献 中间体
【1】 Oxford, A.W. (Glaxo Group Ltd.); An indole derivative.. GB 2162522 .
【2】 Coates, I.H.; Dowle, M.D. (Glaxo Group Ltd.); Heterocyclic compounds.. FR 2530625; GB 2124210; US 4816470 .
【3】 Humphrey, P.P.A.; Feniuk, W.; Perren, M.J.; Oxford, A.W.; Brittain, R.T.; Prous, J.; Castaner, J.; SUMATRIPTAN SUCCINATE < Prop INNM; BAN >. Drugs Fut 1989, 14, 1, 35.
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) 19432 (4-aminophenyl)-N-methylmethanesulfonamide; 4-amino-N-ethylbenzylmethanesulfamide 109903-35-7 C8H12N2O2S 详情 详情
(II) 19433 (4-hydrazinophenyl)-N-methylmethanesulfonamide 88933-16-8 C8H13N3O2S 详情 详情
(III) 19434 2-(phenylsulfanyl)acetaldehyde C8H8OS 详情 详情
(IV) 19435 N-methyl(4-[2-[(E)-2-(phenylsulfanyl)ethylidene]hydrazino]phenyl)methanesulfonamide C16H19N3O2S2 详情 详情
(V) 19436 N-methyl[3-(phenylsulfanyl)-1H-indol-5-yl]methanesulfonamide C16H16N2O2S2 详情 详情
(VI) 19437 1H-indol-5-yl-N-methylmethanesulfonamide C10H12N2O2S 详情 详情
(VII) 19438 N,N-dimethyl-2-(5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl)-2-oxoacetamide C14H17N3O4S 详情 详情

合成路线2

2) The condensation of hydrazine (II) with 4,4-dimethoxy-N,N-dimethylbutylamine (VIII) by means of HCl in water gives the butylidenehydrazino compound (IX), which is cyclized with polyphosphate ester (PPE) in CHCl3.

参考文献 中间体
【1】 Coates, I.H.; Dowle, M.D. (Glaxo Group Ltd.); Heterocyclic compounds.. FR 2530625; GB 2124210; US 4816470 .
【2】 Oxford, A.W. (Glaxo Group Ltd.); An indole derivative.. GB 2162522 .
【3】 Humphrey, P.P.A.; Feniuk, W.; Perren, M.J.; Oxford, A.W.; Brittain, R.T.; Prous, J.; Castaner, J.; SUMATRIPTAN SUCCINATE < Prop INNM; BAN >. Drugs Fut 1989, 14, 1, 35.
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) 19432 (4-aminophenyl)-N-methylmethanesulfonamide; 4-amino-N-ethylbenzylmethanesulfamide 109903-35-7 C8H12N2O2S 详情 详情
(II) 19433 (4-hydrazinophenyl)-N-methylmethanesulfonamide 88933-16-8 C8H13N3O2S 详情 详情
(III) 19439 4,5-diethoxy-N,N-dimethyl-1-pentanamine; N-(4,5-diethoxypentyl)-N,N-dimethylamine C11H25NO2 详情 详情
(IX) 19440 (4-[2-[(E)-4-(dimethylamino)butylidene]hydrazino]phenyl)-N-methylmethanesulfonamide C14H24N4O2S 详情 详情

合成路线3

3) The condensation of indole (VI) with N,N-diethylchloroacetamide (X) by means of POCl3 gives 3-chloroacetyl-N-methyl-1H-indole-5-methanesulfonamide (XI), which is treated with dimethylamine (XII) in refluxing ethanol to afford the dimethylaminoacetyl derivative (XIII), which is finally reduced with NaBH4 in refluxing propanol.

参考文献 中间体
【1】 Oxford, A.W. (Glaxo Group Ltd.); An indole derivative.. GB 2162522 .
【2】 Coates, I.H.; Dowle, M.D. (Glaxo Group Ltd.); Heterocyclic compounds.. FR 2530625; GB 2124210; US 4816470 .
【3】 Humphrey, P.P.A.; Feniuk, W.; Perren, M.J.; Oxford, A.W.; Brittain, R.T.; Prous, J.; Castaner, J.; SUMATRIPTAN SUCCINATE < Prop INNM; BAN >. Drugs Fut 1989, 14, 1, 35.
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) 19441 2-chloro-N,N-diethylacetamide 2315-36-8 C6H12ClNO 详情 详情
(I) 19432 (4-aminophenyl)-N-methylmethanesulfonamide; 4-amino-N-ethylbenzylmethanesulfamide 109903-35-7 C8H12N2O2S 详情 详情
(II) 19433 (4-hydrazinophenyl)-N-methylmethanesulfonamide 88933-16-8 C8H13N3O2S 详情 详情
(III) 19434 2-(phenylsulfanyl)acetaldehyde C8H8OS 详情 详情
(IV) 19435 N-methyl(4-[2-[(E)-2-(phenylsulfanyl)ethylidene]hydrazino]phenyl)methanesulfonamide C16H19N3O2S2 详情 详情
(V) 19436 N-methyl[3-(phenylsulfanyl)-1H-indol-5-yl]methanesulfonamide C16H16N2O2S2 详情 详情
(VI) 19437 1H-indol-5-yl-N-methylmethanesulfonamide C10H12N2O2S 详情 详情
(XI) 19442 [3-(2-chloroacetyl)-1H-indol-5-yl]-N-methylmethanesulfonamide C13H15ClN2O 详情 详情
(XII) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(XIII) 19444 [3-[2-(dimethylamino)acetyl]-1H-indol-5-yl]-N-methylmethanesulfonamide C14H19N3O3S 详情 详情

合成路线4

4) The condensation of hydrazine (II) with 3-nitropropanal (XIV) in water gives the nitrobutylidenehydrazino derivative (XV), which is cyclized with PPE as before yielding N-methyl-3-(2-nitroethyl)-1H-indole-5-methansulfonamide (XVI), which is reduced with H2 over Pd/C in ethyl acetate to afford the 2-aminoethyl compound (XVII). Finally, this compound is methylated with ICH3 and NaHCO3 or with formaldehyde and NaBH4

参考文献 中间体
【1】 Oxford, A.W. (Glaxo Group Ltd.); An indole derivative.. GB 2162522 .
【2】 Coates, I.H.; Dowle, M.D. (Glaxo Group Ltd.); Heterocyclic compounds.. FR 2530625; GB 2124210; US 4816470 .
【3】 Humphrey, P.P.A.; Feniuk, W.; Perren, M.J.; Oxford, A.W.; Brittain, R.T.; Prous, J.; Castaner, J.; SUMATRIPTAN SUCCINATE < Prop INNM; BAN >. Drugs Fut 1989, 14, 1, 35.
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) 19432 (4-aminophenyl)-N-methylmethanesulfonamide; 4-amino-N-ethylbenzylmethanesulfamide 109903-35-7 C8H12N2O2S 详情 详情
(II) 19433 (4-hydrazinophenyl)-N-methylmethanesulfonamide 88933-16-8 C8H13N3O2S 详情 详情
(XIV) 19445 4-nitrobutanal C4H7NO3 详情 详情
(XV) 19446 N-methyl(4-[[(E)-5-nitro-1-pentenyl]amino]phenyl)methanesulfonamide C13H19N3O4S 详情 详情
(XVI) 19447 N-methyl[3-(2-nitroethyl)-1H-indol-5-yl]methanesulfonamide C12H15N3O4S 详情 详情
(XVII) 19448 [3-(2-aminoethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide C13H19N3 详情 详情

合成路线5

5) The condensation of hydrazino compound (II) with 4,4-dimethoxybutyronitrile (XVIII) gives the cyanobutylideneamino derivative (XIX), which is cyclized with PPE as before yielding 3-(cyanomethyl)-N-methyl-1H-indole-5-methanesulfonamide (XX). Finally, this compound is reduced with H2 over Rh/Al2O3 to afford the 2-aminoethyl derivative (XVII), already obtained.

参考文献 中间体
【1】 Oxford, A.W. (Glaxo Group Ltd.); An indole derivative.. GB 2162522 .
【2】 Coates, I.H.; Dowle, M.D. (Glaxo Group Ltd.); Heterocyclic compounds.. FR 2530625; GB 2124210; US 4816470 .
【3】 Humphrey, P.P.A.; Feniuk, W.; Perren, M.J.; Oxford, A.W.; Brittain, R.T.; Prous, J.; Castaner, J.; SUMATRIPTAN SUCCINATE < Prop INNM; BAN >. Drugs Fut 1989, 14, 1, 35.
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) 19432 (4-aminophenyl)-N-methylmethanesulfonamide; 4-amino-N-ethylbenzylmethanesulfamide 109903-35-7 C8H12N2O2S 详情 详情
(II) 19433 (4-hydrazinophenyl)-N-methylmethanesulfonamide 88933-16-8 C8H13N3O2S 详情 详情
(XVII) 19448 [3-(2-aminoethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide C13H19N3 详情 详情
(XVIII) 15350 4,4-diethoxybutanenitrile; 4,4-diethoxy-butanenitrile 18381-45-8 C8H15NO2 详情 详情
(XIX) 19450 (4-[2-[(E)-3-cyanopropylidene]hydrazino]phenyl)-N-methylmethanesulfonamide C12H16N4O2S 详情 详情
(XX) 19451 [3-(cyanomethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide C12H13N3O2S 详情 详情
Extended Information