Almotriptan, PNU-180638, LAS-31416, Almogran, Axert, -Drug Synthesis Database

【结构式】

【药物名称】Almotriptan, PNU-180638, LAS-31416, Almogran, Axert

【化学名称】3-[2-(Dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indole

【CA登记号】154323-57-6

【分子式】C₁₇H₂₅N₃O₂S

【分子量】335.4717

【开发单位】Almirall Prodesfarma (Originator), Kwizda (Marketer), Nycomed Pharma (Marketer), Bayer (Licensee), Lundbeck (Licensee), Ortho-McNeil (Licensee), Solvay (Licensee)

【药理作用】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1

Almotriptan has been obtained by several related ways: 1) The hydrolysis of 4-chlorobutyraldehyde dimethylacetal (I) with HCl gives the corresponding aldehyde (II), which is condensed with 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) by means of HCl in methanol/water, giving 3-(2-aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole (IV). Finally, this compound is methylated with formaldehyde and NaBH4 in methanol. 2) The direct condensation of 4-chlorobutyraldehyde dimethylacetal (I) with 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) by means of HCl in water also yields intermediate 3-(2-aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole (IV). 3) The decarboxylation of 3-[2-(dimethylamino)ethyl]-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole-2-carboxylic acid (V) catalyzed by means of Cu2O in quinoline at 190 C also gives almotriptan.

参考文献中间体

【1】 Fernandez Forner, D.; Puig Duran, C.; Prieto Soto, J.; Vega Noverola, A.; Moragues Mauri, J. (Almirall Prodesfarma, SA); Indol derivs. for the treatment of migraine. EP 0605697; JP 1994511261; US 5565447; WO 9402460 .
【2】 Fernandez Forner, M.D.; Puig Duran, C.; Crespo Crespo, M.I.; Moragues Mauri, J. (Almirall Prodesfarma, SA); Process for the preparation of indole derivs.. ES 2084560 .
【3】 Pujol Noguera, F.; Crespo Crespo, M.I.; Puig Duran, C.; Fernandez Forner, D.; Moragues Mauri, J. (Almirall Prodesfarma, SA); New indole derivs.. ES 2056025 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16870	4-Chlorobutyraldehyde dimethylacetal; 4-Chloro-1-methoxybutyl methyl ether; 4-Chloro-1,1-dimethoxybutane	C₆H₁₃ClO₂	详情	详情
(II)	23428	4-Chlorobutanal	C₄H₇ClO	详情	详情
(III)	23429	1-[(4-hydrazinobenzyl)sulfonyl]pyrrolidine	C₁₁H₁₇N₃O₂S	详情	详情
(IV)	23430	2-[5-[(1-pyrrolidinylsulfonyl)methyl]-1H-indol-3-yl]-1-ethanamine; 2-[5-[(1-pyrrolidinylsulfonyl)methyl]-1H-indol-3-yl]ethylamine	C₁₅H₂₁N₃O₂S	详情	详情
(V)	23431	3-[2-(dimethylamino)ethyl]-5-[(1-pyrrolidinylsulfonyl)methyl]-1H-indole-2-carboxylic acid	C₁₈H₂₅N₃O₄S	详情	详情

合成路线2

4) The intermediate 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) can be obtained as follows: The condensation of pyrrolidine (VI) with 1-(4-nitrobenzylsulfonyl)chloride (VII) in dichloromethane gives the expected sulfonamide (VIII), which is reduced with H2 over RaNi in DMF, yielding 4-(1-pyrrolidinylsulfonylmethyl)aniline (IX). The diazotation of (IX) with NaNO2/HCl affords the corresponding diazo compound (X), which is finally reduced to the target intermediate (III) with SnCl2/HCl.

参考文献中间体

【1】 Fernandez-Forner, D.; New aniline derivatives as key intermediates in th. Res Disclosure 1998, 412, 1088.

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)	23429	1-[(4-hydrazinobenzyl)sulfonyl]pyrrolidine		C₁₁H₁₇N₃O₂S	详情	详情
(VI)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(VII)	23433	(4-nitrophenyl)methanesulfonyl chloride		C₇H₆ClNO₄S	详情	详情
(VIII)	23434	1-[(4-nitrobenzyl)sulfonyl]pyrrolidine		C₁₁H₁₄N₂O₄S	详情	详情
(IX)	23435	4-[(1-pyrrolidinylsulfonyl)methyl]phenylamine; 4-[(1-pyrrolidinylsulfonyl)methyl]aniline		C₁₁H₁₆N₂O₂S	详情	详情
(X)	23436	4-[(1-pyrrolidinylsulfonyl)methyl]benzenediazonium		C₁₁H₁₄N₃O₂S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)