Donitriptan hydrochloride, F-11356, -Drug Synthesis Database

【结构式】

【药物名称】Donitriptan hydrochloride, F-11356

【化学名称】4-[4-[2-[3-(2-Aminoethyl)-1H-indol-5-yloxy]acetyl]piperazin-1-yl]benzonitrile hydrochloride

【CA登记号】170911-68-9, 170912-52-4 (free base), 200615-15-2 (monomethanesufonate salt)

【分子式】C₂₃H₂₆ClN₅O₂

【分子量】439.94897

【开发单位】Pierre Fabre (Originator)

【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3

合成路线1

F-11356 is easily synthesized from serotonin following two synthetic pathways. The first method involves the preparation of 2-[3-[2-[N-(tert-butoxycarbonyl)amino]ethyl]-1H-indol-5-yloxy]acetic acid, which is obtained by protection of serotonin with BOC2O/NaOH, followed by O-alkylation with methyl bromoacetate and saponification of the methyl ester with KOH. The overall yield for the three steps was 81%. A coupling reaction between this acid and a phenyl piperazine derivative afforded the N-BOC-protected desired products which, upon subsequent treatment with trifluoroacetic anhydride, gave the free amines. In the second method, the phenylpiperazine derivatives were first treated with chloroacetylchloride and then the intermediates were allowed to react with N-BOC-serotonin to give the N-BOC-protected desired products. At this stage, and before the final deprotection, the R group can be modified to afford other analogues.

参考文献中间体

【1】 Perez, M.; John, G.W.; Colpaert, F.C.; Pauwels, P.J.; Halazy, S.; F-11356. Drugs Fut 1999, 24, 6, 605.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIa)	26319	4-(1-piperazinyl)benzonitrile		C₁₁H₁₃N₃	详情	详情
(IVa)	26320	4-[4-(2-chloroacetyl)-1-piperazinyl]benzonitrile		C₁₃H₁₄ClN₃O	详情	详情
(VIa)	26322	tert-butyl 2-(5-[2-[4-(4-cyanophenyl)-1-piperazinyl]-2-oxoethoxy]-1H-indol-3-yl)ethylcarbamate		C₂₈H₃₃N₅O₄	详情	详情
(I)	26317	3-(2-Aminoethyl)-5-hydroxyindole; 5-Hydroxytryptamine; 3-(2-Aminoethyl)-1H-indol-5-ol	50-67-9	C₁₀H₁₂N₂O	详情	详情
(II)	26318	2-[(3-[2-[(tert-butoxycarbonyl)amino]ethyl]-1H-indol-5-yl)oxy]acetic acid		C₁₇H₂₂N₂O₅	详情	详情
(V)	26321	tert-butyl 2-(5-hydroxy-1H-indol-3-yl)ethylcarbamate		C₁₅H₂₀N₂O₃	详情	详情

合成路线2

The protection of the 3-(2-aminoethyl)-1H-indol-5-ol (I) with di-tert-butyl dicarbonate gives the corresponding carbamate (II), which is condensed with the chloroacetyl piperazine (III) (obtained by reaction of 4-(1-piperazinyl) benzonitrile (IV) with chloroacetyl chloride (V) by means of CaCO3) using K2CO3 and KI in refluxing 2-butanone to yield the protected target compound (V). Finally, this compound is deprotected with TFA in toluene.

参考文献中间体

【1】 Halazy, S.; Perez, M.; Briley, M.; Pauwels, P. (Pierre Fabre Medicament); Indole-derived azylpiperazines as ligands for 5HT1-like receptors 5HT1B and 5HT1D. EP 0729455; FR 2712591; JP 1997505072; US 5726177; WO 9514004 .

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)	26317	3-(2-Aminoethyl)-5-hydroxyindole; 5-Hydroxytryptamine; 3-(2-Aminoethyl)-1H-indol-5-ol	50-67-9	C₁₀H₁₂N₂O	详情	详情
(II)	26321	tert-butyl 2-(5-hydroxy-1H-indol-3-yl)ethylcarbamate		C₁₅H₂₀N₂O₃	详情	详情
(III)	26319	4-(1-piperazinyl)benzonitrile		C₁₁H₁₃N₃	详情	详情
(IV)	26320	4-[4-(2-chloroacetyl)-1-piperazinyl]benzonitrile		C₁₃H₁₄ClN₃O	详情	详情
(V)	26322	tert-butyl 2-(5-[2-[4-(4-cyanophenyl)-1-piperazinyl]-2-oxoethoxy]-1H-indol-3-yl)ethylcarbamate		C₂₈H₃₃N₅O₄	详情	详情
(VI)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情

合成路线3

The condensation of 2-[3-(2-aminoethyl)-1H-indol-5-yloxy]acetic acid (I) with 4-(1-piperazinyl)benzonitrile (II) by means of ethyl chloroformate in dichloromethane gives the protected target compound (III), which is finally deprotected with methanesulfonic acid in dichloromethane.

参考文献中间体

【1】 Halazy, S.; Perez, M. (Pierre Fabre Medicament); Methanesulphonate salt of an arylpiperazine derived from tryptamine and its solvates for pharmaceutical use. EP 0923549; WO 9748680 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	26318	2-[(3-[2-[(tert-butoxycarbonyl)amino]ethyl]-1H-indol-5-yl)oxy]acetic acid	C₁₇H₂₂N₂O₅	详情	详情
(II)	26319	4-(1-piperazinyl)benzonitrile	C₁₁H₁₃N₃	详情	详情
(III)	26322	tert-butyl 2-(5-[2-[4-(4-cyanophenyl)-1-piperazinyl]-2-oxoethoxy]-1H-indol-3-yl)ethylcarbamate	C₂₈H₃₃N₅O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)