-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】3-[3-[4-(N-Benzyl-N-methylaminomethyl)-4-hydroxypiperidin-1-yl]propyl]-5-(1,2,4-triazol-4-yl)-1H-indole

【CA登记号】177946-34-8, 177946-35-9 (oxalate salt)

【分子式】C₂₇H₃₄N₆O

【分子量】458.61163

【开发单位】Merck & Co. (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 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1

Hydrogenation of p-nitroacetanilide (I) over Pd/C afforded p-aminoacetanilide (II), which was converted to triazolylacetanilide (III) upon treatment with N,N-dimethylformamide azine and p-toluenesulfonic acid. Acid hydrolysis of the acetamide (III) provided triazolylaniline (IV). Subsequent diazotization of (IV), followed by SnCl2 reduction of the diazonium salt furnished hydrazine (V). Fischer indole synthesis employing (V) and dihydropyran (VI) gave rise to the indolylpropanol (VII), which was converted to the intermediate mesylate (VIII) using CH3SO2Cl and Et3N.

参考文献中间体

【1】 Stanton, J.A.; Showell, G.A.; Neduvelil, J.G.; Bourrain, S.; Beer, M.S.; MacLeod, A.M.; 4-Hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidines: Selective h5-HT1D agonists for the treatment of migraine. Bioorg Med Chem Lett 1999, 9, 23, 3369.
【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40722	N'-[(E)-(dimethylamino)methylidene]-N,N-dimethylhydrazonoformamide		C₆H₁₄N₄	详情	详情
(I)	36535	N-(4-nitrophenyl)acetamide	104-04-1	C₈H₈N₂O₃	详情	详情
(II)	29016	N-(4-aminophenyl)acetamide	122-80-5	C₈H₁₀N₂O	详情	详情
(III)	36536	N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide	154594-15-7	C₁₀H₁₀N₄O	详情	详情
(IV)	36537	4-(4H-1,2,4-triazol-4-yl)phenylamine; 4-(4H-1,2,4-triazol-4-yl)aniline		C₈H₈N₄	详情	详情
(V)	25647	4-(4-hydrazinophenyl)-4H-1,2,4-triazole		C₈H₉N₅	详情	详情
(VI)	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	详情	详情
(VII)	36538	3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]-1-propanol		C₁₃H₁₄N₄O	详情	详情
(VIII)	36539	3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl methanesulfonate		C₁₄H₁₆N₄O₃S	详情	详情

合成路线2

An alternative procedure for the synthesis of indolylpropanol (VII) is depicted as follows: alkylation of 2-trimethylsilyl-1,3-dithiane (IX) with bromide (X) employing n-butyllithium in cold THF afforded (XI). Subsequent hydrolysis of the thioacetal group of (XI) by means of HgO/HgCl2 provided acylsilane (XII). Iodoaniline (XIII) was prepared by iodination of p-triazolylaniline (IV) with iodine monochloride. Condensation of iodoaniline (XIII) with acylsilane (XII) in the presence of Pd(OAc)2 produced the silylated indole (XIV). Then acid treatment of (XIV) removed both silyl groups to give (VII).

参考文献中间体

【1】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 .
【2】 Chen, C.-Y.; Larsen, R.D. (Merck & Co., Inc.); Palladium catalyzed indolization. US 5808064; WO 9806725 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	36537	4-(4H-1,2,4-triazol-4-yl)phenylamine; 4-(4H-1,2,4-triazol-4-yl)aniline		C₈H₈N₄	详情	详情
(VII)	36538	3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]-1-propanol		C₁₃H₁₄N₄O	详情	详情
(IX)	16517	1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane	13411-42-2	C₇H₁₆S₂Si	详情	详情
(X)	30994	3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane		C₉H₂₁BrOSi	详情	详情
(XI)	36540	tert-butyl(dimethyl)[3-[2-(trimethylsilyl)-1,3-dithian-2-yl]propoxy]silane; tert-butyl(dimethyl)silyl 3-[2-(trimethylsilyl)-1,3-dithian-2-yl]propyl ether		C₁₆H₃₆OS₂Si₂	详情	详情
(XII)	36541	4-[[tert-butyl(dimethyl)silyl]oxy]-1-(trimethylsilyl)-1-butanone		C₁₃H₃₀O₂Si₂	详情	详情
(XIII)	36542	2-iodo-4-(4H-1,2,4-triazol-4-yl)aniline; 2-iodo-4-(4H-1,2,4-triazol-4-yl)phenylamine		C₈H₇IN₄	详情	详情
(XIV)	36543	3-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-5-(4H-1,2,4-triazol-4-yl)-2-(trimethylsilyl)-1H-indole; tert-butyl(dimethyl)silyl 3-[5-(4H-1,2,4-triazol-4-yl)-2-(trimethylsilyl)-1H-indol-3-yl]propyl ether		C₂₂H₃₆N₄OSi₂	详情	详情

合成路线3

4-(Aminomethyl)-1-benzyl-4-hydroxypiperidine (XV) was protected as the tert-butyl carbamate (XVI) and the benzyl group was subsequently cleaved by transfer hydrogenolysis employing ammonium formate and Pd/C yielding (XVII). Condensation of piperidine (XVII) with mesylate (VIII) in the presence of K2CO3 in boiling isopropanol furnished adduct (XVIII). After deprotection of the Boc group of (XVIII) with trifluoroacetic acid, reductive alkylation of the resulting amine (XIX) with benzaldehyde in the presence of NaBH3CN provided the N-benzyl amine (XX). Finally, a further reductive alkylation of (XX) with formaldehyde and NaBH3CN yielded the title compound.

参考文献中间体

【1】 Stanton, J.A.; Showell, G.A.; Neduvelil, J.G.; Bourrain, S.; Beer, M.S.; MacLeod, A.M.; 4-Hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidines: Selective h5-HT1D agonists for the treatment of migraine. Bioorg Med Chem Lett 1999, 9, 23, 3369.
【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(VIII)	36539	3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl methanesulfonate		C₁₄H₁₆N₄O₃S	详情	详情
(XV)	36544	4-(aminomethyl)-1-benzyl-4-piperidinol		C₁₃H₂₀N₂O	详情	详情
(XVI)	36545	tert-butyl (1-benzyl-4-hydroxy-4-piperidinyl)methylcarbamate		C₁₈H₂₈N₂O₃	详情	详情
(XVII)	36546	tert-butyl (4-hydroxy-4-piperidinyl)methylcarbamate		C₁₁H₂₂N₂O₃	详情	详情
(XVIII)	36547	tert-butyl (4-hydroxy-1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinyl)methylcarbamate		C₂₄H₃₄N₆O₃	详情	详情
(XIX)	36548	4-(aminomethyl)-1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinol		C₁₉H₂₆N₆O	详情	详情
(XX)	36549	4-[(benzylamino)methyl]-1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinol		C₂₆H₃₂N₆O	详情	详情

合成路线4

In an alternative method, the title compound was obtained by desilylation of the 2-silylindole precursor (XXI).

参考文献中间体

【1】 Chen, C.-Y.; Larsen, R.D. (Merck & Co., Inc.); Palladium catalyzed indolization. US 5808064; WO 9806725 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXI)	36550	4-[[benzyl(methyl)amino]methyl]-1-[3-[5-(4H-1,2,4-triazol-4-yl)-2-(trimethylsilyl)-1H-indol-3-yl]propyl]-4-piperidinol		C₃₀H₄₂N₆OSi	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)