3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl methanesulfonate -Drug Synthesis Database

【结构式】

【分子编号】36539

【品名】3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl methanesulfonate

【CA登记号】

【分子式】C₁₄H₁₆N₄O₃S

【分子量】320.3722

【元素组成】C 52.49% H 5.03% N 17.49% O 14.98% S 10.01%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

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

合成目标

【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

该中间体在本合成路线中的序号：(VIII)

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

合成目标

【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

Extended Information