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【结 构 式】 
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【分子编号】26919 【品名】3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indol-5-amine 【CA登记号】 |
【 分 子 式 】C14H17N3 【 分 子 量 】227.3092 【元素组成】C 73.98% H 7.54% N 18.49% |
合成路线1
该中间体在本合成路线中的序号：Bromination of methyl 3-methoxy-4-methylbenzoate (I) with N-bromosuccinimide in the presence of catalytic amounts of 2,2'-azabisisobutyronitrile in chlorobenzene yields benzylic bromide (II). This compound is coupled with 5-nitroindole via treatment with Ag2CO3 in toluene to afford methyl 4-(5-nitroindol-3-ylmethyl)-3-methoxybenzoate (III). N-Methylation of ester (III), using NaH and MeI in DMF, followed by hydrolysis with NaOH in aqueous THF, affords 4-(5-nitro-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (IV). Conversion of acid (IV) to the sulfonimide derivative (V) is achieved by sequentially treating (IV) with: (i) SOCl2 plus a catalytic amount of DMF in dichloromethane and (ii) o-tolylsulfonamide and 4-(N,N-dimethylamino)pyridine (DMAP). This intermediate sulfonimide is isolated as the DMAP salt (V), which is converted to ICI 204219 via treatment with H2 over Pd/C in alkaline aqueous methoxyethanol, followed by acylation with cyclopentylchloroformate.
| 【1】 Brown, F.J.; Bernstein, P.R.; Yee, Y.K.; Matassa, V.G. (AstraZeneca LP); Heterocyclic amide derivs. AU 8656164; EP 0199543; EP 0220066; ES 8801787; ES 8802220; ES 8802493; ES 8802494; JP 1987093274; JP 1987099359; US 4859692; US 4918094; US 5030643; US 5049576; US 5179112 . |
| 【2】 Edwards, M.P.; Sherwood, J.D. (AstraZeneca plc); A physical form of N-[4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, a process for its preparation and pharmaceutical compsns. containing it. EP 0490649; US 5294636 . |
| 【3】 Aharony, D.; Snyder, D.W.; Keith, R.A.; Shapiro, H.S.; Matassa, V.G.; Maduskuie, T.P. Jr.; Hesp, B.; Krell, R.D.; Evolution of a series of peptidoleukotriene antagonists: Synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles. J Med Chem 1990, 33, 6, 1781. |
| 【4】 Bernstein, P.R.; Accolate. Drugs Fut 1994, 19, 3, 217. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26919 | 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indol-5-amine | C14H17N3 | 详情 | 详情 | ||
| (I) | 11919 | methyl 3-methoxy-4-methylbenzoate | 3556-83-0 | C10H12O3 | 详情 | 详情 |
| (II) | 11920 | methyl 4-(bromomethyl)-3-methoxybenzoate; 4-(Bromomethyl)-3-methoxy benzoic acid methyl ester | C10H11BrO3 | 详情 | 详情 | |
| (III) | 11921 | methyl 3-methoxy-4-[(5-nitro-1H-indol-3-yl)methyl]benzoate | C18H16N2O5 | 详情 | 详情 | |
| (IV) | 11922 | 3-Methoxy-4-[(1-methyl-5-nitro-1H-indol-3-yl)methyl]benzoic acid | C18H16N2O5 | 详情 | 详情 | |
| (V) | 11923 | 3-Methoxy-4-(1-methyl-5-nitro-1H-indol-3-ylmethyl)-N-(2-methylphenylsulfonyl)benzamide 4-(dimethylamino)pyridine salt | C32H33N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Condensation of 5-nitroindole (I) with 1-methyl-4-piperidone (II) in the presence of KOH produced tetrahydropyridinyl indole (III). Subsequent catalytic hydrogenation of (III) over Pd/C gave the 5-amino-3-piperidinylindole (VI). In a related procedure, 5-aminoindole (IV) was condensed with piperidone (II), and the resulting tetrahydropyridine (V) was hydrogenated to yield (VI). Aminoindole (VI) was finally condensed with 4-fluorobenzoyl chloride (VII) to produce the corresponding amide, which was isolated as the fumarate salt.
| 【1】 Audia, J.E.; Dressman, B.A.; Droste, J.J.; Fritz, J.E.; Kaldor, S.W.; Koch, D.J.; Krushinski, J.H. Jr.; Nissen, J.S.; Rocco, V.P.; Schaus, J.M.; Thompson, D.C. (Eli Lilly and Company); 5-Substd.-3-(1,2,3,6-tetrahydropyridin-4-yl)- and 3-(piperidin-4-yl)-1H-indoles: New 5-HT1F agonists. EP 0733628; JP 1999502816; US 5708008; WO 9629075 . |
| 【2】 Johnson, K.W.; Phebus, L.A. (Eli Lilly and Company); Use of a serotonin 5-HT1F agonist in the manufacture of a medicament for treating or ameliorating the symptoms of common cold or allergic rhinitis. EP 0824917; US 5962473; WO 9806402 . |
| 【3】 Johnson, K.W.; Phebus, L.A. (Eli Lilly and Company); A method for the prevention of migraine. WO 9811895 . |
| 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) | 26916 | 5-Nitroindole; 5-nitro-1H-indole | 6146-52-7 | C8H6N2O2 | 详情 | 详情 |
| (II) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (III) | 26917 | 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole | C14H15N3O2 | 详情 | 详情 | |
| (IV) | 26918 | Indole-5-amine; 1H-indol-5-ylamine; 5-Aminoindole | 5192-03-0 | C8H8N2 | 详情 | 详情 |
| (V) | 26919 | 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indol-5-amine | C14H17N3 | 详情 | 详情 | |
| (VI) | 26920 | 3-(1-methyl-4-piperidinyl)-1H-indol-5-amine | C14H19N3 | 详情 | 详情 | |
| (VII) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |