【结 构 式】 |
【分子编号】37568 【品名】N,N-Dimethyl-1H-indole-3-methanamine;Gramine;N-(1H-indol-3-ylmethyl)-N,N-dimethylamine; 3-(dimethylaminomethyl)-indole[;]1H-indol-3-yl-N,N-dimethylmethanamine 【CA登记号】87-52-5 |
【 分 子 式 】C11H14N2 【 分 子 量 】174.24564 【元素组成】C 75.82% H 8.1% N 16.08% |
合成路线1
该中间体在本合成路线中的序号:(III)By reaction of 3-(2-methyl-2-aminopropyl)indole (I) and 2-(2,3-epoxypropoxy)benzonitrile (II) by heating at 120-40 C followed by a treatment with HCl in ethanol. The starting products are obtained as follows: 1) The reaction of 3-(dimethylaminomethyl)indole (III) with 2-nitropropane (IV) by means of KOH gives 3-(2-methyl-2-nitropropyl)indole (V), which is then reduced with hydrazine and Raney-Ni in ethanol to yield (I). 2) The reaction of 2-hydroxybenzonitrile (VI) with epichlorohydrin (VII) by means of piperidine affords 2-(3-chloro-2-hydroxypropoxy)benzonitrile (VIII), which is epoxidized again to (II) by treatment with NaOH in hot THF-water.
【1】 Kreighbaum, W.E.; et al.; Antihypertensive indole derivatives of phenoxypropanolamines with beta-adrenergic receptor antagonist and vasodilating activity. J Med Chem 1980, 23, 3, 285-289. |
【2】 Weetman, D.F.; Castaner, J.; Bucindolol Hydrochloride. Drugs Fut 1981, 6, 7, 405. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 | |
(I) | 37566 | 2-(1H-indol-3-yl)-1,1-dimethylethylamine; 1-(1H-indol-3-yl)-2-methyl-2-propanamine | C12H16N2 | 详情 | 详情 | |
(II) | 37567 | 2-(2-oxiranylmethoxy)benzonitrile | C10H9NO2 | 详情 | 详情 | |
(III) | 37568 | N,N-Dimethyl-1H-indole-3-methanamine;Gramine;N-(1H-indol-3-ylmethyl)-N,N-dimethylamine; 3-(dimethylaminomethyl)-indole[;]1H-indol-3-yl-N,N-dimethylmethanamine | 87-52-5 | C11H14N2 | 详情 | 详情 |
(IV) | 21819 | 2-nitropropane | 79-46-9 | C3H7NO2 | 详情 | 详情 |
(V) | 37569 | 3-(2-methyl-2-nitropropyl)-1H-indole | C12H14N2O2 | 详情 | 详情 | |
(VI) | 21990 | 2-hydroxybenzonitrile | 611-20-1 | C7H5NO | 详情 | 详情 |
(VII) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
(VIII) | 37570 | 2-(3-chloro-2-hydroxypropoxy)benzonitrile | C10H10ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VI)Methylation of 6-nitroindole (I) using either iodomethane and NaH or dimethyl carbonate and Na2CO3 provides 1-methyl-6-nitroindole (II), which is subsequently acylated with oxalyl chloride in CH2Cl2 to furnish the glyoxylyl chloride (III). Condensation of chloride (III) with 1-methylindole-3-acetic acid (IV) in the presence of Et3N gives the bis(indolyl)maleic anhydride (V), which is then converted to the target maleimide derivative by heating with ammonia in aqueous DMF in a sealed vessel at 140 °C .
In a related procedure, quaternization of 3-(dimethylaminomethyl)-indole (VI) with butyl bromide, followed by amine displacement with NaCN yields 2-(3-indolyl)acetonitrile (VII), which is alkylated using dimethyl carbonate and K2CO3 in hot DMF to give the 1-methylindole derivative (VIII). Treatment of compound (VIII) with isopropanol and HCl (generated from acetyl chloride and i-PrOH) affords imidate (IX), which is finally condensed with the indoleglyoxylyl chloride (III) in the presence of DIEA, followed by treatment with H2SO4 .
【1】 Davis, P.D., Hill, C.H., Lawton, G. (F. Hoffmann-La Roche AG). Substituted pyrroles. AU 8929658, EP 0328026, JP 1989233281, US 5057614. |
【2】 Davis, P.D., Hill, C.H., Lawton, G. et al. Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem 1992, 35(1): 177-84. |
【3】 Jiang, X. (F. Hoffmann La Roche AG). Methylation of indole compounds using dimethyl carbonate. CA 2405937, EP 1276721, JP 2003531192, JP 2007254487, US 6326501, WO 2001081305. |
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) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
(II) | 39295 | 1-methyl-6-nitro-1H-indole | C9H8N2O2 | 详情 | 详情 | |
(III) | 39296 | 2-(1-methyl-6-nitro-1H-indol-3-yl)-2-oxoacetyl chloride | C11H7ClN2O4 | 详情 | 详情 | |
(IV) | 39297 | 1-Methylindole-3-acetic acid; 2-(1-Methyl-1H-indol-3-yl)acetic acid | 1912-48-7 | C11H11NO2 | 详情 | 详情 |
(V) | 39298 | 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-furandione | C22H15N3O5 | 详情 | 详情 | |
(VI) | 37568 | N,N-Dimethyl-1H-indole-3-methanamine;Gramine;N-(1H-indol-3-ylmethyl)-N,N-dimethylamine; 3-(dimethylaminomethyl)-indole[;]1H-indol-3-yl-N,N-dimethylmethanamine | 87-52-5 | C11H14N2 | 详情 | 详情 |
(VII) | 44291 | 3-Indolylacetonitrile;3-Cyanomethyl-1H-indole;3-(Cyanomethyl)indole;Indole-3-acetonitrile;3-Indoleacetonitrile;2-(3-indolyl)acetonitrile;2-(1H-indol-3-yl)acetonitrile;2-(1H-Indol-3-yl)acetonitrile; 3-Indolylacetonitrile | 771-51-7 | C10H8N2 | 详情 | 详情 |
(VIII) | 69305 | 1-Methylindole-3-acetonitrile;1-Methylindole-3-acetonitrile;N-Methylindole-3-acetonitrile;3-(Cyanomethyl)-1-methylindole;2-(1-methyl-1H-indol-3-yl)acetonitrile | 51584-17-9 | C11H10N2 | 详情 | 详情 |
(IX) | 69306 | isopropyl 2-(1-methyl-1H-indol-3-yl)acetimidate hydrochloride | C14H18N2O.HCl | 详情 | 详情 |