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【结 构 式】 
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【药物名称】NGD-98-1 【化学名称】N-[2-(Dimethylamino)ethyl]-N-isobutyl-N-[2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrido[2,3-b]indol-4-yl]amine 【CA登记号】245733-79-3 【 分 子 式 】C29H38N4 【 分 子 量 】442.65301 |
【开发单位】Neurogen (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, CRF1 Antagonists |
合成路线1
The condensation of 2,4,6-trimethylaniline (I) with adipoin (II) in hot toluene, followed by reaction of the resulting intermediate (III) with malononitrile (IV), gave rise to the tetrahydroindole (V). Subsequent condensation of amino nitrile (V) with 2-methoxypropene (VI) produced the tetrahydropyrido[2,3-b]indole system (VII), which was dehydrogenated to (VIII) by means of Pd/C in boiling decalin. Acylation of (VIII) with isobutyryl chloride (IX) afforded amide (X), which was reduced to amine (XI) employing borane-dimethyl sulfide complex. Further acylation with chloroacetyl chloride (XII), and then reduction of the resulting chloroacetamide (XIII) with borane-dimethyl sulfide, provided the chloroethyl amine (XIV). This was finally treated with dimethylamine in hot N-methylpyrrolidinone in a steel bomb to furnish the desired dimethylamino compound.
| 【1】 Darrow, J.W.; Maynard, G.D.; Horvath, R.F. (Neurogen Corp.); Aminoalkyl substd. 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivs.. EP 1068207; US 6147085; WO 9951600 . |
| 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) | 28804 | 2,4,6-trimethylaniline | 88-05-1 | C9H13N | 详情 | 详情 |
| (II) | 44979 | 2-hydroxycyclohexanone | 533-60-8 | C6H10O2 | 详情 | 详情 |
| (III) | 44980 | 2-(mesitylamino)-1-cyclohexen-1-ol | C15H21NO | 详情 | 详情 | |
| (IV) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (V) | 44981 | 2-amino-1-mesityl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile | C18H21N3 | 详情 | 详情 | |
| (VI) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VII) | 44982 | 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-amine | C21H25N3 | 详情 | 详情 | |
| (VIII) | 44983 | 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine | C21H21N3 | 详情 | 详情 | |
| (IX) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (X) | 44984 | N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)-2-methylpropanamide | C25H27N3O | 详情 | 详情 | |
| (XI) | 44985 | N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine | C25H29N3 | 详情 | 详情 | |
| (XII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XIII) | 44986 | 2-chloro-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)acetamide | C27H30ClN3O | 详情 | 详情 | |
| (XIV) | 44987 | N-(2-chloroethyl)-N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-(2-chloroethyl)-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine | C27H32ClN3 | 详情 | 详情 |