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【结 构 式】 
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【药物名称】U-99194A, PNU-99194A 【化学名称】5,6-Dimethoxy-N,N-dipropyl-2,3-dihydro-1H-inden-2-amine hydrochloride 【CA登记号】83598-46-3, 82668-33-5 (free base) 【 分 子 式 】C17H28ClNO2 【 分 子 量 】313.87121 |
【开发单位】Pfizer (Originator) 【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D3 Antagonists |
合成路线1
Nitrosation of 5,6-dimethoxy-1-indanone (I) with n-butyl nitrite and HCl in MeOH at 40 C provided oxime (II). Subsequent catalytic hydrogenation of ketone and oxime groups of (II) afforded the 2-aminoindan (III). Reductive alkylation of (III) using propionic acid and NaBH4 then gave the target dipropylamino compound, which was isolated as the hydrochloride salt after separation of some unreacted material by treatment with phenyl isocyanate.
| 【1】 Cannon, J.G.; et al.; Conformationally restricted congeners of dopamine derived from 2-aminoindan. J Med Chem 1982, 25, 12, 1442. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 | |
| 31340 | butyl nitrite | 544-16-1 | C4H9NO2 | 详情 | 详情 | |
| (I) | 13430 | 5,6-Dimethoxy-1-indanone; 2,3-Dihydro-5,6-dimethoxy-1H-inden-1-one | 2107-69-9 | C11H12O3 | 详情 | 详情 |
| (II) | 27302 | 5,6-dimethoxy-1H-indene-1,2(3H)-dione 2-oxime | C11H11NO4 | 详情 | 详情 | |
| (III) | 27303 | 5,6-dimethoxy-2,3-dihydro-1H-inden-2-ylamine | C11H15NO2 | 详情 | 详情 |
合成路线2
Knoevenagel condensation of 3,4-dimethoxybenzaldehyde (I) with malonic acid produced the cinnamic acid (II), which was further reduced to (III) by catalytic hydrogenation using Pd/C. Conversion of (III) to the corresponding acid chloride (IV), followed by Friedel-Crafts intramolecular cyclization gave the indanone (V). Nitrosation of (V) yielded the oximino derivative (VI), which was subsequently silylated with t-butyldimethylsilyl chloride and imidazole to afford the O-silyl oxime (VII). Reduction of (VII) with borane-dimethyl sulfide complex produced the amino alcohol (VIII). Without isolation, (VIII) was converted to the dipropylamino compound (IX) by reductive alkylation with propionaldehyde and NaBH(OAc)3. Amino alcohol (IX) was finally deoxygenated by means of triethylsilane in the presence of boron trifluoride etherate.
| 【1】 Haadsma-Svensson, S.R.; Cleek, K.A.; Dinh, D.M.; et al.; Dopamine D3 receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans. J Med Chem 2001, 44, 26, 4716. |
| 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) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (II) | 28568 | (E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid | 2316-26-9 | C11H12O4 | 详情 | 详情 |
| (III) | 40182 | 3-(3,4-dimethoxyphenyl)propionic acid | 2107-70-2 | C11H14O4 | 详情 | 详情 |
| (IV) | 56565 | 3-(3,4-dimethoxyphenyl)propanoyl chloride | C11H13ClO3 | 详情 | 详情 | |
| (V) | 13430 | 5,6-Dimethoxy-1-indanone; 2,3-Dihydro-5,6-dimethoxy-1H-inden-1-one | 2107-69-9 | C11H12O3 | 详情 | 详情 |
| (VI) | 27302 | 5,6-dimethoxy-1H-indene-1,2(3H)-dione 2-oxime | C11H11NO4 | 详情 | 详情 | |
| (VII) | 56566 | 5,6-dimethoxy-1H-indene-1,2(3H)-dione 2-{O-[tert-butyl(dimethyl)silyl]oxime} | C17H25NO4Si | 详情 | 详情 | |
| (VIII) | 56567 | 2-amino-5,6-dimethoxy-1-indanol | C11H15NO3 | 详情 | 详情 | |
| (IX) | 56568 | 2-(dipropylamino)-5,6-dimethoxy-1-indanol | C17H27NO3 | 详情 | 详情 |