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【结 构 式】 
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【分子编号】35058 【品名】2,6-diethylphenylamine; 2,6-diethylaniline 【CA登记号】579-66-8 |
【 分 子 式 】C10H15N 【 分 子 量 】149.23584 【元素组成】C 80.48% H 10.13% N 9.39% |
合成路线1
该中间体在本合成路线中的序号：(VI)The required benzothiophenecarboxylic acid precursor (IV) was prepared by Friedel-Crafts acylation of 5-(methylthio)indan (I) with 2-methylbenzoyl chloride (II) followed by condensation of the resulting mercapto ketone (III) with hot chloroacetic acid. Curtius rearrangement of carboxylic acid (IV) using diphenylphosphoryl azide produced isocyanate (V), which was subsequently condensed with 2,6-diethylaniline (VI) to yield the title urea.
| 【1】 Nagamine, M.; Yamamoto, K.; Matsui, Y.; Horiuchi, K.; Yoshida, M. (Nihon Nohyaku Co., Ltd.); N-Heteroaryl-N'-phenylurea derivs., their production and use. CA 2116286; EP 0613894; JP 1994340647; US 5464863 . |
| 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) | 50709 | 2,3-dihydro-1H-inden-5-yl methyl sulfide; 5-(methylsulfanyl)indane | C10H12S | 详情 | 详情 | |
| (II) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
| (III) | 50710 | (2-methylphenyl)[6-(methylsulfanyl)-2,3-dihydro-1H-inden-5-yl]methanone | C18H18OS | 详情 | 详情 | |
| (IV) | 50711 | 3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]thiophene-2-carboxylic acid | C19H16O2S | 详情 | 详情 | |
| (V) | 50712 | 3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]thiophen-2-yl isocyanate; 2-isocyanato-3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]thiophene | C19H15NOS | 详情 | 详情 | |
| (VI) | 35058 | 2,6-diethylphenylamine; 2,6-diethylaniline | 579-66-8 | C10H15N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Condensation of piperonal (I) with nitromethane in the presence of ammonium acetate in AcOH provided nitrostyrene (II). Ketoester (IV) was prepared by carbethoxylation of 4'-propoxyacetophenone (III) with diethyl carbonate. Subsequent conjugate addition of ketoester (IV) to nitrostyrene (II) using DBU provided adduct (V). Hydrogenation of the nitro group of (V) over Raney Nickel, with concomitant ring closure formed the cyclic imine (VI), and further reduction of (VI) with NaBH3CN yielded the corresponding pyrrolidine as a diastereomeric mixture. Chromatographic separation removed the cis,cis isomer, affording a mixture of trans,trans and cis,trans pyrrolidines (VIIa, VIIb). 2,6-Diethylbromoacetanilide (IX) was prepared by acylation of 2,6-diethylaniline (VIII) with bromoacetyl bromide. N-Alkylation of the mixture of pyrrolidines (VIIa, VIIb) with bromoacetanilide (IX) furnished (Xa, Xb).
| 【1】 Sorensen, B.K.; Tasker, A.S.; von Geldern, T.W.; et al.; Pyrrolide-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ETB selectivity. J Med Chem 1999, 42, 18, 3668. |
| 【2】 Tasker, A.S.; Boyd, S.A.; Sorensen, B.K.; Winn, M.; Jae, H.-S.; Von Geldern, T.W.; Henry, K.J. (Abbott Laboratories Inc.); 4-(Benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivs. as endothelin antagonists. EP 0888340; JP 2000504727; WO 9730046 . |
| 【3】 Tasker, A.S.; Henry, K.J.; Boyd, S.A.; Von Geldern, T.W.; Sorensen, B.K.; Jae, H.-S.; Winn, M. (Abbott Laboratories Inc.); Pyrrolidine carboxylic acid derivs. as endothelin antagonists. EP 0991620; WO 9857933 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 | |
| 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIa) | 35056 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C23H27NO5 | 详情 | 详情 | |
| (VIIb) | 35057 | ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C23H27NO5 | 详情 | 详情 | |
| (Xa) | 35060 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C35H42N2O6 | 详情 | 详情 | |
| (Xb),(XI) | 35061 | ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C35H42N2O6 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35052 | 1-(4-propoxyphenyl)-1-ethanone | C11H14O2 | 详情 | 详情 | |
| (IV) | 35053 | ethyl 3-oxo-3-(4-propoxyphenyl)propanoate | C14H18O4 | 详情 | 详情 | |
| (V) | 35054 | ethyl 3-(1,3-benzodioxol-5-yl)-4-nitro-2-(4-propoxybenzoyl)butanoate | C23H25NO8 | 详情 | 详情 | |
| (VI) | 35055 | ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-propoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate | C23H25NO5 | 详情 | 详情 | |
| (VIII) | 35058 | 2,6-diethylphenylamine; 2,6-diethylaniline | 579-66-8 | C10H15N | 详情 | 详情 |
| (IX) | 35059 | 2-bromo-N-(2,6-diethylphenyl)acetamide | C12H16BrNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The target product can be obtained by reaction of homophthalic anhydride (I) with amine (II) at high temperature (160-180 C).
| 【1】 Miyachi, H.; et al.; Novel potent nonpeptide aminopeptidase N inhibitors with a cyclic imide skeleton. J Med Chem 1998, 41, 3, 263. |