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【结 构 式】 
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【分子编号】27492 【品名】4-(tert-butyl)aniline 【CA登记号】769-92-6 |
【 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：(I)Michael addition of itaconic acid (II) to 4-tert-butylaniline (I), and further lactamization afforded pyrrolidone carboxylic acid (III). This was esterified with H2SO4 in MeOH, and the resulting methyl ester (IV) was reduced to alcohol (V) with NaBH4 in boiling tetrahydrofuran. Optical resolution of (V) was achieved by condensation with phthalic anhydride (VI) to give amide (VII), followed by coupling of the remaining carboxylic acid group of (VII) with chiral alpha-methylbenzyl amine (VIII) yielding (IX). After separation of the diastereomeric mixture (IX), hydrolysis of the phthalate ester furnished the required (S)-alcohol (X) (2). Mesylate (XI), prepared from alcohol (X) and MsCl in the presence of Et3N, was condensed with methyl 4-hydroxybenzoate (XII) to afford ether (XIII). Then, basic hydrolysis of the methyl ester of (XIII) provided the title compound.
| 【1】 Yano, S.; Ogawa, K.; Shirasaka, T.; Ohno, T. (Taiho Pharmaceutical Co., Ltd.); Optically active 1-phenylpyrrolidine derivative, intermediate for producing the same, and process for producing both. WO 9406767 . |
| 【2】 Watanabe, S.; et al.; Synthesis of 4-[1-(substituted phenyl)-2-oxo-pyrrolidin-4-yl]methyloxybenzoic acids and related compounds, and their inhibitory capacities toward fatty-acid and sterol biosyntheses. Eur J Med Chem 1994, 29, 675. |
| 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) | 27492 | 4-(tert-butyl)aniline | 769-92-6 | C10H15N | 详情 | 详情 |
| (II) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (III) | 27494 | 1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (IV) | 27495 | methyl 1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (V) | 27496 | 1-[4-(tert-butyl)phenyl]-4-(hydroxymethyl)-2-pyrrolidinone | C15H21NO2 | 详情 | 详情 | |
| (VI) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (VII) | 27497 | 2-[([1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinyl]methoxy)carbonyl]benzoic acid | C23H25NO5 | 详情 | 详情 | |
| (VIII) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (IX) | 27498 | [1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinyl]methyl 2-[[(1-phenylethyl)amino]carbonyl]benzoate | C31H34N2O4 | 详情 | 详情 | |
| (X) | 27499 | (4S)-1-[4-(tert-butyl)phenyl]-4-(hydroxymethyl)-2-pyrrolidinone | C15H21NO2 | 详情 | 详情 | |
| (XI) | 27500 | [(3S)-1-[4-(tert-butyl)phenyl]-5-oxopyrrolidinyl]methyl methanesulfonate | C16H23NO4S | 详情 | 详情 | |
| (XII) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XIII) | 27501 | methyl 4-([(3S)-1-[4-(tert-butyl)phenyl]-5-oxopyrrolidinyl]methoxy)benzoate | C23H27NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The Michael addition of 4-tert-butylaniline (I) with 2-methylenesuccinic acid (II) followed by cyclization gives racemic 1-(4-tert-butylphenyl)-5-oxopyrrolidine-3-carboxylic acid (III) (1), which is treated with SOCl2 and condensed with (S)(-)-1-(4-methylphenyl)ethylamine (IV) to yield a diastereomeric mixture of amides (V). The resolution of (V) by silicagel chromatography affords the (S,S)-diastereomer (VI), which is treated with N2O4 and NaOAc in CCl4 to provide 1-(4-tert-butylphenyl)-5-oxopyrrolidine-3(S)-carboxylic acid (VII). The reduction of (VII) with BH3/THF in dichloromethane gives the corresponding carbinol (VIII), which is treated with MsCl and TEA in dichloromethane to yield the mesylate (IX). The condensation of (IX) with 4-hydroxybenzoic acid methyl ester (X) by means of K2CO3 in DMF affords the corresponding phenyl ether (XI), which is finally hydrolyzed with HCl/AcOH to furnish the target compound.
| 【1】 Ohno, T.; Ogawa, K.; Yano, S.; Kobayashi, K.; Shirasaka, T.; Yamada, H.; Yamamoto, A.; Synthesis of the optical isomers of 4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-yl]methyloxybenzoic acid (S-2) and their biological evaluation as antilipidemic agent. Chem Pharm Bull 1999, 47, 11, 1549. |
| 【2】 Watanabe, S.; et al.; Synthesis of 4-[1-(substituted phenyl)-2-oxo-pyrrolidin-4-yl]methyloxybenzoic acids and related compounds, and their inhibitory capacities toward fatty-acid and sterol biosyntheses. Eur J Med Chem 1994, 29, 675. |
| 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) | 27492 | 4-(tert-butyl)aniline | 769-92-6 | C10H15N | 详情 | 详情 |
| (II) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (III) | 27494 | 1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (IV) | 37195 | (2S)-2-(4-methylphenyl)-1-propanamine; (2S)-2-(4-methylphenyl)propylamine | C10H15N | 详情 | 详情 | |
| (V) | 37196 | 1-[4-(tert-butyl)phenyl]-N-[(2S)-2-(4-methylphenyl)propyl]-5-oxo-3-pyrrolidinecarboxamide | C25H32N2O2 | 详情 | 详情 | |
| (VI) | 37197 | (3S)-1-[4-(tert-butyl)phenyl]-N-[(2S)-2-(4-methylphenyl)propyl]-5-oxo-3-pyrrolidinecarboxamide | C25H32N2O2 | 详情 | 详情 | |
| (VII) | 37198 | (3S)-1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (VIII) | 27499 | (4S)-1-[4-(tert-butyl)phenyl]-4-(hydroxymethyl)-2-pyrrolidinone | C15H21NO2 | 详情 | 详情 | |
| (IX) | 37199 | (4S)-1-[4-(tert-butyl)phenyl]-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2-pyrrolidinone | C18H27NO2S | 详情 | 详情 | |
| (X) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XI) | 27501 | methyl 4-([(3S)-1-[4-(tert-butyl)phenyl]-5-oxopyrrolidinyl]methoxy)benzoate | C23H27NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded tryptamine (V). In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VIII) was prepared by treatment of amine (VI) with N-carbethoxyphthalimide (VII). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (IX), which was deprotected with hydrazine to furnish the corresponding tryptamine (V). Subsequent condensation of (V) with di-tert-butyl dicarbonate gave carbamate (X). This was finally reduced by means of LiAlH4 providing the target N-methyl tryptamine.
| 【1】 Xu, Y.-C.; Schaus, J.M.; Walker, C.; Krushinski, J.; Adhamm, N.; Zgombick, J.M.; Liang, S.X.; Kohlman, D.T.; Audia, J.E.; N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist. J Med Chem 1999, 42, 3, 526. |
| 【2】 Audia, J.E.; Cohen, M.L.; Gidda, J.S.; Nelson, D.L.G.; Baker, S.R.; Ezquerra-Carrera, J.; Lamas-Peteira, C.; Pedregal-Tercero, C. (Eli Lilly and Company); Method for treating 5HT2B receptor related conditions. EP 0749313; JP 1997510216; US 5663178; WO 9524200; WO 9624351 . |
| 【3】 Audia, J.E.; et al. (Eli Lilly and Company); Intermediates to tetrahydro-beta-carbolines. US 5635528 . |
| 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) | 27492 | 4-(tert-butyl)aniline | 769-92-6 | C10H15N | 详情 | 详情 |
| (II) | 29269 | 1-[4-(tert-butyl)phenyl]hydrazine | C10H16N2 | 详情 | 详情 | |
| (III) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (IV) | 23428 | 4-Chlorobutanal | C4H7ClO | 详情 | 详情 | |
| (V) | 29270 | 2-[5-(tert-butyl)-1H-indol-3-yl]-1-ethanamine | C14H20N2 | 详情 | 详情 | |
| (VI) | 23323 | 4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine | 6346-09-4 | C8H19NO2 | 详情 | 详情 |
| (VII) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (VIII) | 23325 | 2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione | C16H21NO4 | 详情 | 详情 | |
| (IX) | 29271 | 2-[2-[5-(tert-butyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione | C22H22N2O2 | 详情 | 详情 | |
| (X) | 29272 | tert-butyl 2-[5-(tert-butyl)-1H-indol-3-yl]ethylcarbamate | C19H28N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded the target tryptamine. In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VII) was prepared by treatment of amine (V) with N-carbethoxyphthalimide (VI). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (VIII), which was deprotected with hydrazine to furnish the corresponding tryptamine.
| 【1】 Xu, Y.-C.; Schaus, J.M.; Walker, C.; Krushinski, J.; Adhamm, N.; Zgombick, J.M.; Liang, S.X.; Kohlman, D.T.; Audia, J.E.; N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist. J Med Chem 1999, 42, 3, 526. |
| 【2】 Audia, J.E.; Cohen, M.L.; Gidda, J.S.; Nelson, D.L.G.; Baker, S.R.; Ezquerra-Carrera, J.; Lamas-Peteira, C.; Pedregal-Tercero, C. (Eli Lilly and Company); Method for treating 5HT2B receptor related conditions. EP 0749313; JP 1997510216; US 5663178; WO 9524200; WO 9624351 . |
| 【3】 Audia, J.E.; et al. (Eli Lilly and Company); Intermediates to tetrahydro-beta-carbolines. US 5635528 . |
| 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) | 27492 | 4-(tert-butyl)aniline | 769-92-6 | C10H15N | 详情 | 详情 |
| (II) | 29269 | 1-[4-(tert-butyl)phenyl]hydrazine | C10H16N2 | 详情 | 详情 | |
| (III) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (IV) | 23428 | 4-Chlorobutanal | C4H7ClO | 详情 | 详情 | |
| (V) | 23323 | 4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine | 6346-09-4 | C8H19NO2 | 详情 | 详情 |
| (VI) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (VII) | 23325 | 2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione | C16H21NO4 | 详情 | 详情 | |
| (VIII) | 29271 | 2-[2-[5-(tert-butyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione | C22H22N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded tryptamine (V). In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VIII) was prepared by treatment of amine (VI) with N-carbethoxyphthalimide (VII). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (IX), which was deprotected with hydrazine to furnish the corresponding tryptamine (V). Finally, dimethylation of (V) by means of methyl methanesulfonate provided the target N,N-dimethyl tryptamine.
| 【1】 Xu, Y.-C.; Schaus, J.M.; Walker, C.; Krushinski, J.; Adhamm, N.; Zgombick, J.M.; Liang, S.X.; Kohlman, D.T.; Audia, J.E.; N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist. J Med Chem 1999, 42, 3, 526. |
| 【2】 Audia, J.E.; Cohen, M.L.; Gidda, J.S.; Nelson, D.L.G.; Baker, S.R.; Ezquerra-Carrera, J.; Lamas-Peteira, C.; Pedregal-Tercero, C. (Eli Lilly and Company); Method for treating 5HT2B receptor related conditions. EP 0749313; JP 1997510216; US 5663178; WO 9524200; WO 9624351 . |
| 【3】 Audia, J.E.; et al. (Eli Lilly and Company); Intermediates to tetrahydro-beta-carbolines. US 5635528 . |
| 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) | 27492 | 4-(tert-butyl)aniline | 769-92-6 | C10H15N | 详情 | 详情 |
| (II) | 29269 | 1-[4-(tert-butyl)phenyl]hydrazine | C10H16N2 | 详情 | 详情 | |
| (III) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (IV) | 23428 | 4-Chlorobutanal | C4H7ClO | 详情 | 详情 | |
| (V) | 29270 | 2-[5-(tert-butyl)-1H-indol-3-yl]-1-ethanamine | C14H20N2 | 详情 | 详情 | |
| (VI) | 23323 | 4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine | 6346-09-4 | C8H19NO2 | 详情 | 详情 |
| (VII) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (VIII) | 23325 | 2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione | C16H21NO4 | 详情 | 详情 | |
| (IX) | 29271 | 2-[2-[5-(tert-butyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione | C22H22N2O2 | 详情 | 详情 |