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【结 构 式】 
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【分子编号】47881 【品名】(1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine 【CA登记号】 |
【 分 子 式 】C15H17N 【 分 子 量 】211.30672 【元素组成】C 85.26% H 8.11% N 6.63% |
合成路线1
该中间体在本合成路线中的序号：(XII)Silylation of 4(R)-hydroxy-2-pyrrolidone (I) with TBDMS-Cl and imidazole in DMF gives the silyl ether (II), which is protected at the NH group with Boc2O, TEA and DMAP in acetonitrile to yield the protected pyrrolidone derivative (III). Reaction of pyrrolidone (III) with the Grignard reagent (IV) in THF affords the 2-hydroxypyrrolidine adduct (V) in equilibrium with an open-chain form (VI). Reduction of the ketonic group of (VI) with NaBH4 in methanol in the same vessel provides the alcohol (VII), which is cyclized by means of MsCl and TEA in dichloromethane and then treated with TsOH in THF/H2O to furnish the pyrrolidine-benzaldehyde (VIII). The Wittig condensation of the aldehyde group of (VIII) with the phosphonate (IX) by means of NaH in THF gives the cinnamic ester derivative (X), which is desilylated with TBAF in THF to yield the hydroxy pyrrolidine (XI). Stereo-controlled condensation of (XI) with the chiral amine (XII) by means of BuLi in THF affords the N-alkylated b-amino ester (XIII), which is debenzylated with H2 over Pd(OH)2/C in HOAc/methanol to provide the free amino ester (XIV). The protection of the NH2 group of (XIV) with Boc2O and TEA in dioxane/water gives the N-protected amino ester (XV), which is hydrolyzed with NaOH in hot ethanol to afford the carboxylic acid (XVI).
| 【1】 Yamada, K.; Miura, K.; Nishimura, I.; Shimizu, A.; Morishima, H.; Abe, S.; Nakajima, S.; Sakuraba, S.; Imamura, H.; Sato, H.; Sugimoto, Y.; Stereoselective synthesis of a broad spectrum 1 beta-methylcarbapenem, J-114,870. Tetrahedron 2000, 56, 39, 7705. |
| 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) | 48236 | (R)-4-hydroxy-2-pyrrolidinone | 22677-21-0 | C4H7NO2 | 详情 | 详情 |
| (II) | 48237 | (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 30850 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-1-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (IV) | 30851 | bromo[4-(dimethoxymethyl)phenyl]magnesium | C9H11BrMgO2 | 详情 | 详情 | |
| (V) | 48228 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(dimethoxymethyl)phenyl]-2-hydroxy-1-pyrrolidinecarboxylate | C24H41NO6Si | 详情 | 详情 | |
| (VI) | 48229 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-oxobutylcarbamate | C24H41NO6Si | 详情 | 详情 | |
| (VII) | 43977 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-hydroxybutylcarbamate | C24H43NO6Si | 详情 | 详情 | |
| (VIII) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (IX) | 25637 | tert-butyl 2-(diethoxyphosphoryl)acetate | 6273-47-8 | C10H21O5P | 详情 | 详情 |
| (X) | 48230 | tert-butyl (2R,4R)-2-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C28H45NO5Si | 详情 | 详情 | |
| (XI) | 48231 | tert-butyl (2R,4R)-2-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C22H31NO5 | 详情 | 详情 | |
| (XII) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (XIII) | 48232 | tert-butyl (2R,4R)-2-[4-[(1S)-1-[benzyl[(1R)-1-phenylethyl]amino]-3-(tert-butoxy)-3-oxopropyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C37H48N2O5 | 详情 | 详情 | |
| (XIV) | 48233 | tert-butyl (2R,4R)-2-[4-[(1S)-1-amino-3-(tert-butoxy)-3-oxopropyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C22H34N2O5 | 详情 | 详情 | |
| (XV) | 48234 | tert-butyl (2R,4R)-2-(4-[(1S)-3-(tert-butoxy)-1-[(tert-butoxycarbonyl)amino]-3-oxopropyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C27H42N2O7 | 详情 | 详情 | |
| (XVI) | 48235 | (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-[(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]phenyl]propionic acid | C23H34N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The resin-bound aminohydroxyacid (IX) was prepared as follows. 2-Heptenoic acid (I) was converted to the corresponding tert-butyl ester (II) upon treatment with dimethylformamide di-tert-butylacetal. Conjugate addition to (II) of the chiral amine (III) followed by oxidative treatment with (+)-(camphorsulfonyl)oxaziridine then furnished the amino hydroxyester (IV). Hydrogenolytic cleavage of the N-benzyl groups of (IV) produced the primary amine (V), which was subsequently protected as the N-Fmoc derivative (VI) by using O-Fmoc-hydroxysuccinimide. Tert-butyl ester cleavage in (VI) by means of trifluoroacetic acid gave carboxylic acid (VII). This was then attached to Rink resin using TBTU as the coupling reagent to yield resin (VIII). Deprotection of the N-Fmoc group of (VIII) with piperidine in DMF produced the resin-bound aminohydroxyacid (IX).
| 【1】 Jones, P.S.; Kay, P.B.; Wilson, F.X.; Raynham, T.M.; Hurst, D.N. (Hoffmann-La Roche, Inc.); alpha-Ketoamide derivs.. US 6187905 . |
| 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) | 47873 | (E)-2-heptenoic acid | 10352-88-2 | C7H12O2 | 详情 | 详情 |
| (II) | 47874 | tert-butyl (E)-2-heptenoate | C11H20O2 | 详情 | 详情 | |
| (III) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (IV) | 47875 | tert-butyl (2S,3S)-3-[benzyl[(1R)-1-phenylethyl]amino]-2-hydroxyheptanoate | C26H37NO3 | 详情 | 详情 | |
| (V) | 47876 | tert-butyl (2S,3S)-3-amino-2-hydroxyheptanoate | C11H23NO3 | 详情 | 详情 | |
| (VI) | 47877 | tert-butyl (2S,3S)-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-hydroxyheptanoate | C26H33NO5 | 详情 | 详情 | |
| (VII) | 47878 | (2S,3S)-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-hydroxyheptanoic acid | C22H25NO5 | 详情 | 详情 | |
| (VIII) | 47879 | 9H-fluoren-9-ylmethyl (1S)-1-[(1S)-2-amino-1-hydroxy-2-oxoethyl]pentylcarbamate | C22H26N2O4 | 详情 | 详情 | |
| (IX) | 47880 | (2S,3S)-3-amino-2-hydroxyheptanamide | C7H16N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Ethyl 3-fluorocinnamate (III) was prepared by Wittig condensation of 3-fluorobenzaldehyde (I) with phosphorane (II). Conjugate addition of (R)-N-benzyl-alpha-methylbenzylamine (IV) to the unsaturated ester (III) furnished the chiral amino ester (V). The primary amine (VI) was then obtained by hydrogenolysis of the N-benzyl groups in the presence of palladium hydroxyde. Coupling of the known pyrrolidinoneacetic acid (VII) to the amino ester (VI) by means of EDC/HOBt afforded amide (VIII). Finally, saponification of the ethyl ester group of (VIII) led to the corresponding carboxylic acid.
| 【1】 Brashear, K.M.; Hunt, C.A.; Coleman, P.J.; et al.; Non-peptide alphavbeta3 antagonists. Part 3: Identification of potent RGD mimetics incorporating novel beta-amino acids as aspartic acid replacements. Bioorg Med Chem Lett 2002, 12, 1, 31. |
| 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) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (II) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (III) | 59701 | Ethyl (E)-3-(3-fluorophenyl)-2-propenoate; Ethyl 3-fluorocinnamate | C11H11FO2 | 详情 | 详情 | |
| (IV) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (V) | 59702 | ethyl (3S)-3-{benzyl[(1R)-1-phenylethyl]amino}-3-(3-fluorophenyl)propanoate | C26H28FNO2 | 详情 | 详情 | |
| (VI) | 59703 | ethyl (3S)-3-amino-3-(3-fluorophenyl)propanoate | C11H14FNO2 | 详情 | 详情 | |
| (VII) | 59704 | 2-{(3S)-2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidinyl}acetic acid | C16H21N3O3 | 详情 | 详情 | |
| (VIII) | 59705 | ethyl (3S)-3-(3-fluorophenyl)-3-[(2-{(3S)-2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidinyl}acetyl)amino]propanoate | C27H33FN4O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The Michael addition of the chiral amine (II) to methyl 4-(benzyloxy)cinnamate (I) in the presence of butyllithium produces diastereoselectively the amino ester (III) as the major isomer. After catalytic hydrogenolysis of the benzyl groups of (III), the resultant amino ester (IV) is converted to the N-Boc derivative (V) upon treatment with Boc2O. O-alkylation of phenol (V) with iodomethane in the presence of Cs2CO3 yields methyl ether (VI). The N-Boc group of (VI) is subsequently removed under acidic conditions to furnish (VII).
| 【1】 Kopka, I.E.; Mumford, R.A.; Lin, L.S.; et al.; The discovery of acylated beta-amino acids as potent and orally bioavailable VLA-4 antagonists. Bioorg Med Chem Lett 2002, 12, 4, 611. |
| 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) | 59017 | methyl (E)-3-[4-(benzyloxy)phenyl]-2-propenoate | C17H16O3 | 详情 | 详情 | |
| (II) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (III) | 59018 | methyl (3R)-3-[4-(benzyloxy)phenyl]-3-{benzyl[(1R)-1-phenylethyl]amino}propanoate | C32H33NO3 | 详情 | 详情 | |
| (IV) | 59019 | methyl (3R)-3-amino-3-(4-hydroxyphenyl)propanoate | C10H13NO3 | 详情 | 详情 | |
| (V) | 59020 | methyl (3R)-3-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | C15H21NO5 | 详情 | 详情 | |
| (VI) | 59021 | methyl (3R)-3-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C16H23NO5 | 详情 | 详情 | |
| (VII) | 59022 | methyl (3R)-3-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 |