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【结 构 式】 
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【分子编号】38470 【品名】(1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine 【CA登记号】38235-77-7 |
【 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：(IX)Treatment of 3,4-(methylenedioxy)cinnamic (VII) with SOCl2 and then with EtOH provided ethyl ester (VIII). Subsequent conjugate addition of the chiral amine (IX) to ester (VIII) in the presence of BuLi gave amino ester (X). Cleavage of benzyl and alpha-methylbenzyl protecting groups of (X) was then achieved by catalytic hydrogenolysis over Pd/C. The resulting primary amine (XI) was acylated with 4-nitrophenyl chloroformate (XII) to produce carbamate (XIII), which was condensed with amine (VI) to generate urea (XIV). Finally, basic hydrolysis of the ethyl ester of (XIV) furnished the title carboxylic acid.
| 【1】 Scott, I.L.; et al.; Novel N,N-disubstituted amides that are highly potent VLA-4 antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 284. |
| 【2】 Raju, B.G.; Scott, I.L.; Biediger, R.J.; Market, R.V.; Grabbe, V.O.; Kassir, J.M.; Kogan, T.P.; Lin, S. (Texas Biotechnology Corp.); N,N-Disubstd. amides that inhibit the binding of integrins to their receptors. US 6096773; WO 9952493; WO 9952898 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 38468 | (2S)-2-amino-N,N-bis(2-thienylmethyl)hexanamide | C16H22N2OS2 | 详情 | 详情 | |
| (VII) | 11634 | (E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid | 2373-80-0 | C10H8O4 | 详情 | 详情 |
| (VIII) | 38469 | ethyl (E)-3-(1,3-benzodioxol-5-yl)-2-propenoate | C12H12O4 | 详情 | 详情 | |
| (IX) | 38470 | (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine | 38235-77-7 | C15H17N | 详情 | 详情 |
| (X) | 38471 | ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-[benzyl[(1S)-1-phenylethyl]amino]propanoate | C27H29NO4 | 详情 | 详情 | |
| (XI) | 38472 | ethyl (3S)-3-amino-3-(1,3-benzodioxol-5-yl)propanoate | C12H15NO4 | 详情 | 详情 | |
| (XII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIII) | 38473 | ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-[[(4-nitrophenoxy)carbonyl]amino]propanoate | C19H18N2O8 | 详情 | 详情 | |
| (XIV) | 38474 | ethyl (3S)-3-(1,3-benzodioxol-5-yl)-3-([[((1S)-1-[[bis(2-thienylmethyl)amino]carbonyl]pentyl)amino]carbonyl]amino)propanoate | C29H35N3O6S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The desired enantiomer was prepared by two chiral routes. Monoalkylation of (S)-alpha-methylbenzylamine (I) with benzyl bromide in N,N'-dimethylpropyleneurea gave the chiral secondary amine (II). Diastereoselective Michael addition of the lithium amide of (II) to benzyl crotonate (III) provided adduct (IV). The chiral ester (IV) was then reacted with the Grignard reagent (V) to yield the diaryl carbinol (VI). This was subsequently dehydrated to (VII) using H2SO4 in glacial HOAc. Double bond reduction and N-debenzylation of (VII) over Pearlman抯 catalyst provided the target primary amine, which was finally isolated as the hydrochloride salt.
| 【1】 Moe, S.T.; DelMar, E.G.; Smith, D.L.; et al.; Chiral synthesis and pharmacological evaluation of NPS 1407: A potent, stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 2000, 10, 21, 2411. |
| 【2】 Moe, S.T.; Mueller, A.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9856752 . |
| 【3】 Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 . |
| 【4】 Barmore, R.M.; DelMar, E.G.; Balandrin, M.F.; VanWagenen, B.C.; Artman, L.D.; Mueller, A.L.; Moe, S.T. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. US 6071970 . |
| 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) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (II) | 38470 | (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine | 38235-77-7 | C15H17N | 详情 | 详情 |
| (III) | 46908 | benzyl (E)-2-butenoate | C11H12O2 | 详情 | 详情 | |
| (IV) | 46909 | benzyl (3S)-3-[benzyl[(1S)-1-phenylethyl]amino]butanoate | C26H29NO2 | 详情 | 详情 | |
| (V) | 35384 | bromo(3-fluorophenyl)magnesium | C6H4BrFMg | 详情 | 详情 | |
| (VI) | 46910 | (3S)-3-[benzyl[(1S)-1-phenylethyl]amino]-1,1-bis(3-fluorophenyl)-1-butanol | C31H31F2NO | 详情 | 详情 | |
| (VII) | 46911 | (2S)-N-benzyl-4,4-bis(3-fluorophenyl)-N-[(1S)-1-phenylethyl]-3-buten-2-amine; N-benzyl-N-[(1S)-3,3-bis(3-fluorophenyl)-1-methyl-2-propenyl]-N-[(1S)-1-phenylethyl]amine | C31H29F2N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The synthesis of the intermediate (S,S)-3-(Fmoc-amino)-2-methyl-5-phenyl-4-pentenoic acid (XI) has been performed as follows: The Horner-Wadsworth-Emmons condensation of cinnamaldehyde (I) with phosphonate (II) by means of NaH in THF gives (E,E)-5-phenyl-2,4-pentadienoic acid ethyl ester (III), which is condensed with (S)-N-benzyl-N-(alpha-methylbenzyl)amine (IV) by means of BuLi in THF to yield the chiral adduct (V). The reaction of (V) with LDA affords the corresponding lithium enolate, which is methylated with methyl iodide in THF to afford the enantioselectively methylated compound (VI). The hydrogenation of (VI) with H2 over Pd(OH)2 in methanol/water/HOAc provides (S,S)-3-amino-2-methyl-5-phenylpentanoic acid methyl ester (VII), which is treated with Boc2O and NaHCO3 in dioxane/water to give the N-protected ester (VIII). The reaction of (VIII) with NBS in CCl4, followed by treatment with DBU at 60 C, yields the pentenoic ester derivative (IX), which is treated first with LiOH and then with TFA to provide (S,S)-3-amino-2-methyl-5-phenyl-4-pentanoic acid (X). Finally, this compound is N-protected by reaction with Fmoc-Cl and K2CO3 in dioxane/water to furnish the target pentenoic acid intermediate (XI).
| 【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696. |
| 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) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
| (II) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (III) | 52431 | methyl 5-phenyl-2,4-pentadienoate | C12H12O2 | 详情 | 详情 | |
| (IV) | 38470 | (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine | 38235-77-7 | C15H17N | 详情 | 详情 |
| (V) | 52432 | methyl 5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate | C27H29NO2 | 详情 | 详情 | |
| (VI) | 52433 | methyl 2-methyl-5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate | C28H31NO2 | 详情 | 详情 | |
| (VII) | 52434 | methyl 3-amino-2-methyl-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 52435 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenylpentanoate | C18H27NO4 | 详情 | 详情 | |
| (IX) | 52436 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (X) | 52437 | 3-amino-2-methyl-5-phenyl-4-pentenoic acid | C12H15NO2 | 详情 | 详情 | |
| (XI) | 52438 | 3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid | C27H25NO4 | 详情 | 详情 |