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【结 构 式】 
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【分子编号】26295 【品名】(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid 【CA登记号】609-23-4 |
【 分 子 式 】C12H23NO4 【 分 子 量 】245.31896 【元素组成】C 58.75% H 9.45% N 5.71% O 26.09% |
合成路线1
该中间体在本合成路线中的序号：(XXXIV)Treatment of N-Boc-N-methyl-L-leucine (XXXIV) with isobutene and H2SO4 in CH2Cl2 generated tert-butyl ester (XXXV) with simultaneous removal of the Boc group. Subsequent coupling of (XXXV) with N-Boc-5-propyl-L-leucine (X) utilizing EDC and HOAt provided dipeptide (XXXVI). Selective removal of the N-Boc group of (XXXVI) was accomplished by treatment with formic acid at r.t. The resulting amine (XXXVII) was then coupled with hydroxyacid (XXXIII) to yield the target tripeptide (XXXVIII).
| 【1】 Boger, D.L.; et al.; Total synthesis of HUN-7293. J Am Chem Soc 1999, 121, 26, 6197. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 26272 | (2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-methyloctanoic acid | C14H27NO4 | 详情 | 详情 | |
| (XXXIII) | 26294 | (2S)-4-cyano-2-hydroxybutyric acid | C5H7NO3 | 详情 | 详情 | |
| (XXXIV) | 26295 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | 609-23-4 | C12H23NO4 | 详情 | 详情 |
| (XXXV) | 26296 | tert-butyl (2S)-4-methyl-2-(methylamino)pentanoate | C11H23NO2 | 详情 | 详情 | |
| (XXXVI) | 26297 | tert-butyl (2S)-2-[[(2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-methyloctanoyl](methyl)amino]-4-methylpentanoate | C25H48N2O5 | 详情 | 详情 | |
| (XXXVII) | 26298 | tert-butyl (2S)-2-[[(2S,4R)-2-amino-4-methyloctanoyl](methyl)amino]-4-methylpentanoate | C20H40N2O3 | 详情 | 详情 | |
| (XXXVIII) | 26299 | tert-butyl (2S)-2-[((2S,4R)-2-[[(2S)-4-cyano-2-hydroxybutanoyl]amino]-4-methyloctanoyl)(methyl)amino]-4-methylpentanoate | C25H45N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)In a related procedure, N-Boc-N-methylleucine (XI) was coupled with O-benzyltyrosine amide (III) in the presence of HBTU to give the protected dipeptide (XII). Trifluoroacetic acid-promoted cleavage of the Boc group of (XII) provided amine (XIII). Finally, reductive alkylation of (XIII) with 4-tert-butylbenzaldehyde (VII) gave rise to the title compound.
| 【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; Structure-activity relationship of N-methyl-N-aralkyl-peptidylamines as novel N-type calcium channel blockers. Bioorg Med Chem Lett 1999, 9, 15, 2151. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 30798 | (2S)-2-amino-3-[4-(benzyloxy)phenyl]-N-(tert-butyl)propanamide | C20H26N2O2 | 详情 | 详情 | |
| (VII) | 16638 | 4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde | 939-97-9 | C11H14O | 详情 | 详情 |
| (XI) | 26295 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | 609-23-4 | C12H23NO4 | 详情 | 详情 |
| (XII) | 34646 | tert-butyl (1S)-1-([[(1S)-1-[4-(benzyloxy)benzyl]-2-(tert-butylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl(methyl)carbamate | C32H47N3O5 | 详情 | 详情 | |
| (XIII) | 34647 | (2S)-N-[(1S)-1-[4-(benzyloxy)benzyl]-2-(tert-butylamino)-2-oxoethyl]-4-methyl-2-(methylamino)pentanamide | C27H39N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Condensation of 4,4-bis(4-fluorophenyl)butyl bromide (I) with potassium phthalimide (II) in hot DMF yielded the substituted phthalimide (III). Deprotection of the phthalimido group of (III) to give primary amine (IV) was effected by treatment with NaBH4, followed by methanolic HCl. Subsequent coupling of (IV) with N-Boc-N-methyl-L-leucine (V) by means of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate furnished amide (VI). Finally, the Boc group of (VI) was deprotected using trifluoroacetic acid in CH2Cl2 and treated with HCl.
| 【1】 Song, Y.; Connor, D.T.; Bowersox, S.S.; et al.; (S)-4-methyl-2-(methylamino)pentanoic acid [4,4-bis(4-fluorophenyl)butyl]amide hydrochloride, a novel calcium channel antagonist, is efficacious in several animal models of pain. J Med Chem 2000, 43, 19, 3474. |
| 【2】 Song, Y.; Rafferty, M.F.; Ryder, T.R.; Sercel, A.D.; Connor, D.T.; Malone, T.C.; Hu, L.-Y.; Roth, B.D. (Pfizer Inc.); Substd. diarylalkyl amides as calcium channel antagonists. WO 9955688 . |
| 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) | 35603 | 1-[4-bromo-1-(4-fluorophenyl)butyl]-4-fluorobenzene | C16H15BrF2 | 详情 | 详情 | |
| (II) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (III) | 35604 | 2-[4,4-bis(4-fluorophenyl)butyl]-1H-isoindole-1,3(2H)-dione | C24H19F2NO2 | 详情 | 详情 | |
| (IV) | 35605 | 4,4-bis(4-fluorophenyl)-1-butanamine; 4,4-bis(4-fluorophenyl)butylamine | C16H17F2N | 详情 | 详情 | |
| (V) | 26295 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | 609-23-4 | C12H23NO4 | 详情 | 详情 |
| (VI) | 35607 | tert-butyl (1S)-1-([[4,4-bis(4-fluorophenyl)butyl]amino]carbonyl)-3-methylbutyl(methyl)carbamate | C28H38F2N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)2-N-(Benzyloxycarbonyl)-L-2,4-diaminobutyric acid (I) is esterified by means of SOCl2 in MeOH to afford the corresponding methyl ester (II). Subsequent coupling of (II) with N-Boc-N-methyl-L-leucine (III) leads to dipeptide (IV). The N-benzyloxycarbonyl group of (IV) is removed by catalytic hydrogenation over Pd/C to furnish amine (V), which is further acylated with N-benzyloxycarbonyl-L-proline succinimidyl ester (VI) yielding tripeptide (VII). Then, acidic cleavage of the N-Boc protecting group (VII) produces (VIII).
| 【1】 Lee, W.-C.; Scott, D.; Cornebise, M.; Petter, R. (Biogen Idec Inc.); Cell adhesion inhibitors. EP 1265606; JP 2003506491; US 6630503; WO 0112186 . |
| 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) | 64984 | 4-amino-2-({[(phenylmethyl)oxy]carbonyl}amino)butanoic acid | C12H16N2O4 | 详情 | 详情 | |
| (II) | 64985 | methyl 4-amino-2-({[(phenylmethyl)oxy]carbonyl}amino)butanoate | C13H18N2O4 | 详情 | 详情 | |
| (III) | 26295 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | 609-23-4 | C12H23NO4 | 详情 | 详情 |
| (IV) | 64986 | methyl 4-({2-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]-4-methylpentanoyl}amino)-2-({[(phenylmethyl)oxy]carbonyl}amino)butanoate | C25H39N3O7 | 详情 | 详情 | |
| (V) | 64987 | methyl 2-amino-4-({2-[{[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]-4-methylpentanoyl}amino)butanoate | C17H33N3O5 | 详情 | 详情 | |
| (VI) | 64988 | phenylmethyl 2-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-1-pyrrolidinecarboxylate | C17H18N2O6 | 详情 | 详情 | |
| (VII) | 64989 | phenylmethyl 2-[9,12,12-trimethyl-3-[(methyloxy)carbonyl]-8-(2-methylpropyl)-7,10-dioxo-11-oxa-2,6,9-triazatridec-1-anoyl]-1-pyrrolidinecarboxylate | C30H46N4O8 | 详情 | 详情 | |
| (VIII) | 64990 | phenylmethyl 2-[({3-{[4-methyl-2-(methylamino)pentanoyl]amino}-1-[(methyloxy)carbonyl]propyl}amino)carbonyl]-1-pyrrolidinecarboxylate | C25H38N4O6 | 详情 | 详情 |