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【结 构 式】 
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【分子编号】30798 【品名】(2S)-2-amino-3-[4-(benzyloxy)phenyl]-N-(tert-butyl)propanamide 【CA登记号】 |
【 分 子 式 】C20H26N2O2 【 分 子 量 】326.43872 【元素组成】C 73.59% H 8.03% N 8.58% O 9.8% |
合成路线1
该中间体在本合成路线中的序号：(III)Coupling of N-Boc-O-benzyl-L-tyrosine (I) with tert-butylamine by means of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) afforded amide (II). Subsequent acid cleavage of the Boc group of (II) gave O-benzyltyrosine tert-butyl amide (III).
| 【1】 Ryder, T.R.; et al.; Multiple parallel synthesis of N,N-dialkyldipeptidylamines as N-type calcium channel blockers. Bioorg Med Chem Lett 1999, 9, 13, 1813. |
| 【2】 Szoke, B.G.; Rafferty, M.F.; Silva, D.F.; Song, Y.; Malone, T.C.; Hu, L.-Y.; Urge, L.; Nadasdi, L.; Ryder, T.R. (Neurex Corp.; Pfizer Inc.); Substd. peptidylamine calcium channel blockers. WO 9854123 . |
| 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) | 30396 | (2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | 54784-43-9 | C21H25NO5 | 详情 | 详情 |
| (II) | 30797 | tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-(tert-butylamino)-2-oxoethylcarbamate | C25H34N2O4 | 详情 | 详情 | |
| (III) | 30798 | (2S)-2-amino-3-[4-(benzyloxy)phenyl]-N-(tert-butyl)propanamide | C20H26N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)N-Methyl-L-leucine (IV) was converted to tert-butyl ester (V) by treatment with isobutylene and H2SO4. Formation of the N,N-dialkyl derivative (VIII) was achieved by either alkylation of (V) with p-tert-butylbenzyl bromide (VI) or by reductive condensation of (V) with p-tert-butylbenzaldehyde (VII) and NaBH(OAc)3. Deprotection of the tert-butyl ester of (VIII) with trifluoroacetic acid gave amino acid (IX), which was activated as the mixed anhydride (X) upon treatment with isobutyl chloroformate and a polymer-supported morpholine base. Coupling of (X) with tyrosine amide (III) then afforded the title dipeptide amide. Unreacted starting materials were captured by the addition of polymer-supported polyamine and isocyanate resins.
| 【1】 Ryder, T.R.; et al.; Multiple parallel synthesis of N,N-dialkyldipeptidylamines as N-type calcium channel blockers. Bioorg Med Chem Lett 1999, 9, 13, 1813. |
| 【2】 Szoke, B.G.; Rafferty, M.F.; Silva, D.F.; Song, Y.; Malone, T.C.; Hu, L.-Y.; Urge, L.; Nadasdi, L.; Ryder, T.R. (Neurex Corp.; Pfizer Inc.); Substd. peptidylamine calcium channel blockers. WO 9854123 . |
| 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 | |
| (IV) | 34642 | (2S)-4-methyl-2-(methylamino)pentanoic acid | C7H15NO2 | 详情 | 详情 | |
| (V) | 26296 | tert-butyl (2S)-4-methyl-2-(methylamino)pentanoate | C11H23NO2 | 详情 | 详情 | |
| (VI) | 20588 | 1-(bromomethyl)-4-(tert-butyl)benzene | 18880-00-7 | C11H15Br | 详情 | 详情 |
| (VII) | 16638 | 4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde | 939-97-9 | C11H14O | 详情 | 详情 |
| (VIII) | 34643 | tert-butyl (2S)-2-[[4-(tert-butyl)benzyl](methyl)amino]-4-methylpentanoate | C22H37NO2 | 详情 | 详情 | |
| (IX) | 34644 | (2S)-2-[[4-(tert-butyl)benzyl](methyl)amino]-4-methylpentanoic acid | C18H29NO2 | 详情 | 详情 | |
| (X) | 34645 | C23H37NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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4
该中间体在本合成路线中的序号：(III)The precursor amino acid derivatives were obtained as follows: The condensation of N-Boc-O-benzyltyrosine (I) with tert-butylamine using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) gave amide (II). Subsequent deprotection of the Boc group of (II) by means of trifluoroacetic acid provided O-benzyltyrosine tert-butyl amide (III). N-Methyl leucine benzyl ester (IV) was alkylated with 3-bromocyclohexene (V), yielding the cyclohexenyl amine (VI). Hydrogenation of the olefinic double bond of (VI) with concomitant benzyl ester hydrogenolysis in the presence of Pd/C furnished N-cyclohexyl-N-methylleucine (VII). The title dipeptide was finally obtained by HBTU-promoted coupling of amino acids (III) and (VII).
| 【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; N,N-dialkyl-dipeptidylamines as novel N-type calcium channel blockers. Bioorg Med Chem Lett 1999, 9, 6, 907. |
| 【2】 Szoke, B.G.; Rafferty, M.F.; Silva, D.F.; Song, Y.; Malone, T.C.; Hu, L.-Y.; Urge, L.; Nadasdi, L.; Ryder, T.R. (Neurex Corp.; Pfizer Inc.); Substd. peptidylamine calcium channel blockers. WO 9854123 . |
| 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) | 30396 | (2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | 54784-43-9 | C21H25NO5 | 详情 | 详情 |
| (II) | 30797 | tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-(tert-butylamino)-2-oxoethylcarbamate | C25H34N2O4 | 详情 | 详情 | |
| (III) | 30798 | (2S)-2-amino-3-[4-(benzyloxy)phenyl]-N-(tert-butyl)propanamide | C20H26N2O2 | 详情 | 详情 | |
| (IV) | 30799 | benzyl (2S)-4-methyl-2-(methylamino)pentanoate | C14H21NO2 | 详情 | 详情 | |
| (V) | 30800 | 3-bromo-1-cyclohexene | 1521-51-3 | C6H9Br | 详情 | 详情 |
| (VI) | 30801 | benzyl (2S)-2-[2-cyclohexen-1-yl(methyl)amino]-4-methylpentanoate | C20H29NO2 | 详情 | 详情 | |
| (VII) | 30802 | (2S)-2-[cyclohexyl(methyl)amino]-4-methylpentanoic acid | C13H25NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)Alternatively, the compound was prepared using polymer-supported resins. Dialkyl leucine (VII) was first treated with isobutyl chloroformate and morpholine resin, tyrosine derivative (III) was added, and was then treated with isocyanate resin and tris(2-aminomethyl)amine resin. Filtration of the insoluble resins provided a solution of pure dipeptide derivative.
| 【1】 Szoke, B.G.; Rafferty, M.F.; Silva, D.F.; Song, Y.; Malone, T.C.; Hu, L.-Y.; Urge, L.; Nadasdi, L.; Ryder, T.R. (Neurex Corp.; Pfizer Inc.); Substd. peptidylamine calcium channel blockers. WO 9854123 . |