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【结 构 式】 
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【分子编号】22252 【品名】Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate 【CA登记号】 |
【 分 子 式 】C13H19NO2 【 分 子 量 】221.2994 【元素组成】C 70.56% H 8.65% N 6.33% O 14.46% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reaction of N-(2-oxo-2-phenylethyl)acetamide (I) with glyoxylic acid (II) by means of NaHCO3 in water gives threo-(2RS)-3-acetylamino-2-hydroxy-4-oxo-4-phenylbutanoic acid (III), which is reduced with H2 over Pd/C in acetic acid yielding threo-(2RS)-3-acetylamino-2-hydroxy-4-phenylbutanoic acid (IV). The treatment of (IV) with (S)-1-phenylethylamine followed by a fractionated crystallization affords (2S,3R)-3-acetyl-amino-2-hydroxy-4-phenylbutanoic acid (IV), which is hydrolyzed with HCl in refluxing water to afford (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (V). The protection of (V) with benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate (VI) by means of triethylamine in dioxane - water gives (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (VII), which is condensed whh benzyl (S)-leucinate (VIII) by means of di-cyclohexylcarbodiimide and p-toluenesulfonic acid yielding benzyl (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyl-(S)-leucinate (IX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in acetic acid.
| 【1】 Umezawa, H.; Aoyagi, T.; Shirai, T.; Nishizawa, R.; Suzuki, M.; Saino, T. (Nippon Kayaku Co., Ltd.); Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them. DE 2947140; ES 486572; FR 2442227; GB 2090595; US 4281180 . |
| 【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Bestatin. Drugs Fut 1981, 6, 10, 604. |
| 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) | 14601 | N-(2-oxo-2-phenylethyl)acetamide | C10H11NO2 | 详情 | 详情 | |
| (II) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (III) | 32263 | (2S,3S)-3-(acetamido)-2-hydroxy-4-oxo-4-phenylbutyric acid; threo-(2RS)-3-acetamido-2-hydroxy-4-oxo-4-phenylbutyric acid | C12H13NO5 | 详情 | 详情 | |
| (IV) | 32264 | (2S,3R)-3-(acetamido)-2-hydroxy-4-phenylbutyric acid; threo-(2RS)-3-acetamido-2-hydroxy-4-phenylbutyric acid | C12H15NO4 | 详情 | 详情 | |
| (V) | 32265 | (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid; (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid | 62023-63-6 | C10H13NO3 | 详情 | 详情 |
| (VI) | 32266 | O-benzyl S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate; benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate | C14H14N2O2S | 详情 | 详情 | |
| (VII) | 32267 | (2S,3R)-3-benzyIoxycarbonyIamino-2-hydroxy-4-phenylbutyric acid; (2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid | C18H19NO5 | 详情 | 详情 | |
| (VIII) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (IX) | 32268 | benzyl (2S)-2-[((2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutanoyl)amino]-4-methylpentanoate; benzyl (2S,3R)-3-Benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyI-(S)-Ieucinate | C31H36N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Acylation of L-leucine benzyl ester (I) with bromoacetic acid (II) in the presence of DCC and DMAP gave bromoacetamide (III), which upon reaction with triphenyl phosphine was converted to phosphonium salt (IV). After treatment of (IV) with Et3N, the resulting ylide was condensed with N-Boc-L-leucine (V) to yield the acyl- phosphonate (VI). Acid deprotection of the N-Boc group of (VI) provided amine (VII), which was condensed with the depsipeptide (VIII) using EDC and HOBt yielding (IX). Removal of the N-Fmoc group from tetrapeptide (IX) was effected by treatment with piperidine in DMF, and the resulting amino compound was further condensed with protected L-asparagine (X) to furnish peptide (XI). After hydrogenolytic removal of the benzyl and carbobenzoxy groups of (XI), treatment with diphenyl phosphoryl azide and NaHCO3 produced the cyclic depsipeptide (XII).
| 【1】 Wasserman, H.H.; et al.; The chemistry of vicinal tricarbonyls: Total syntheses of elastase inhibitors YM-47141 and YM-47142. Helv Chim Acta 2000, 83, 9, 2607. |
| 【2】 Wasserman, H.H.; et al.; Total syntheses of depsipeptide elastase inhibitor. J Am Chem Soc 1999, 121, 6, 1401. |
| 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) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (II) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (III) | 23661 | benzyl (2S)-2-[(2-bromoacetyl)amino]-4-methylpentanoate | C15H20BrNO3 | 详情 | 详情 | |
| (IV) | 23662 | benzyl (2S)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate | C33H36NO3P | 详情 | 详情 | |
| (V) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VI) | 23664 | benzyl (2S)-2-[[(4S)-4-[(tert-butoxycarbonyl)amino]-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C44H53N2O6P | 详情 | 详情 | |
| (VII) | 23665 | benzyl (2S)-2-[[(4S)-4-amino-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C39H45N2O4P | 详情 | 详情 | |
| (VIII) | 23666 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid | C27H32N2O8 | 详情 | 详情 | |
| (IX) | 23667 | benzyl (5R,8S,9S,12S,17S)-9-[(tert-butoxycarbonyl)amino]-1-(9H-fluoren-9-yl)-12,17-diisobutyl-5,8-dimethyl-3,6,10,13,15-pentaoxo-14-(triphenylphosphoranylidene)-2,7-dioxa-4,11,16-triazaoctadecan-18-oate | C66H75N4O11P | 详情 | 详情 | |
| (X) | 23668 | C13H16N2O5 | 详情 | 详情 | ||
| (XI) | 23669 | C64H79N6O13P | 详情 | 详情 | ||
| (XII) | 23670 | C49H65N6O10P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Acylation of L-leucine benzyl ester (I) with bromoacetic acid (II) in the presence of DCC and DMAP gave bromoacetamide (III), which upon reaction with triphenyl phosphine was converted to phosphonium salt (IV). After treatment of (IV) with Et3N, the resulting ylide was condensed with N-Boc-L-leucine (V) to yield the acyl- phosphonate (VI). Acid deprotection of the N-Boc group of (VI) provided amine (VII), which was condensed with the depsipeptide (VIII) using EDC and HOBt yielding (IX). Removal of the N-Fmoc group from tetrapeptide (IX) was effected by treatment with piperidine in DMF, and the resulting amino compound was further condensed with protected L-asparagine (X) to furnish peptide (XI). After hydrogenolytic removal of the benzyl and carbobenzoxy groups of (XI), treatment with diphenyl phosphoryl azide and NaHCO3 produced the cyclic depsipeptide (XII).
| 【1】 Wasserman, H.H.; et al.; The chemistry of vicinal tricarbonyls: Total syntheses of elastase inhibitors YM-47141 and YM-47142. Helv Chim Acta 2000, 83, 9, 2607. |
| 【2】 Wasserman, H.H.; et al.; Total syntheses of depsipeptide elastase inhibitor. J Am Chem Soc 1999, 121, 6, 1401. |
| 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) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (II) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (III) | 23661 | benzyl (2S)-2-[(2-bromoacetyl)amino]-4-methylpentanoate | C15H20BrNO3 | 详情 | 详情 | |
| (IV) | 23662 | benzyl (2S)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate | C33H36NO3P | 详情 | 详情 | |
| (V) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VI) | 23664 | benzyl (2S)-2-[[(4S)-4-[(tert-butoxycarbonyl)amino]-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C44H53N2O6P | 详情 | 详情 | |
| (VII) | 23665 | benzyl (2S)-2-[[(4S)-4-amino-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C39H45N2O4P | 详情 | 详情 | |
| (VIII) | 23666 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid | C27H32N2O8 | 详情 | 详情 | |
| (IX) | 23667 | benzyl (5R,8S,9S,12S,17S)-9-[(tert-butoxycarbonyl)amino]-1-(9H-fluoren-9-yl)-12,17-diisobutyl-5,8-dimethyl-3,6,10,13,15-pentaoxo-14-(triphenylphosphoranylidene)-2,7-dioxa-4,11,16-triazaoctadecan-18-oate | C66H75N4O11P | 详情 | 详情 | |
| (X) | 23668 | C13H16N2O5 | 详情 | 详情 | ||
| (XI) | 23669 | C64H79N6O13P | 详情 | 详情 | ||
| (XII) | 23670 | C49H65N6O10P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Coupling of N-(Boc)-3-methyl-L-valine (I) with L-leucine benzyl ester (II) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) in the presence of N-ethylmorpholine gave the N-Boc-dipeptide (III), which was deprotected with trifluoroacetic acid in CH2Cl2 to afford (IV). Subsequent coupling of (IV) with N-Fmoc-2-methyl-L-phenylalanine (V) mediated by EDC and HOBt provided the N-Fmoc-tripeptide (VI). Deprotection of the fluorenylmethoxycarbonyl group of (VI) was effected with piperidine in CH2Cl2 to yield (VII). Further coupling and deprotection cycles with N-Fmoc-O-tert-butyl-L-glutamic acid (VIII) and then with N-Fmoc-O-tert-butyl-L-aspartic acid (X) provided peptides (IX) and (XI), respectively. This latter was then coupled to mono-tert--butyl succinate (XII) to furnish (XIII).
| 【1】 Attwood, M.R.; Campbell, A.D.; Bennett, J.M.; et al.; The design and synthersis of potent inhibitors of hepatitis C virus NS3-4A proteinase. Antivir Chem Chemother 1999, 10, 5, 259. |
| 【2】 Attwood, M.R.; Hurst, D.N.; Jones, P.S.; Kay, P.B.; Raynham, T.M.; Wilson, F.X. (F. Hoffmann-La Roche AG); Antiviral peptide derivs.. JP 2000508344; WO 9822496 . |
| 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) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (III) | 22253 | benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]amino)-4-methylpentanoate | C24H38N2O5 | 详情 | 详情 | |
| (IV) | 22254 | benzyl (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoate | C19H30N2O3 | 详情 | 详情 | |
| (V) | 22255 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid | C25H23NO4 | 详情 | 详情 | |
| (VI) | 22256 | benzyl (5S,8S,11S)-8-(tert-butyl)-1-(9H-fluoren-9-yl)-11-isobutyl-5-(2-methylbenzyl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate | C44H51N3O6 | 详情 | 详情 | |
| (VII) | 22257 | benzyl (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoate | C29H41N3O4 | 详情 | 详情 | |
| (VIII) | 22258 | (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 104091-08-9 | C24H27NO6 | 详情 | 详情 |
| (IX) | 22259 | benzyl (2S,5S,8S,11S)-11-amino-5-(tert-butyl)-2-isobutyl-16,16-dimethyl-8-(2-methylbenzyl)-4,7,10,14-tetraoxo-15-oxa-3,6,9-triazaheptadecan-1-oate | C38H56N4O7 | 详情 | 详情 | |
| (X) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XI) | 22261 | 1-benzyl 16-(tert-butyl) (2S,5S,8S,11S,14S)-14-amino-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecane-1,16-dioate | C46H69N5O10 | 详情 | 详情 | |
| (XII) | 22262 | 4-(tert-butoxy)-4-oxobutyric acid | C8H14O4 | 详情 | 详情 | |
| (XIII) | 22263 | 1-benzyl 19-(tert-butyl) (2S,5S,8S,11S,14S)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazanonadecane-1,19-dioate | C54H81N5O13 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Coupling of N-(Boc)-3-methyl-L-valine (I) with L-leucine benzyl ester (II) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) in the presence of N-ethylmorpholine gave the N-Boc-dipeptide (III), which was deprotected with trifluoroacetic acid in CH2Cl2 to afford (IV). Subsequent coupling of (IV) with N-Fmoc-2-methyl-L-phenylalanine (V) mediated by EDC and HOBt provided the N-Fmoc-tripeptide (VI). Deprotection of the fluorenylmethoxycarbonyl group of (VI) was effected with piperidine in CH2Cl2 to yield (VII). Further coupling and deprotection cycles with N-Fmoc-O-tert-butyl-L-glutamic acid (VIII) and then with N-Fmoc-O-tert-butyl-L-aspartic acid (X) provided peptides (IX) and (XI), respectively. This latter was then coupled to mono-tert--butyl succinate (XII) to furnish (XIII).
| 【1】 Attwood, M.R.; Hurst, D.N.; Jones, P.S.; Kay, P.B.; Raynham, T.M.; Wilson, F.X. (F. Hoffmann-La Roche AG); Antiviral peptide derivs.. JP 2000508344; WO 9822496 . |
| 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) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (III) | 22253 | benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]amino)-4-methylpentanoate | C24H38N2O5 | 详情 | 详情 | |
| (IV) | 22254 | benzyl (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoate | C19H30N2O3 | 详情 | 详情 | |
| (V) | 22255 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid | C25H23NO4 | 详情 | 详情 | |
| (VI) | 22256 | benzyl (5S,8S,11S)-8-(tert-butyl)-1-(9H-fluoren-9-yl)-11-isobutyl-5-(2-methylbenzyl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate | C44H51N3O6 | 详情 | 详情 | |
| (VII) | 22257 | benzyl (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoate | C29H41N3O4 | 详情 | 详情 | |
| (VIII) | 22258 | (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 104091-08-9 | C24H27NO6 | 详情 | 详情 |
| (IX) | 22259 | benzyl (2S,5S,8S,11S)-11-amino-5-(tert-butyl)-2-isobutyl-16,16-dimethyl-8-(2-methylbenzyl)-4,7,10,14-tetraoxo-15-oxa-3,6,9-triazaheptadecan-1-oate | C38H56N4O7 | 详情 | 详情 | |
| (X) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XI) | 22261 | 1-benzyl 16-(tert-butyl) (2S,5S,8S,11S,14S)-14-amino-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecane-1,16-dioate | C46H69N5O10 | 详情 | 详情 | |
| (XII) | 22262 | 4-(tert-butoxy)-4-oxobutyric acid | C8H14O4 | 详情 | 详情 | |
| (XIII) | 22263 | 1-benzyl 19-(tert-butyl) (2S,5S,8S,11S,14S)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazanonadecane-1,19-dioate | C54H81N5O13 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)By condensation of N-(perhydroazepin-1-ylcarbonyl)-L-leucine (V) with 4-O-benzyl-L-tyrosine tert-butyl ester (VIII) by means of HOBT and diisopropylethylamine in DMF. The two peptide intermediates (V) and (VIII) have been obtaines a follows: L-Leucine fragment (V): The carbonatation of perhydroazepine (I) with CO2 and pyridine followed by reaction with SOCl2 gives perhydroazepin-1-ylcarbonyl chloride (II), which is condensed with L-leucine benzyl ester (III) yielding the N-acylated leucine ester (IV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in THF to afford the target intermediate (V). Tyrosine fragment (VIII): By esterification of 4-O-benzyl-L-tyrosine (VI) with isobutylene (VII) by means of sulfuric acid in dioxane.
| 【1】 Malone, T.; et al.; Identification and SAR studies of PD 151307, a novel N-type calcium channel blocker. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 122. |
| 【2】 Roth, B.D.; Connor, D.T.; Malone, T.C.; Hamilton, H.W.; Rafferty, M.F.; Hu, L.-Y.; Cody, W.L.; He, J.X.; Nadasdi, L.; Brogley, L.; Urge, L.; Silva, D.F.; Song, Y.; Szoke, B.G.; Booth, R.J.; Lescosky, J. (Neurex Corp.; Pfizer Inc.); Peptidyl calcium channel blockers. US 6423689 . |
| 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) | 18672 | azepane | 111-49-9 | C6H13N | 详情 | 详情 |
| (II) | 26713 | 1-azepanecarbonyl chloride | C7H12ClNO | 详情 | 详情 | |
| (III) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (IV) | 26714 | benzyl (2S)-2-[(1-azepanylcarbonyl)amino]-4-methylpentanoate | C20H30N2O3 | 详情 | 详情 | |
| (V) | 26715 | (2S)-2-[(1-azepanylcarbonyl)amino]-4-methylpentanoic acid | C13H24N2O3 | 详情 | 详情 | |
| (VI) | 26716 | (2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid | 16652-64-5 | C16H17NO3 | 详情 | 详情 |
| (VII) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (VIII) | 26717 | tert-butyl (2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoate | C20H25NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XXX)Coupling between N-Boc-L-serine (XXIX) and L-leucine benzyl ester (XXX) furnished the Boc-dipeptide (XXXI), which was deprotected by means of a solution of HCl in isopropyl acetate. The resultant seryl-leucine benzyl ester (XXXII) was condensed with N-Boc-L-glutamine (XXXIII) to afford (XXXIV), which after N-Boc deprotection yielded tripeptide ester (XXXV). Further coupling of (XXXV) with N-Boc-L-cyclohexylglycine (XXXVI), followed by acidic deprotection, gave tetrapeptide (XXXVII). This was finally acylated with the glutaryl tripeptide (XXVIII) to provide the desired peptide intermediate (XVII).
| 【1】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 53673 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-1-{(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}-6,15-bis(hydroxymethyl)-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C52H72N8O15 | 详情 | 详情 |
| (XXVIII) | 53682 | (2S)-2-({(2S)-2-[({(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}carbonyl)amino]propanoyl}amino)-3-hydroxypropanoic acid | n/a | C30H35N3O9 | 详情 | 详情 |
| (XXIX) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (XXX) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (XXXI) | 53672 | benzyl (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl}amino)-4-methylpentanoate | n/a | C21H32N2O6 | 详情 | 详情 |
| (XXXII) | 53683 | benzyl (2S)-2-{[(2S)-2-amino-3-hydroxypropanoyl]amino}-4-methylpentanoate | n/a | C16H24N2O4 | 详情 | 详情 |
| (XXXIII) | 31820 | (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13726-85-7 | C10H18N2O5 | 详情 | 详情 |
| (XXXIV) | 53684 | benzyl (6S,9S,12S)-6-(3-amino-3-oxopropyl)-9-(hydroxymethyl)-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate | n/a | C26H40N4O8 | 详情 | 详情 |
| (XXXV) | 53685 | benzyl (2S)-2-[((2S)-2-{[(2S)-2,5-diamino-5-oxopentanoyl]amino}-3-hydroxypropanoyl)amino]-4-methylpentanoate | n/a | C21H32N4O6 | 详情 | 详情 |
| (XXXVI) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
| (XXXVII) | 53686 | benzyl (2S)-2-({(2S)-2-[((2S)-5-amino-2-{[(2S)-2-amino-2-cyclohexylethanoyl]amino}-5-oxopentanoyl)amino]-3-hydroxypropanoyl}amino)-4-methylpentanoate | n/a | C29H45N5O7 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VIII)Coupling between N-Boc-O-benzyl-L-threonine (VII) and L-leucine benzyl ester (VIII) by means of DCC/HOBt gives the protected dipeptide (IX). Subsequent N-Boc group cleavage in (IX) upon treatment with formic acid yields (X). Further coupling of dipeptide (X) with N-Boc-L-phenylalanine (XI), followed by formic acid deprotection, leads to the benzyl-protected tripeptide (XII).
| 【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 50782 | (2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid | C16H23NO5 | 详情 | 详情 | |
| (VIII) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (IX) | 65160 | benzyl (2S)-2-({(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)-4-methylpentanoate | C29H40N2O6 | 详情 | 详情 | |
| (X) | 65158 | benzyl (2S)-2-{[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino}-4-methylpentanoate | C24H32N2O4 | 详情 | 详情 | |
| (XI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XII) | 65159 | benzyl (2S)-2-{[(2S,3R)-2-{[(2S)-2-amino-3-phenylpropanoyl]amino}-3-(benzyloxy)butanoyl]amino}-4-methylpentanoate | C33H41N3O5 | 详情 | 详情 |