|
【结 构 式】 
|
【药物名称】YM-47142 【化学名称】[3R-(3alpha,6beta,9beta,17alpha,18alpha)]-6-(Carbamoylmethyl)-9,14-diisobutyl-3,18-dimethyl-17-(3-methylbutyryl-L-phenylalanyl-L-threonylamino)-1-oxa-4,7,10,15-tetraazacyclooctadecane-2,5,8,11,12,13,16-heptaone 【CA登记号】 【 分 子 式 】C43H64N8O13 【 分 子 量 】901.03533 |
【开发单位】Yamanouchi (Originator) 【药理作用】Antiarthritic Drugs, Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, Pulmonary Emphysema, Agents for, Respiratory Distress Syndrome, Agents for, RESPIRATORY DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Elastase Inhibitors |
合成路线1
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2
The tert-butoxycarbonyl and 4,4'-dimethoxybenzhydryl groups of (XII) were then deprotected using trifluoroacetic acid, and the resulting compound (XIII) was coupled with the isovaleryl dipeptide (XIV) to form (XV). Finally, the phosphorus ylide of (XV) was transformed to the desired carbonyl function by means of ozonolytic cleavage of the C=P double bond.
| 【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 |
|---|---|---|---|---|---|---|
| (XII) | 23670 | C49H65N6O10P | 详情 | 详情 | ||
| (XIII) | 23671 | 2-[(3R,6S,9S,14S,17S,18S)-17-amino-9,14-diisobutyl-3,18-dimethyl-2,5,8,11,13,16-hexaoxo-12-(triphenylphosphoranylidene)-1-oxa-4,7,10,15-tetraazacyclooctadecan-6-yl]acetamide | C43H55N6O8P | 详情 | 详情 | |
| (XIV) | 23674 | (2S,3S)-3-hydroxy-2-([(2S)-2-[(3-methylbutanoyl)amino]-3-phenylpropanoyl]amino)butyric acid | C18H26N2O5 | 详情 | 详情 | |
| (XV) | 23675 | (2S,3S)-N-[(3R,6S,9S,14S,17S,18S)-6-(2-amino-2-oxoethyl)-9,14-diisobutyl-3,18-dimethyl-2,5,8,11,13,16-hexaoxo-12-(triphenylphosphoranylidene)-1-oxa-4,7,10,15-tetraazacyclooctadecan-17-yl]-3-hydroxy-2-([(2S)-2-[(3-methylbutanoyl)amino]-3-phenylpropan | C61H79N8O12P | 详情 | 详情 |