|
【结 构 式】 
|
【分子编号】69392 【品名】(R)-2-((S)-4-methyl-2-((R)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoic acid 【CA登记号】 |
【 分 子 式 】C31H42N4O6 【 分 子 量 】566.698 【元素组成】C 65.70% H 7.47% N 9.89% O 16.94% |
合成路线1
该中间体在本合成路线中的序号：(IV)Condensation of the chloroacetyl tripeptide (I) with morpholine (II) by means of KI in THF gives the tetrapeptide derivative (III), which is hydrolyzed with LiOH in MeOH/H2O to yield the corresponding carboxylic acid (IV) . Alternatively, reaction of the trifluoroacetate salt of tripeptide (V) with 4-morpholinoacetic acid (VI) in the presence of DIEA and PyBOP in DMF affords the tetrapeptide benzyl ester (VII), which is then debenzylated by means of H2 over Pd/C in MeOH/EtOAc to give the carboxylic acid (IV) . Finally, the carboxylic acid building block (IV) is coupled with either 2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one trifluoroacetate salt (VIII) in the presence of DIEA, HOBt and PyBOP in acetonitrile , or BOP in DMF, or HBTU in DMF or acetonitrile , or with the formic acid salt (IX) by means of DIEA, HOBt and HBTU in acetonitrile . The corresponding citrate salt is prepared by treatment of carfilzomib with citric acid in THF .
| 【1】 Phiasivongsa, P., Sehl, L.C., Fuller, W.D., Laidig, G.J. (Proteolix, Inc.). Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides. WO 2009045497. |
| 【2】 Smyth, M.S., Laidig, G.J. (Proteolix, Inc.). Compounds for proteasome enzyme inhibition. CA 2589765, EP 1781688, JP 2008509166, US 2009131421, WO 2006017842. |
| 【4】 Smyth, M.S., Laidig, G.J. (Proteolix, Inc.). Compounds for enzyme inhibition. US 2006030533, US 7417042. |
| 【3】 Smyth, M.S., Laidig, G.J., Borchardt, R.T. et al. (Proteolix, Inc.). Compounds for proteasome enzyme inhibition. EP 1745064, JP 2008501637, US 2005245435, US 2008200398, US 7232818, WO 2005105827. |
| 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) | 69390 | (R)-methyl 2-((S)-2-((R)-2-(2-chloroacetamido)-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate | C28H36ClN3O5 | 详情 | 详情 | |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 69391 | (R)-methyl 2-((S)-4-methyl-2-((R)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoate | C32H44N4O6 | 详情 | 详情 | |
| (IV) | 69392 | (R)-2-((S)-4-methyl-2-((R)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoic acid | C31H42N4O6 | 详情 | 详情 | |
| (V) | 69393 | (R)-benzyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate | C32H39N3O4.C2HF3O2 | 详情 | 详情 | |
| (VI) | 69394 | 4-morpholinoacetic acid;2-(4-Morpholinyl)aceticacid;2-(Morpholino)acetic acid;Morpholin-4-ylaceticacid;Morpholinoacetic acid;N-(Carboxymethyl)morpholine | 3235-69-6 | C6H11NO3 | 详情 | 详情 |
| (VII) | 69395 | (R)-benzyl 2-((S)-4-methyl-2-((R)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamido)-3-phenylpropanoate | C38H48N4O6 | 详情 | 详情 | |
| (VIII) | 69396 | 2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one trifluoroacetate salt | C9H17NO2.C2HF3O2 | 详情 | 详情 | |
| (IX) | 69397 | (S)-2-amino-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-1-one formate | C9H17NO2.CH2O2 | 详情 | 详情 |