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【结 构 式】

【分子编号】69390

【品名】(R)-methyl 2-((S)-2-((R)-2-(2-chloroacetamido)-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate

【CA登记号】

【 分 子 式 】C28H36ClN3O5

【 分 子 量 】530.064

【元素组成】C 63.45% H 6.85% Cl 6.69% N 7.93% O 15.09%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(I)

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

合成路线2

该中间体在本合成路线中的序号:(I)

Condensation of N-Boc-L-leucine (X) with L-phenylalanine methyl ester (XI) in the presence of DIEA, HOBt and BOP in DMF gives the protected dipeptide (XII). Dipeptide (XII) is then deprotected by means of TFA in CH2Cl2 to yield L-Leu-L-Phe-OMe trifluoroacetate salt (XIII), which without isolation is then condensed with N-Boc-Lhomophenylalanine (XIV) in the presence of DIEA, HOBt and BOP in acetonitrile to yield the protected tripeptide (XV) . Then, N-deprotection of peptide (XV) by means of TFA in CH2Cl2 gives tripeptide (XVI), which is finally coupled with chloroacetyl chloride (XVII) in the presence of DIEA in DMF .

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.
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
(X) 23663 (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine C11H21NO4 详情 详情
(XI) 12324 methyl (2R)-2-amino-3-phenylpropanoate 21685-51-8 C10H13NO2 详情 详情
(XII) 69398 L-Phenylalanine,N-[(1,1-dimethylethoxy)carbonyl]-L-leucyl-, methyl ester;tert-butyloxycarbonyl-leucylphenylalanine methyl ester;(R)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-phenylpropanoate 5874-73-7 C21H32N2O5 详情 详情
(XIII) 69399 (R)-methyl 2-((S)-2-amino-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate;L-Leu-L-Phe-OMe trifluoroacetate salt C16H24N2O3.C2HF3O2 详情 详情
(XIV) 12874 (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine 13734-34-4 C14H19NO4 详情 详情
(XV) 69400 (6S,9S,12R)-methyl 12-benzyl-9-isobutyl-2,2-dimethyl-4,7,10-trioxo-6-phenethyl-3-oxa-5,8,11-triazatridecan-13-oate C31H43N3O6 详情 详情
(XVI) 69401 (R)-methyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate C26H35N3O4.C2HF3O2 详情 详情
(XVII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
Extended Information