(R)-benzyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate -Drug Synthesis Database

【结构式】

【分子编号】69393

【品名】(R)-benzyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate

【CA登记号】

【分子式】C₃₂H₃₉N₃O₄.C₂HF₃O₂

【分子量】643.703

【元素组成】C 63.44% H 6.26% F 8.85% N 6.53% O 14.91%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(V)

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 .

参考文献中间体

合成目标

【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：(V)

The tripeptide benzyl ester precursor (IV) is prepared by the following procedure. Condensation of N-Boc-L-leucine (X) with L-phenylalanine benzyl ester (XVIII) in the presence of DIEA, HOBt and PyBOP in acetonitrile gives the protected dipeptide (XIX), which upon deprotection by means of TFA in CH2Cl2 yields dipeptide (XX). Without isolation, intermediate (XX) is then condensed with N-Boc-L-homophenylalanine (XIV) in the presence of DEEA (diethyl-aminoethanol), HOBt and PyBOP in acetonitrile to provide protected tripeptide (XXI) , which is finally N-deprotected by means of TFA in CH2Cl2 .

参考文献中间体

合成目标

【1】 Smyth, M.S., Laidig, G.J. (Proteolix, Inc.). Compounds for proteasome enzyme inhibition. CA 2589765, EP 1781688, JP 2008509166, US 2009131421, WO 2006017842.
【2】 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.
【3】 Smyth, M.S., Laidig, G.J. (Proteolix, Inc.). Compounds for enzyme inhibition. US 2006030533, US 7417042.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(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
(X)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	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
(XVIII)	27693	benzyl (2S)-2-amino-3-phenylpropanoate；L-phenylalanine benzyl ester		C₁₆H₁₇NO₂	详情	详情
(XIX)	69402	(R)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-phenylpropanoate		C₂₇H₃₆N₂O₅	详情	详情
(XX)	69403	(R)-benzyl 2-((S)-2-amino-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate		C₂₂H₂₈N₂O₃.C₂HF₃O₂	详情	详情
(XXI)	69404	(6S,9S,12R)-benzyl 12-benzyl-9-isobutyl-2,2-dimethyl-4,7,10-trioxo-6-phenethyl-3-oxa-5,8,11-triazatridecan-13-oate		C₃₇H₄₇N₃O₆	详情	详情

Extended Information