2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one trifluoroacetate salt -Drug Synthesis Database

【结构式】

【分子编号】69396

【品名】2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one trifluoroacetate salt

【CA登记号】

【分子式】C₉H₁₇NO₂.C₂HF₃O₂

【分子量】285.263

【元素组成】C 46.32% H 6.36% F 19.98% N 4.91% O 22.43%

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：(VIII)

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：(VIII)

The epoxide building blocks (VIII) and (IX) are prepared starting from N-Cbz-4(S)-amino-2,6-dimethyl-1-hepten-3-one (XXII). Reduction of ketone (XXII) with NaBH4 in the presence of CeCl3·7H2O in MeOH gives a diastereomeric mixture of allylic alcohols (XXIIIa) and (XXIIIb), which by epoxidation with mCPBA in CH2Cl2 or VO(acac)2 and t-BuOOH also in CH2Cl2 yields a mixture of oxiranes (XXIVa) and (XXIVb). Oxidation of the mixture of alcohols (XXIVa) and (XXIVb) by means of NMO and TPAP in CH2Cl2 or Dess Martin periodinane in DMSO or by Swern oxidation (treatment with DMSO and [COCl]2 in CH2Cl2, followed by Et3N in CH2Cl2), and then chromatographic separation of the diastereomers affords N-Cbz-2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one (XXV) , which is then deprotected by transfer hydrogenation with HCOOH and Pd/C or by catalytic hydrogenation over Pd/C in the presence of TFA, providing the corresponding formic acid salt (IX) and TFA salt (VIII) . Alternatively, deprotection of the epoxy amino acid (XXVI) by means of TFA also gives the TFA salt (VIII) .

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】 Laidig, G.J., Radel, P.A., Smyth, M.S. (Proteolix, Inc.). Synthesis of amino acid keto-epoxides. EP 1756079, JP 2007538081, US 2005256324, WO 2005111009.
【3】 Sin, N., Kim, K.B., Elofsson, M., Meng, L., Auth, H., Kwok, B.H.B., Crews, C.M. Total synthesis of the potent proteasome inhibitor epoximicin: A useful tool for understanding proteosome biology. Bioorg Med Chem Lett 1999, 9(15): 2283-8.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXIIIa)	69406	benzyl ((3S,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate	C₁₇H₂₅NO₃	详情	详情
(XXIIIb)	69407	benzyl ((3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate	C₁₇H₂₅NO₃	详情	详情
(XXIVa)	69408	benzyl ((1S,2S)-1-hydroxy-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-2-yl)carbamate	C₁₇H₂₅NO₄	详情	详情
(XXIVb)	69409	benzyl ((1R,2S)-1-hydroxy-4-methyl-1-((R)-2-methyloxiran-2-yl)pentan-2-yl)carbamate	C₁₇H₂₅NO₄	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
(XXII)	69405	(R)-benzyl (2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate	C₁₇H₂₃NO₃	详情	详情
(XXV)	69410	benzyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；N-Cbz-2(S)-amino-4-methyl-1-[2(R)-methyloxiran-2-yl]pentan-1-one	C₁₇H₂₃NO₄	详情	详情
(XXVI)	43028	tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；tert-butyl (1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butylcarbamate	C₁₄H₂₅NO₄	详情	详情

Extended Information