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【结 构 式】 
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【药物名称】PR-171;Carfilzomib 【化学名称】N-[2(S)-[2-(4-Morpholinyl)acetamido]-4-phenylbutyryl]-L-leucyl-N1-[3-methyl-1(S)-[2(R)-methyloxiran-2-ylcarbonyl]butyl]-L-phenylalaninamide 【CA登记号】868540-17-4 【 分 子 式 】C40H57N5O7 【 分 子 量 】719.9099 |
【开发单位】Proteolix, Inc. (US) 【药理作用】Proteasome Inhibitor;Oncolytic |
合成路线1
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
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 |
合成路线3
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 .
| 【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 |
合成路线4
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) .
| 【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 | CAS号 | 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 |
合成路线5
Condensation of N-Boc-leucine (X) with N,O-dimethylhydroxylamine hydrochloride by means of i-BuOCOCl, NMM and Et3N in CH2Cl2 gives N-Boc-L-leucine Weinreb amide (XXVII) , which is then coupled with isopropenyl magnesium bromide (XXVIII) in THF (1) or 2-bromopropene (XXIX) in the presence of BuLi in Et2O at –78 °C to yield the heptenone derivative (XXX) . Reduction of heptenone (XXX) with NaBH4 and CeCl3·7H2O in MeOH results in a diastereomeric mixture of allylic alcohols (XXXIa) and (XXXIb), which is then epoxidized by treatment with mCPBA in CH2Cl2 to afford a mixture of oxiranes (XXXIIa) and (XXXIIb). Finally, this mixture is oxidized with Dess Martin periodinane in acetonitrile, followed by chromatographic separation . Compound (XXVI) can also be prepared by epoxidation of heptenone derivative (XXX) with H2O2 in the presence of PhCN and DIEA in MeOH or NaOCl in pyridine or Ca(OCl)2 in NMP , followed by separation by means of column chromatography .
| 【2】 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. |
| 【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 |
|---|---|---|---|---|---|---|
| (XXXIa) | 69411 | tert-butyl ((3S,4R)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate | C14H27NO3 | 详情 | 详情 | |
| (XXXIb) | 69412 | tert-butyl ((3R,4R)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate | C14H27NO3 | 详情 | 详情 | |
| (XXXIIa) | 69413 | tert-butyl ((1R,2S)-1-hydroxy-4-methyl-1-(2-methyloxiran-2-yl)pentan-2-yl)carbamate | C14H27NO4 | 详情 | 详情 | |
| (XXXIIb) | 69414 | tert-butyl ((1S,2S)-1-hydroxy-4-methyl-1-(2-methyloxiran-2-yl)pentan-2-yl)carbamate | C14H27NO4 | 详情 | 详情 | |
| (X) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 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 | |
| (XXVII) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (XXVIII) | 43649 | bromo(isopropenyl)magnesium；isopropenyl magnesium bromide；1-Methylvinylmagnesiumbromide;1-Propen-2-ylmagnesium bromide;a-Methylvinylmagnesium bromide | 13291-18-4 | C3H5BrMg | 详情 | 详情 |
| (XXIX) | 42375 | 2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide | 557-93-7 | C3H5Br | 详情 | 详情 |
| (XXX) | 43027 | tert-butyl (1S)-1-isobutyl-3-methyl-2-oxo-3-butenylcarbamate | C14H25NO3 | 详情 | 详情 |