WO2015121769A1 - Procédé pour la préparation de méthyl n-[(benzyloxy)-carbonyl]-l-leucyl-l-phénylalaninate - Google Patents
Procédé pour la préparation de méthyl n-[(benzyloxy)-carbonyl]-l-leucyl-l-phénylalaninate Download PDFInfo
- Publication number
- WO2015121769A1 WO2015121769A1 PCT/IB2015/050763 IB2015050763W WO2015121769A1 WO 2015121769 A1 WO2015121769 A1 WO 2015121769A1 IB 2015050763 W IB2015050763 W IB 2015050763W WO 2015121769 A1 WO2015121769 A1 WO 2015121769A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- phenylalaninate
- benzyloxy
- carbonyl
- methyl
- Prior art date
Links
- USPFMEKVPDBMCG-LBPRGKRZSA-N CC(C)C[C@@H](C(O)=O)NC(OCc1ccccc1)=O Chemical compound CC(C)C[C@@H](C(O)=O)NC(OCc1ccccc1)=O USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 1
- VSDUZFOSJDMAFZ-VIFPVBQESA-N COC([C@H](Cc1ccccc1)N)=O Chemical compound COC([C@H](Cc1ccccc1)N)=O VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
Definitions
- the present invention provides a process for the preparation of methyl N-
- Carfilzomib is a proteasome inhibitor disclosed in U.S. Patent Nos. 7,417,042 and 7,232,818. It is chemically designated as (25)-JV-((5)-l-((5)-4-methyl-l-((R)-2- methyloxiran-2-yl)-l-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((5)-2-(2- mo ⁇ holinoacetamido)-4-phenylbutanamido)-4-methylpentanamide, having the structure depicted b Formula I.
- U.S. Patent No. 8,367,617 discloses a process for the preparation ofN- [(benzyloxy)carbonyl] -protected L-leucyl-L-phenylalaninate by reacting methyl L- phenylalaninate with N-[(benzyloxy)carbonyl] -protected L-leucine in the presence of hydroxybenzotriazole (HOBT), N ⁇ V-diisopropylethylamine (DIEA) and (benzotriazol- 1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP).
- HOBT hydroxybenzotriazole
- DIEA N ⁇ V-diisopropylethylamine
- BOP benzotriazol- 1- yloxy
- Such reactions are not eco-friendly and not preferred at industrial scale. Also, these reactions are exothermic in nature, and produce carcinogenic hexamethylphosphoramide
- the present invention provides an efficient, cost effective, less time consuming, and industrially feasible process for the preparation of methyl N-[(benzyloxy)carbonyl]-L- leucyl-L-phenylalaninate of Formula II, which employs boric acid as a catalyst.
- boric acid as a catalyst.
- the advantage of using boric acid is that it is readily available, inexpensive, and non-toxic.
- the present invention provides a process for the preparation of methyl N- [(benzyloxy)carbonyl] -L-leucyl-L-phenylalaninate of Formula II, which is used as an intermediate for the preparation of carfilzomib.
- a first aspect of the present invention provides a process for the preparation of methyl N-[(benzyloxy)carbon l] -L-leucyl-L-phenylalaninate of Formula II,
- a second aspect of the present invention provides a process for the preparation of carfilzomib of Formula I,
- salt refers to the acid addition salts of a compound, wherein the acid can be selected from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, or the like) or organic acids (e.g., formic acid, acetic acid, lactic acid, malonic acid, citric acid, quinic acid, succinic acid, oxalic acid, maleic acid, tartaric acid, fumaric acid, and camphor sulfonic acid).
- inorganic acids e.g., hydrochloric acid, hydrobromic acid, or the like
- organic acids e.g., formic acid, acetic acid, lactic acid, malonic acid, citric acid, quinic acid, succinic acid, oxalic acid, maleic acid, tartaric acid, fumaric acid, and camphor sulfonic acid.
- the methyl L-phenylalaninate of Formula III or its salt can be prepared according to the process disclosed in Organic & Biomolecular Chemistry, 4(22) p. 4206-4213 (2006).
- N-[(benzyloxy)carbonyl]-L-leucine of Formula IV can be prepared according to the process disclosed in European Patent No. EP 1 908 761.
- [(benzyloxy)carbonyl]-L-leucyl -L-phenylalaninate of Formula II is carried out in the presence of boric acid, a base, and a solvent at a temperature of about 20°C to the reflux temperature of the solvent.
- the base to be used for the condensation of methyl L-phenylalaninate of Formula III or its salt with N-[(benzyloxy)carbonyl]-L-leucine of Formula IV can be selected from inorganic and organic bases.
- inorganic bases include sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
- organic bases examples include NN- diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-fert-butyl-4- dimethylaminopyridine, l,4-diazabicyclo[2.2.2]-octane, l,8-Diazabicyclo[5.4.0]undec-7- ene, and mixtures thereof.
- a preferred base used in the condensation reaction is sodium bicarbonate.
- the solvent to be used for the condensation of methyl L-phenylalaninate of Formula III or its salt with N-[(benzyloxy)carbonyl]-L-leucine of Formula IV can be selected from aromatic hydrocarbons, nitriles, chlorinated hydrocarbons, and mixtures thereof.
- aromatic hydrocarbons include toluene and xylene.
- nitriles include acetonitrile, propionitrile, butyronitrile, and valeronitrile.
- Examples of chlorinated hydrocarbons include dichloromethane, dichloroethane, chlorobenzene, and chloroform.
- a preferred solvent used in the condensation reaction is toluene.
- Formula II into carfilzomib can be carried out by processes known in the art, such as by the processes disclosed in U.S. Patent Nos. 7,417,042 and 8,367,617, which are incorporated herein by reference.
- methyl L-phenylalaninate hydrochloride (Formula III; 5.0 g) and toluene (100 mL) were added at about 25°C to about 35°C.
- saturated sodium bicarbonate solution (4 g in 50 mL of deionized water) was added while stirring.
- the reaction mixture was stirred at about 45 °C to about 50°C for about 30 minutes. The layers were allowed to settle and the toluene layer was separated.
- the toluene layer was added to another round bottom flask containing N- [(benzyloxy)carbonyl]-L-leucine (Formula IV; 6.15 g) and boric acid (1.43 g) at about 25°C to about 35°C.
- the reaction mixture was stirred and heated to reflux for about 4 hours to about 6 hours. Water was removed azeotropically from the reaction mixture.
- the reaction mixture was allowed to cool at about 25°C to about 35°C for about 1 hour, and then the solid obtained was filtered. The filtrate was collected and washed with saturated sodium bicarbonate solution (4 g in 50 mL of deionized water).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN405/DEL/2014 | 2014-02-13 | ||
IN405DE2014 | 2014-02-13 |
Publications (1)
Publication Number | Publication Date |
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WO2015121769A1 true WO2015121769A1 (fr) | 2015-08-20 |
Family
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PCT/IB2015/050763 WO2015121769A1 (fr) | 2014-02-13 | 2015-02-02 | Procédé pour la préparation de méthyl n-[(benzyloxy)-carbonyl]-l-leucyl-l-phénylalaninate |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050256324A1 (en) | 2004-05-10 | 2005-11-17 | Proteolix, Inc. | Synthesis of amino acid keto-epoxides |
US7232818B2 (en) | 2004-04-15 | 2007-06-19 | Proteolix, Inc. | Compounds for enzyme inhibition |
EP1908761A1 (fr) | 2006-10-04 | 2008-04-09 | Speedel Experimenta AG | Composés organiques |
US8207297B2 (en) | 2004-04-15 | 2012-06-26 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8367617B2 (en) | 2007-10-04 | 2013-02-05 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
-
2015
- 2015-02-02 WO PCT/IB2015/050763 patent/WO2015121769A1/fr active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7232818B2 (en) | 2004-04-15 | 2007-06-19 | Proteolix, Inc. | Compounds for enzyme inhibition |
US8207297B2 (en) | 2004-04-15 | 2012-06-26 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US20050256324A1 (en) | 2004-05-10 | 2005-11-17 | Proteolix, Inc. | Synthesis of amino acid keto-epoxides |
US7417042B2 (en) | 2004-08-06 | 2008-08-26 | Proteolix, Inc. | Compounds for enzyme inhibition |
EP1908761A1 (fr) | 2006-10-04 | 2008-04-09 | Speedel Experimenta AG | Composés organiques |
US8367617B2 (en) | 2007-10-04 | 2013-02-05 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
Non-Patent Citations (4)
Title |
---|
KONRAD JASTRZABEK ET AL: "Bis(4,6-dimethoxy-1,3,5-triazin-2-yl) Ether as Coupling Reagent for Peptide Synthesis", CHEMISTRY & BIODIVERSITY, vol. 10, no. 5, 17 May 2013 (2013-05-17), pages 952 - 961, XP055179340, ISSN: 1612-1872, DOI: 10.1002/cbdv.201200369 * |
NOMURA R ET AL: "Facile One-Pot Amidation of Carboxylic Acids by Amines Catalyzed by Triphenylstibine Oxide/Tetraphosphorus Decasulfide (Ph3SbO/P4S10)", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 56, no. 12, 1 January 1991 (1991-01-01), pages 4076 - 4078, XP002542730, ISSN: 0022-3263, DOI: 10.1021/JO00012A058 * |
ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 4, no. 22, 2006, pages 4206 - 4213 |
VIJAYA R. PATTABIRAMAN ET AL: "Rethinking amide bond synthesis", NATURE, vol. 480, no. 7378, 21 December 2011 (2011-12-21), pages 471 - 479, XP055084032, ISSN: 0028-0836, DOI: 10.1038/nature10702 * |
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