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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 PDF

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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
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2015/050763
Other languages
English (en)
Inventor
Prakash Bhimaji Kshirsagar
Satish Manohar Bhoge
Anand Prakash Tiwari
Kaptan Singh
Mohan Prasad
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2015121769A1 publication Critical patent/WO2015121769A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

L'invention concerne un procédé de préparation de méthyl N-[(benzyloxy)-carbonyl]-l-leucyl-l-phénylalaninate de formule (II), qui peut être utilisé comme intermédiaire pour la préparation de carfilzomib.
PCT/IB2015/050763 2014-02-13 2015-02-02 Procédé pour la préparation de méthyl n-[(benzyloxy)-carbonyl]-l-leucyl-l-phénylalaninate Ceased WO2015121769A1 (fr)

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
WO2015121769A1 true WO2015121769A1 (fr) 2015-08-20

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/050763 Ceased WO2015121769A1 (fr) 2014-02-13 2015-02-02 Procédé pour la préparation de méthyl n-[(benzyloxy)-carbonyl]-l-leucyl-l-phénylalaninate

Country Status (1)

Country Link
WO (1) WO2015121769A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022134673A (ja) * 2021-03-03 2022-09-15 国立大学法人東海国立大学機構 アミド及びペプチドの製造方法

Citations (5)

* Cited by examiner, † Cited by third party
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

Patent Citations (6)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022134673A (ja) * 2021-03-03 2022-09-15 国立大学法人東海国立大学機構 アミド及びペプチドの製造方法
JP7667998B2 (ja) 2021-03-03 2025-04-24 国立大学法人東海国立大学機構 アミド及びペプチドの製造方法

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