WO2015121769A1 - Process for the preparation of methyl n-[(benzyloxy)-carbonyl]-l-leucyl-l-phenylalaninate - Google Patents
Process for the preparation of methyl n-[(benzyloxy)-carbonyl]-l-leucyl-l-phenylalaninate Download PDFInfo
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- 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
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- phenylalaninate
- benzyloxy
- carbonyl
- methyl
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- 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
The present invention provides a process for the preparation of methyl N- [(benzyloxy)carbonyl]-L-leucyl-L-phenylalaninate of Formula (II), which can be used as an intermediate for the preparation of carfilzomib.
Description
PROCESS FOR THE PREPARATION OF METHYL 7V-[(BENZYLOXY)- CARBONYLJ-L-LEUCYL-L-PHENYLALANINATE
Field of the Invention
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.
Formula II
Background of the Invention
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- moφholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide, having the structure depicted b Formula I.
Formula I
Processes for the preparation of carfilzomib and its intermediates are disclosed in U.S. Patent Nos. 8,207,297 and 8,367,617, and U.S. Publication No. 2005/0256324.
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). Such reactions are not eco-friendly and not preferred at industrial scale. Also, these reactions are exothermic in nature, and produce carcinogenic hexamethylphosphoramide as a by-product.
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. The advantage of using boric acid is that it is readily available, inexpensive, and non-toxic.
Summary of the Invention
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,
Formula II
comprising condensing methyl L-phenylalaninate of Formula III or its salt with N- [(benzyloxy)carbonyl] -L-leucine of Formula IV in the presence of boric acid.
Formula III Formula IV
A second aspect of the present invention provides a process for the preparation of carfilzomib of Formula I,
Formula I
the steps of:
condensing methyl L-phenylalaninate of Formula III or its salt with N- [(benzyloxy)carbonyl]-L-leucine of Formula IV in the resence of boric acid
Formula III Formula IV to obtain methyl N-[(benzyloxy)carbonyl]-L-leucyl -L-phenylalaninate of Formula II: and
Formula II
ii) converting the methyl N-[(benzyloxy)carbonyl]-L-leucyl-L-phenylalaninate of Formula II to carfilzomib of Formula I.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "salt," as used herein, 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).
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).
The N-[(benzyloxy)carbonyl]-L-leucine of Formula IV can be prepared according to the process disclosed in European Patent No. EP 1 908 761.
The condensation of methyl L-phenylalaninate of Formula III or its salt with N- [(benzyloxy)carbonyl]-L-leucine of Formula IV to obtain methyl N-
[(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. Examples of inorganic bases include sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Examples of organic bases 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. Examples of aromatic hydrocarbons include toluene and xylene. Examples of 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.
The conversion of methyl N-[(benzyloxy)carbonyl]-L-leucyl -L-phenylalaninate of
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.
Example: Preparation of methyl N-r(benzyloxy)carbonyll-L-leucyl-L-phenylalaninate (Formula ID
In a round bottom flask, methyl L-phenylalaninate hydrochloride (Formula III; 5.0 g) and toluene (100 mL) were added at about 25°C to about 35°C. To the solution, 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). The layers were separated and the toluene layer was concentrated under vacuum at about 45 °C to obtain methyl N- [(benzyloxy)carbonyl]-L-leucyl -L-phenylalaninate as a thick oily residue.
Yield: 60%.
Claims
We Claim:
1. A process for the preparation of methyl N-[(benzyloxy)carbonyl]-L-leucyl-L- phenylalaninate of Formula II
Formula II
comprising condensing methyl L-phenylalaninate of Formula III or its salt with N- [(benzyloxy)carbonyl]-L-leucine of Formula IV in the resence of boric acid.
Formula III Formula IV
2. The process according to claim 1, wherein the condensation of methyl L- phenylalaninate of Formula III or its salt with N-[(benzyloxy)carbonyl]-L-leucine of Formula IV is carried out in the presence of a base.
3. The process according to claim 2, wherein the base is selected from inorganic and organic bases.
4. The process according to claim 2, wherein the base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, N,N-diisopropylethylamine, triethylamine, triisopropylamine, N,N-2-trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-tert-butyl-4-dimethylaminopyridine, 1,4- diazabicyclo[2.2.2]-octane, l,8-diazabicyclo[5.4.0]undec-7-ene, and mixtures thereof. 5. The process according to claim 2, wherein the base is sodium bicarbonate.
6. The process according to claim 1, wherein the condensation of methyl L- phenylalaninate of Formula III or its salt with N-[(benzyloxy)carbonyl]-L-leucine of Formula IV is carried out in the presence of a solvent.
7. The process according to claim 6, wherein the solvent is selected from aromatic hydrocarbons, nitriles, chlorinated hydrocarbons, and mixtures thereof.
8. The process according to claim 6, wherein the solvent is selected from the group consisting of toluene, xylene, acetonitrile, propionitrile, butyronitrile, valeronitrile, dichloromethane, dichloroethane, chlorobenzene, and chloroform.
9. The process according to claim 6, wherein the solvent is toluene.
10. The process according to claim 1, further comprising converting the methyl N- [(benzyloxy)carbonyl]-L-leucyl-L-phenylalaninate of Formula II to carfilzomib of Formula I
Formula I
A process for the reparation of carfilzomib of Formula I,
comprising the steps of:
i) condensing methyl L-phenylalaninate of Formula III or its salt with N- [(benzyloxy)carbonyl]-L-leucine of Formula IV in the presence of boric acid
Formula III Formula IV to obtain methyl N-[(benzyloxy)carbonyl]-L-leucyl-L-phenylalaninate of Formula II: and
Formula II
ii) converting the methyl N-[(benzyloxy)carbonyl]-L-leucyl-L-phenylalaninate of
Formula II to carfilzomib of Formula I.
12. The process according to claim 11, wherein the condensation of methyl L- phenylalaninate of Formula III or its salt with N-[(benzyloxy)carbonyl]-L-leucine of Formula IV is carried out in the presence of sodium bicarbonate as a base and toluene as a solvent.
13. The process according to claim 11, wherein the condensation of methyl L- phenylalaninate of Formula III or its salt with N-[(benzyloxy)carbonyl]-L-leucine of Formula IV is carried out in the presence of sodium bicarbonate.
14. The process according to claim 11, wherein the condensation of methyl L- phenylalaninate of Formula III or its salt with N-[(benzyloxy)carbonyl]-L-leucine of Formula IV is carried out in the presence of toluene.
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| IN405/DEL/2014 | 2014-02-13 | ||
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022134673A (en) * | 2021-03-03 | 2022-09-15 | 国立大学法人東海国立大学機構 | Method for producing amides and peptides |
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2015
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| 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 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022134673A (en) * | 2021-03-03 | 2022-09-15 | 国立大学法人東海国立大学機構 | Method for producing amides and peptides |
| JP7667998B2 (en) | 2021-03-03 | 2025-04-24 | 国立大学法人東海国立大学機構 | Methods for Producing Amides and Peptides |
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