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US20160115198A1 - Methods of making carfilzomib and intermediates thereof - Google Patents

Methods of making carfilzomib and intermediates thereof Download PDF

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Publication number
US20160115198A1
US20160115198A1 US14/923,068 US201514923068A US2016115198A1 US 20160115198 A1 US20160115198 A1 US 20160115198A1 US 201514923068 A US201514923068 A US 201514923068A US 2016115198 A1 US2016115198 A1 US 2016115198A1
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US
United States
Prior art keywords
compound
formula
carfilzomib
compound according
making
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.)
Abandoned
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US14/923,068
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English (en)
Inventor
Ravishanker Kovi
Jayaraman Kannapan
Vasanthakumar G Ramu
Alaparthi Lakshmi Prasad
Talluri Bhushaiah Chowdary
Gaurav Kulkarni
Saiyed Akeel Ahmed Shakeel Ahmed
Veerabhadra Rao Bobbili
N V Raghavalu Dusanapudi
Anand V. Mantri
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.)
Mylan Pharmaceuticals Inc
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Apicore US LLC
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Priority to US14/923,068 priority Critical patent/US20160115198A1/en
Assigned to APICORE US LLC reassignment APICORE US LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHOWDARY, Talluri Bhushaiah, MANTRI, ANAND V., PRASAD, ALAPARTHI LAKSHMI, KULKARNI, GAURAV, RAMU, VASANTHAKUMAR G., AHMED, SAIYED AKEEL AHMED SHAKEEL, BOBBILI, VEERABHADRA RAO, DUSANAPUDI, N V RAGHAVALU, KANNAPAN, JAYARAMAN, KOVI, RAVISHANKER
Publication of US20160115198A1 publication Critical patent/US20160115198A1/en
Priority to US15/228,689 priority patent/US9822145B2/en
Assigned to MEDICURE INC. reassignment MEDICURE INC. SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: APICORE US LLC
Assigned to APICORE US LLC reassignment APICORE US LLC RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MEDICURE INC.
Priority to US15/785,966 priority patent/US20180037606A1/en
Assigned to MYLAN API US LLC reassignment MYLAN API US LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: APICORE US LLC
Assigned to MYLAN PHARMACEUTICALS INC. reassignment MYLAN PHARMACEUTICALS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MYLAN API US LLC
Abandoned legal-status Critical Current

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    • 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
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • 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
    • C07K5/06078—Dipeptides 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp

Definitions

  • the presently disclosed subject matter relates to the synthesis of carfilzomib.
  • Carfilzomib an epoxomicin derivative, is a selective proteasome inhibitor. Carfilzomib is used to treat patients with multiple myeloma who have already been treated with at least two other medications.
  • Novel methods and intermediates are disclosed for the production of carfilzomib. Processes disclosed herein may be employed to produce amorphous form carfilzomib.
  • methods employ a fragment-based approach involving active esters.
  • active esters obtained from hydroxyl-benzotriazoles, hydroxy-aza-benzotriazoles, succinimide esters, substituted phenols, etc. may be employed.
  • the methods are efficient and highly reproducible in large scale industrial processes.
  • the methods employ fragment condensation using novel synthetic intermediates and provide racemization-free approaches.
  • the disclosed methods produce carfilzomib in a reduced number of steps compared to existing methods in the literature.
  • powder x-ray diffraction reveals the resulting carfilzomib active pharmaceutical ingredient (API) made according to a method disclosed herein is in amorphous form.
  • Y is 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), or fluoroenylmethyl (OFm).
  • OBt 1-hydroxybenzotriazole
  • OAt azabenzotriazole
  • OSu O-succinimidyl
  • OPfp pentafluorophenyl
  • OTcp trichlorophenyl
  • nitrophenyl ONp
  • pentachlorophenyl Opcp
  • 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl Dhbt
  • Compounds of formula I may include active esters obtained from corresponding hydroxy compounds and substituted phenols. Compounds of formula I may be employed as intermediates in methods disclosed herein for making carfilzomib.
  • active esters of formula I may be synthesized using reagents such as carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N′-dicyclohexylcarbodiimide (DCC), and N,N′-diisopropylcarbodiimide (DIPC).
  • CDI carbonyldiimidazole
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DCC N,N′-dicyclohexylcarbodiimide
  • DIPC N,N′-diisopropylcarbodiimide
  • methods involve obtaining a free acid of a compound of formula I by various chemical methods and activating a resulting intermediate using a hydroxy and/or phenolic compound.
  • chemical methods include but are not limited to bis-silylation, using silylating agents, an organic base, and/or hydrolysis of esters by using alkali metal hydroxides including NaOH, KOH, LiOH and their corresponding carbonates, etc.
  • Compounds of formula I may be isolated using various organic solvents including but not limited to methanol, ethanol, acetonitrile, MDC, chloroform, ethylacetate, etc.
  • Morpholino Y 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3- benzotriazinyl (Dhbt), or fluoroenylmethyl (OFm).
  • Formula II, III and IV active esters may be obtained from corresponding hydroxy compounds and phenols.
  • active esters of formulas II, III, and IV may be synthesized using reagents such as CDI, EDC, DCC, and DIPC.
  • methods involve obtaining a free acid of a compound of formula II, III, and IV by various chemical methods and activating a resulting intermediate using a hydroxy and/or phenolic compound.
  • chemical methods include but are not limited to bis-silylation, using silylating agents, an organic base, and/or hydrolysis of esters by using alkali metal hydroxides including NaOH, KOH, LiOH and their corresponding carbonates, etc.
  • Compounds of formula II, III, and IV may be isolated using various organic solvents including but not limited to methanol, ethanol, acetonitrile, MDC, chloroform, ethylacetate, etc.
  • Purification of compounds I, II, III and IV may be effected using any suitable technique including but not limited to preparative RP-HPLC.
  • a method of making amorphous form carfilzomib which employs the synthetic route:
  • Y is 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), or fluoroenylmethyl (OFm);
  • X is HCl, trifluoroacetic acid (TFA), HCOOH, p-toluenesulfonic acid (TsOH), or methanesulfonic acid (MsOH); and R is H, methyl (Me), ethyl (Et), benzyl (Bzl), or isopropyl (iPr).
  • a method of making amorphous form carfilzomib which employs the synthetic route:
  • Y is OBt, OAt, OSu, OPfp, OTcp, ONp, Opcp, Dhbt, or OFm and X is HCl, TFA, HCOOH, TsOH, or MsOH.
  • Amorphous carfilzomib may be isolated using organic solvent extraction wherein the solvent may be MDC, chloroform, ethylacetate, diethylether, methyl-tert-butyl ether, diisopropyl ether, etc.
  • solvent may be MDC, chloroform, ethylacetate, diethylether, methyl-tert-butyl ether, diisopropyl ether, etc.
  • amorphous form of carfilzomib is disclosed.
  • X-ray powder diffraction data of amorphous carfilzomib made in accordance with a method disclosed herein is shown in FIG. 1 .
  • FIG. 1 is a graphical depiction of powder XRD data of a batch of carfilzomib made in accordance with at least one embodiment of the present disclosure.
  • the present invention describes in one aspect the synthesis of amorphous carfilzomib by employing active esters as novel intermediates.
  • Y is 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), or fluoroenylmethyl (OFm),
  • X is HCl, TFA, HCOOH, TsOH, or MsOH, and
  • R is H, methyl (Me), ethyl (Et), benzyl (Bzl), or isopropyl (IPr).
  • Y is 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), or fluoroenylmethyl (OFm); and X is HCl, trifluoroacetic acid (TFA), HCOOH, p-toluenesulfonic acid (TsOH), or methanesulfonic acid (MsOH) or isopropyl (iPr).
  • OBt 1-hydroxybenzotriazole
  • OAt azabenzotriazole
  • OSu O-succinimidyl
  • OPfp pentafluorophenyl
  • OTcp
  • a 500 mL three-neck round bottom flask equipped with a mechanical stirrer and thermometer pocket was arranged in a tub.
  • a hydrochloride salt of H-hPhe-OMe (30 g) and MDC (200 mL) were charged into the flask and stirred under nitrogen atmosphere.
  • Triethylamine (2 equiv.) was slowly added into the reaction mass at 0° C. to 10° C. and stirred for 10 min., followed by chloroacetyl chloride (1.1 equiv.) added drop wise at 0° C. to 10° C. with vigorous stirring. After 15 min. the temperature of the reaction mixture was raised to 30° C. and maintained 3 h.
  • reaction mass was diluted with MDC (200 mL), quenched with process water and washed with process water (2 ⁇ 200 mL) and brine (200 mL).
  • the organic layer was dried over anhydrous sodium sulfate (10 g) and concentrated under vacuum at below 40° C. and precipitated by adding diethyl ether.
  • a 500 mL single neck flask equipped with a magnetic stirrer was arranged in a tub.
  • Morpholine-4-yl-acetic acid (100 mmol) and DMF (200 mL) were charged into the flask and stirred at 20-30° C.
  • DIPEA (100 mmol) was added slowly into the reaction mixture at 20-30° C., followed by addition of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HBTU) (100 mmol) and hydroxybenzotriazole (HOBt) (100 mmol) and the reaction mixture was stirred at 20-30° C.
  • HBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate
  • HOBt hydroxybenzotriazole
  • the reaction was concentrated under reduced pressure and the residue was dissolved in 10% Na 2 CO 3 and washed with ether.
  • the aqueous phase was acidified with citric acid and extracted with 500 mL EtOAc/MDC.
  • the organic layer was washed with water (2 ⁇ 200 mL) and brine (1 ⁇ 200 mL) and dried over anhydrous Na 2 SO 4 .
  • the solvent was evaporated under reduced pressure to give a dipeptide acid of Formula V.
  • the reaction was concentrated under reduced pressure and the residue was dissolved in 10% Na 2 CO 3 and washed with ether.
  • the aqueous phase was acidified with citric acid and extracted with 500 mL EtOAc/MDC.
  • the organic layer was washed with water (2 ⁇ 200 mL) and brine (1 ⁇ 200 mL) and dried over anhydrous Na 2 SO 4 .
  • the Na 2 SO 4 was removed by filtration and the solvent evaporated under reduced pressure to give the tripeptide acid of Formula IIIa.
  • the reaction was concentrated under reduced pressure and the residue was dissolved in 10% Na 2 CO 3 and washed with ether.
  • the aqueous phase was acidified with citric acid and extracted with 500 mL EtOAc/MDC.
  • the organic layer was washed with water (2 ⁇ 200 mL) and brine (1 ⁇ 200 mL) and dried over anhydrous Na 2 SO 4 .
  • the solvent was evaporated under reduced pressure to give the dipeptide acid of Formula IX.
  • the reaction was concentrated under reduced pressure and the residue was dissolved in 10% Na 2 CO 3 and washed with ether.
  • the aqueous phase was acidified with 1N HCl and extracted with 500 rut MDC.
  • the organic layer was washed with water (2 ⁇ 200 mL) and brine (1 ⁇ 200 mL) and dried over anhydrous Na 2 SO 4 .
  • the Na 2 SO 4 was removed by filtration and the solvent evaporated under reduced pressure to give the tetrapeptide acid of Formula XI.
  • Carfilzomib crude was dissolved in dimethylformamide, a polar aprotic solvent.
  • suitable polar aprotic solvents include but are not limited to dimethylformamide, dimethylsulfoxide, or acetonitrile.
  • To the solution was added 10% to 20% of citric acid solution. The resulting solution was stirred for 5 to 6 hours then filtered off to obtain the pure carfilzomib.
  • This purification method provides highly pure carfilzomib in which the diasteromeric impurity is controlled at 5 to 10 percent. This method improves yield and reduces the time cycle in scale up purifications.
  • the purified carfilzomib is further purified by preparative HPLC to obtain the drug substance of carfilzomib with amorphous form.
  • the eluted fractions from preparative HPLC were collected and made pH basic, preferably 8-10, most preferably 8-9.
  • the resulting reaction mass was distilled off in such a way to remain 40% of reaction mass, under vacuum at below 30° C. and stirred for 60 to 90 minutes. Filtered off the reaction mass and again the wet solids were dissolved in MDC and treated with brine solution and sodium sulphate. The resulting reaction mass was subjected to distillation and strip out with diethyl ether. Finally the compound was dried under vacuum to obtain the drug substance of carfilzomib with amorphous form.
  • the XRD profile of the compound is shown in FIG. 1 .
  • compositions and methods of the present disclosure have been described with reference to exemplary embodiments thereof, the present disclosure is not limited thereby. Indeed, the exemplary embodiments are implementations of the disclosed compositions and methods are provided for illustrative and non-limitative purposes. Changes, modifications, enhancements and/or refinements to the disclosed systems and methods may be made without departing from the spirit or scope of the present disclosure. Accordingly, such changes, modifications, enhancements and/or refinements are encompassed within the scope of the present invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US14/923,068 2014-10-27 2015-10-26 Methods of making carfilzomib and intermediates thereof Abandoned US20160115198A1 (en)

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US14/923,068 US20160115198A1 (en) 2014-10-27 2015-10-26 Methods of making carfilzomib and intermediates thereof
US15/228,689 US9822145B2 (en) 2014-10-27 2016-08-04 Methods of making carfilzomib and intermediates thereof
US15/785,966 US20180037606A1 (en) 2014-10-27 2017-10-17 Methods of making carfilzomib and intermediates thereof

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Cited By (1)

* Cited by examiner, † Cited by third party
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US11078231B2 (en) 2016-09-14 2021-08-03 Fresenius Kabi Oncology Ltd Process for purification of carfilzomib intermediate

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US10364269B2 (en) 2015-05-21 2019-07-30 Laurus Labs Limited Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof

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Publication number Priority date Publication date Assignee Title
US11078231B2 (en) 2016-09-14 2021-08-03 Fresenius Kabi Oncology Ltd Process for purification of carfilzomib intermediate

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US20160340388A1 (en) 2016-11-24
US9822145B2 (en) 2017-11-21
US20180037606A1 (en) 2018-02-08

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