WO2018024645A1 - Process for making carfilzomib - Google Patents

Process for making carfilzomib Download PDF

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Publication number
WO2018024645A1
WO2018024645A1 PCT/EP2017/069241 EP2017069241W WO2018024645A1 WO 2018024645 A1 WO2018024645 A1 WO 2018024645A1 EP 2017069241 W EP2017069241 W EP 2017069241W WO 2018024645 A1 WO2018024645 A1 WO 2018024645A1
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Prior art keywords
formula
compound
carfilzomib
mixture
process according
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PCT/EP2017/069241
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French (fr)
Inventor
Petr Bartos
Miroslav Zabadal
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Synthon B.V.
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Priority to EP17746084.7A priority Critical patent/EP3494126A1/en
Publication of WO2018024645A1 publication Critical patent/WO2018024645A1/en

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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
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • Carfilzomib chemically N-[2(S)-[2-(4-Morpholinyl)acetamido]-4-phenylbutyryl]-L- leucyl-Nl-[3-methyl-l(S)-[2(R)-methyloxiran-2-ylcarbonyl]butyl]-L-phenylalaninamide,
  • Carfilzomib is a pharmaceutical active substance that is used for the treatment of patients with multiple myeloma.
  • Carfilzomib inhibits the chymotrypsin-like protease in the core of the proteasome. It is a synthetic analog of epoxomicin.
  • Carfilzomib binds through a covalent, selective and stereo- specific linkage to the chymotryptic subunit (20S) of the proteome.
  • the product is marketed as a powder for infusion under trade name Kyprolis.
  • Carfilzomib has been first disclosed in US7232818 by Proteolix Inc. Specific routes for preparation of Carfilzomib are disclosed in WO2005105827, WO2006017842 or
  • Compound Prot-5 is deprotected in the presence of an acid using for example hydrogenation or a deprotection by the acid.
  • the resulting compound of formula 5 or a salt thereof then reacts with the compound of formula 6 to provide Carfilzomib.
  • the disadvantage of the acids disclosed in the prior art is that they react with the epoxide ring of compound of formula Prot-5 resulting in opening the ring and creation of impurities that are difficult to be removed from either the compound of formula 5 or from the final Carfilzomib.
  • WO2009045497 describes several salts of the epoxide compound of formula (5), e.g. trifluoroacetate salt and a solid form thereof.
  • the application also describes a process for preparation of the solid trifluoroacetate salt of the epoxide compound of formula (5).
  • Trifluoroacetic acid used in the process has the disadvantage that it is volatile, toxic and persistent environmental contaminant.
  • the object of the present invention is to provide a process for Carfilzomib preparation with a high yield and purity. Further, the use of hazardous and toxic substances should be avoided as much as possible.
  • the invention relates to a process for preparation of Carfilzomib of formula
  • Figure 1 is an XRPD (X-ray powder diffraction) pattern of crystalline compound of formula 1
  • Figure 2 is a DSC (differential scanning calorimetry) thermogram of crystalline compound of formula 1
  • Figure 3 is an XRPD (X-ray powder diffraction) pattern of crystalline compound of formula 2
  • Figure 4 is a DSC (differential scanning calorimetry) thermogram of crystalline compound of formula 2
  • Figure 5 is XRPD (X-ray powder diffraction) pattern of crystalline compound prepared according to Example 6 XRPD spectra were obtained using the following measurement conditions:
  • the invention relates to a process for preparation of Carfilzomib of formula
  • Carfilzomib in a solvent in the presence of a coupling agent to provide Carfilzomib; d.
  • a coupling agent to provide Carfilzomib
  • d optionally isolating a solid form of Carfilzomib or a salt thereof.
  • PG is a suitable nitrogen-protecting group, preferably selected from carbamates, amides, N-alkyl and N-aryl amines, quaternary ammonium salts, N-sulfonyl derivatives, halogen, such as phthaloyl (Phth), tetrachlorophthaloyl (TCP), dithiasuccinyl (Dts),
  • PG is preferably selected from Boc and Cbz can be deprotected and a solid salt of the compound of formula 5,
  • Acids of general formula CF 3 (CF 2 ) m COOH, m is between 1 and 7, are commercially available. In comparison with trifluoroacetic acid, the acids of general formula
  • CF 3 (CF 2 ) m COOH, m is between 1 and 7 show good crystalinity and stability. They can be used not only for purification of compound of formula 5 but also for subsequent reaction of compound of formula 5 with compound of formula 6 providing Carfilzomib in excellent yield and purity,
  • a derivative of Carfilzomib By replacing the compound of formula 6 with a derivative thereof, a derivative of Carfilzomib can be obtained.
  • Such derivatives are disclosed for example in WO2005105827, WO2006017842, WO2009045497, WO2015032621 applications.
  • the compound of Formula 3 has preferably structures (1) or (2),
  • the organic solvent in reaction step a can be for example alcohols (for example methanol, ethanol, propanol, butanol) or haloalkanes (for example dichloromethane, chloroform) or acetates (for example ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, propyl acetate) or ethers(for example diethyl ether, methyl tert-butyl ether), tetrahydrofurane, dimethylformamide, dimethysulfoxide or a combination thereof.
  • alcohols for example methanol, ethanol, propanol, butanol
  • haloalkanes for example dichloromethane, chloroform
  • acetates for example ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, propyl acetate
  • ethers for example dieth
  • the organic solvent is dichloromethane.
  • the acid of a structure CF 3 (CF 2 ) m COOH are added into the solution of the compound Prot-5 at a temperature range between -10°C and room temperature (20-25°C), preferably at 0 °C.
  • the solution is then warmed to a temperature between room temperature and the boiling point of the used solvent, preferably at the room temperature.
  • the mixture is stirred at this temperature for 1 to 10 hours, preferably for 3 to 6 hours.
  • reaction progress might be monitored by a suitable analytical technique, e.g. by
  • the molar ratio between the acid and the compound of formula Prot-5 can be between 1:1 and 100: 1, preferably it is between 1: 1 and 10: 1 and more preferably between 1: 1 and 5: 1
  • the concentration of compound of formula Prot-5 in the organic solvent can be between 0.01 g/ml and 0.5 g/ml, preferably 0.1 g/ml.
  • the solid form of compound 1 is also characterized by XRPD pattern having 20 values:
  • the solid form of compound 2 is further characterized by XRPD pattern having 20 values:
  • the isolation step b. can comprise an addition of an anti-solvent (for example hexanes or heptanes), allowing the solution to cool, reducing the volume of the solution (e.g., by distilling the solution), or any combination thereof.
  • an anti-solvent for example hexanes or heptanes
  • the solvents are distilled off from the mixture and to the residue an organic solvent or a mixture of organic solvents is added.
  • a mixture of methyl-tert-butyl ether and n-heptane (1: 1) is added.
  • the crystals are isolated from the mixture using for example filtration.
  • the isolated crystals can be washed by an organic solvent or by a mixture of organic solvents.
  • the crystals are washed by a mixture of methyl-tert-butyl ether and n-heptane (1: 1).
  • the isolated crystals can be dried.
  • the obtained crystalline compound of formula 1 can be solvated i.e. the crystal lattice comprises molecules of used solvent(s), or not solvated.
  • the compounds of formulas 1 or 2 according to presented invention show good crystallinity and stability.
  • m is between 1 and 7 ⁇ '
  • Carfilzomib or a salt thereof is prepared by reaction of a compound of formula 1 or 2 or 3 with a compound of formula:
  • the reaction can be performed in an organic solvent selected from alcohols (for example methanol, ethanol, propanol, butanol) or haloalkanes (for example dichloromethane, chloroform) or acetates (for example ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, propyl acetate) or ethers (for example diethyl ether, methyl tert-butyl ether) or tetrahydrofurane or dimethylformamide or dimethysulfoxide or acetonitrile or 1,3-Dimethyl- 3,4,5, 6-tetrahydro-2(lH)-pyrimidinone (DMPU) or in a combination thereof.
  • the organic solvent can be also combined with water.
  • the reaction is performed in the presence of a coupling agent.
  • coupling agents are DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), HOBt (1- hydroxy-benzotriazole), HOAt (l-hydroxy-7-aza-benzotriazole), BOP (benzotriazol-1- yloxy)tris(dimethylamio)phosphonium hexafluorophosphate), PyBOP (benzotriazol-1- yloxy)tris(pyrrolidino)phosphonium hexafluorophosphat, PyBroP (bromo)tris(pyrrolidino) phosphonium hexafluorophosphate), BroP (bromo)tris(dimethylamio)phosphonium hexafluorophosphate), HBTU (2-(lH-benzotriazole-l-yl)- 1, 1,3 ,3-tetramethyluronium he
  • Both the cyclic and the linear triphosphates of the above formula are well soluble in water and in various organic solvents and can thus be easily removed from the reaction product. They are stable, non-toxic compounds with low sensitization potential, which may be handled by standard means.
  • the amidation reaction proceeds generally at ambient and/or lower than ambient temperature.
  • the reaction proceeds in the presence of a base, preferably an organic base.
  • a base preferably an organic base.
  • organic base are triethylamine and DIPEA (diisopropylethylamine), in particular DIPEA.
  • the reaction temperature is typically from -20°C and 0°C.
  • the reaction time is about 2 and 10 hours.
  • the amount of coupling agent with respect to compound of formula 2 is advantageously from 1 to 10, preferably from 1 to 5 molar equivalents.
  • the reaction progress might be monitored by a suitable analytical technique, e.g. by HPLC or GC.
  • Carfilzomib can be isolated from a mixture by any isolation technique, for example by an addition of an anti-solvent (for example acetonitrile, methanol, ethanol, ethyl acetate, acetone, water or a mixture thereof), allowing the solution to cool, reducing the volume of the solution (e.g., by distilling the solution), or any combination thereof.
  • an anti-solvent for example acetonitrile, methanol, ethanol, ethyl acetate, acetone, water or a mixture thereof.
  • Carfilzomib can be optionally isolated in form of a salt thereof.
  • Carfilzomib is isolated as a salt with a compound of formula CF 3 (CF 2 ) m COOH, wherein m is between 1 and 7. More preferably Carfilzomib is isolated as a salt with a compound of formula
  • the solid salt form of Carfilzomib is prepared by a process comprising dissolving Carfilzomib in a solvent and addition of a compound of general formula CF 3 (CF 2 ) m COOH, wherein m is between 1 and 7, preferably of formula CF 3 CF 2 COOH or CF 3 (CF 2 ) 2 COOH into the solution.
  • the solvent can be for example an alcohol, such as methanol, ethanol, isopropanol, propanol or an ether, such as tert-butyl-methyl ether, diethyl ether, THF or acetonitrile or acetone or an acetate, such as ethyl acetate or toluene or a mixture thereof or a mixture thereof with water.
  • an alcohol such as methanol, ethanol, isopropanol, propanol or an ether, such as tert-butyl-methyl ether, diethyl ether, THF or acetonitrile or acetone or an acetate, such as ethyl acetate or toluene or a mixture thereof or a mixture thereof with water.
  • the molar ration between Carfilzomib and the acid can be between 1: 1 to 1: 10, preferably between 1: 1 and 1:3.
  • the compound of formula CF 3 (CF 2 ) m COOH can be added into Carfilzomib solution at a temperature between -10°C and 30°C, preferably between 0°C and 10°C.
  • the mixture can be heated at a temperature between 0°C and the boiling point of the solvent, preferably it is heated at the room temperature.
  • reaction time after compound of formula CF 3 (CF 2 ) m COOH is added can be between 1 and 10 hours, preferably it is between 1 and 3 hours.
  • the salt of Carfilzomib can be isolated from a mixture by any isolation technique, for example by an addition of an anti- solvent (for example acetonitrile, methanol, ethanol, ethyl acetate, acetone, water or a mixture thereof), allowing the solution to cool, reducing the volume of the solution (e.g., by distilling the solution), or any combination thereof.
  • the salt of Carfilzomib can be isolated in an amorphous or crystalline state. Obtained solid Carfilzomib or a salt thereof can be washed with an organic solvent, with a mixture of organic solvents or a mixture of organic solvent(s) and water.
  • an organic solvent Preferably acetonitrile, methanol, ethanol, ethyl acetate, acetone or combination thereof is used.
  • Obtained salts of Carfilzomib can be subsequently transformed into Carfilzomib after dissolving in a solvent and addition of a base.
  • Carfilzomib obtainable by described process may be formulated into pharmaceutical compositions, for instance to powders for infusion, and may be used in medicine, for instance in a treatment of multiple myeloma.
  • the compound Prot-5a (5 g) was dissolved in dichloromethane (76 ml). The mixture was cooled down to 0°C. The solution was stirred under argon and pentafluoropropanoic acid (49 g, 0.3mol) was added. The mixture was warmed to 25°C and it was stirred for 4 hrs. Then the mixture was distilled off on rotavap and the residue was dissolved in 76 ml of dichloromethane. The mixture was distilled off on rotavap and the residue was dissolved in 76 ml of dichloromethane. The mixture was distilled off on rotavap.
  • the compound Prot-5a (5 g) was dissolved in dichloromethane (76 ml). The mixture was cooled down to 0°C. The solution was stirred under argon and heptafluorobutyric acid (43 g, 0.2 mol) was added. The mixture was warmed to 23°C and it was stirred for 2 hrs. Then the mixture was distilled off on rotavap and the residue was dissolved in 76 ml of dichloromethane. The mixture was distilled off on rotavap and the residue was dissolved in 76 ml of dichloromethane. The mixture was distilled off on rotavap.
  • the organic layer was concentrated to provide Carfilzomib in a very high yield.

Abstract

The present invention relates to a process for preparation of Carfilzomib of formula (I).

Description

PROCESS FOR MAKING CARFILZOMIB FIELD OF THE INVENTION
Carfilzomib, chemically N-[2(S)-[2-(4-Morpholinyl)acetamido]-4-phenylbutyryl]-L- leucyl-Nl-[3-methyl-l(S)-[2(R)-methyloxiran-2-ylcarbonyl]butyl]-L-phenylalaninamide,
Figure imgf000002_0001
is a pharmaceutical active substance that is used for the treatment of patients with multiple myeloma. Carfilzomib inhibits the chymotrypsin-like protease in the core of the proteasome. It is a synthetic analog of epoxomicin. Carfilzomib binds through a covalent, selective and stereo- specific linkage to the chymotryptic subunit (20S) of the proteome.
The product is marketed as a powder for infusion under trade name Kyprolis.
BACKGROUND OF THE PRESENT INVENTION
Carfilzomib has been first disclosed in US7232818 by Proteolix Inc. Specific routes for preparation of Carfilzomib are disclosed in WO2005105827, WO2006017842 or
WO2009045497 describing as a last step of the synthesis route a coupling of an epoxide compound of formula 5,
Figure imgf000002_0002
Formula (5), with a compound of formula 6,
Figure imgf000003_0001
Formula (6),
to obtain Carfilzomib. A synthesis of the epoxide compound of formula (5) is described in Crews CM., et. al, Bioorg. Med. Chem. Letters 1999, 9, 2283-2288.
The process for preparation of Carfilzomib disclosed in prior art documents is depicted in following scheme:
Figure imgf000003_0002
Carfilzomib
Compound Prot-5 is deprotected in the presence of an acid using for example hydrogenation or a deprotection by the acid. The resulting compound of formula 5 or a salt thereof then reacts with the compound of formula 6 to provide Carfilzomib. The disadvantage of the acids disclosed in the prior art is that they react with the epoxide ring of compound of formula Prot-5 resulting in opening the ring and creation of impurities that are difficult to be removed from either the compound of formula 5 or from the final Carfilzomib.
WO2009045497 describes several salts of the epoxide compound of formula (5), e.g. trifluoroacetate salt and a solid form thereof. The application also describes a process for preparation of the solid trifluoroacetate salt of the epoxide compound of formula (5).
Trifluoroacetic acid used in the process has the disadvantage that it is volatile, toxic and persistent environmental contaminant.
The object of the present invention is to provide a process for Carfilzomib preparation with a high yield and purity. Further, the use of hazardous and toxic substances should be avoided as much as possible.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The invention relates to a process for preparation of Carfilzomib of formula,
Figure imgf000004_0001
or a salt thereof, the process comprising steps:
a. Reacting a compound of formula,
Figure imgf000004_0002
wherein PG is a protecting group, with a compound of formula CF3(CF2)mCOOH, wherein m is between 1 and 7, in an organic solvent to obtain compound of formula (3), H
Figure imgf000005_0001
Optionally isolating of a solid form of compound of formula (3);
Reacting of compound of formula (3) with compound of formula,
Figure imgf000005_0002
in a solvent in the presence of a coupling agent to provide Carfilzomib, optionally isolating a solid form of Carfilzomib or a salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an XRPD (X-ray powder diffraction) pattern of crystalline compound of formula 1
Figure 2 is a DSC (differential scanning calorimetry) thermogram of crystalline compound of formula 1
Figure 3 is an XRPD (X-ray powder diffraction) pattern of crystalline compound of formula 2
Figure 4 is a DSC (differential scanning calorimetry) thermogram of crystalline compound of formula 2
Figure 5 is XRPD (X-ray powder diffraction) pattern of crystalline compound prepared according to Example 6 XRPD spectra were obtained using the following measurement conditions:
Bruker-AXS D8 Vario diffractometer with Θ/2Θ geometry (reflection mode), equipped with a Vantec PSD detector
Figure imgf000006_0002
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The invention relates to a process for preparation of Carfilzomib of formula,
Figure imgf000006_0001
or a salt thereof, the process comprising steps: a. Reacting a compound of formula,
Figure imgf000007_0001
wherein PG is a protecting group,
with a compound of formula CF3(CF2)mCOOH, wherein m is between 1 and 7, in an organic solvent to obtain compound of formula (3), H
Figure imgf000007_0002
Optionally isolating of a solid form of compound of formula (3);
Reacting of compound of formula (3) with compound of formula,
Figure imgf000007_0003
in a solvent in the presence of a coupling agent to provide Carfilzomib; d. Optionally isolating a solid form of Carfilzomib or a salt thereof.
This invention is based on the surprising finding that the compound of formula Prot-5,
Figure imgf000007_0004
Prot-5
wherein PG is a suitable nitrogen-protecting group, preferably selected from carbamates, amides, N-alkyl and N-aryl amines, quaternary ammonium salts, N-sulfonyl derivatives, halogen, such as phthaloyl (Phth), tetrachlorophthaloyl (TCP), dithiasuccinyl (Dts),
Trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, tert-Butoxycarbonyl (Boc),
Benzyloxycarbonyl (Cbz), allyloxycarbonyl {Allot), 9-fluorenylmethoxycarbonyl (Fmoc), 2- (trimethylsilyeethoxycarbonyl (Teoc), 2,2,2- trichloroethoxycarbonyl (Troc), phenylsulfonyl, p-tolylsulfonyl (Ts), 2- and 4-nitrophenylsulfonyl (Ns), 2- (trimethylsilyeethylsulfonyl (SES), benzyl (Bn), diphenylmethyl (Dpm), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), p-methoxyphenyl (PMP) and allyl. PG is preferably selected from Boc and Cbz can be deprotected and a solid salt of the compound of formula 5,
Figure imgf000008_0001
(5)
can be formed in the presence of an acid of general formula CF3(CF2)mCOOH, wherein m is between 1 and 7. These acids do not react with the epoxide ring of compound of formula Prot- 5 or 5 and the formation of impurities is thereby suppressed.
Acids of general formula CF3(CF2)mCOOH, m is between 1 and 7, are commercially available. In comparison with trifluoroacetic acid, the acids of general formula
CF3(CF2)mCOOH, m is between 1 and 7, are less volatile, less toxic and more environmental friendly. The solid salts of compound of formula 5 with the acids of general formula
CF3(CF2)mCOOH, m is between 1 and 7 show good crystalinity and stability. They can be used not only for purification of compound of formula 5 but also for subsequent reaction of compound of formula 5 with compound of formula 6 providing Carfilzomib in excellent yield and purity,
Figure imgf000009_0001
(6)
By replacing the compound of formula 6 with a derivative thereof, a derivative of Carfilzomib can be obtained. Such derivatives are disclosed for example in WO2005105827, WO2006017842, WO2009045497, WO2015032621 applications.
The compound of Formula 3 has preferably structures (1) or (2),
Figure imgf000009_0002
The organic solvent in reaction step a. can be for example alcohols (for example methanol, ethanol, propanol, butanol) or haloalkanes (for example dichloromethane, chloroform) or acetates (for example ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, propyl acetate) or ethers(for example diethyl ether, methyl tert-butyl ether), tetrahydrofurane, dimethylformamide, dimethysulfoxide or a combination thereof.
Preferably the organic solvent is dichloromethane.
In the reaction step a. the acid of a structure CF3(CF2)mCOOH are added into the solution of the compound Prot-5 at a temperature range between -10°C and room temperature (20-25°C), preferably at 0 °C. The solution is then warmed to a temperature between room temperature and the boiling point of the used solvent, preferably at the room temperature. The mixture is stirred at this temperature for 1 to 10 hours, preferably for 3 to 6 hours.
The reaction progress might be monitored by a suitable analytical technique, e.g. by
HPLC or GC. The molar ratio between the acid and the compound of formula Prot-5 can be between 1:1 and 100: 1, preferably it is between 1: 1 and 10: 1 and more preferably between 1: 1 and 5: 1 The concentration of compound of formula Prot-5 in the organic solvent can be between 0.01 g/ml and 0.5 g/ml, preferably 0.1 g/ml.
The compound of formula (1),
Figure imgf000010_0001
(1 )
can be isolated in a solid form characterized by XRPD pattern having 20 values 8.64°, 17.26°, 22.26°, 26.0° (+0.2). The solid form is further characterized by XRPD spectrum depicted in Figure 1 and DSC thermogram depicted in Figure 2.
The solid form of compound 1 is also characterized by XRPD pattern having 20 values:
Figure imgf000010_0002
The compound of formula (2),
Figure imgf000011_0001
(2)
can be isolated in a solid form characterized by XRPD pattern having 20 values 8.10°, 12.96°, 16.96°, 22.49° (+0.2). The solid form is further characterized by XRPD spectrum depicted in Figure 3 and DSC thermogram depicted in Figure 4.
The solid form of compound 2 is further characterized by XRPD pattern having 20 values:
Figure imgf000011_0002
The isolation step b. can comprise an addition of an anti-solvent (for example hexanes or heptanes), allowing the solution to cool, reducing the volume of the solution (e.g., by distilling the solution), or any combination thereof. Preferably the solvents are distilled off from the mixture and to the residue an organic solvent or a mixture of organic solvents is added. Preferably a mixture of methyl-tert-butyl ether and n-heptane (1: 1) is added. The crystals are isolated from the mixture using for example filtration. The isolated crystals can be washed by an organic solvent or by a mixture of organic solvents. Preferably the crystals are washed by a mixture of methyl-tert-butyl ether and n-heptane (1: 1). The isolated crystals can be dried. The obtained crystalline compound of formula 1 can be solvated i.e. the crystal lattice comprises molecules of used solvent(s), or not solvated.
The compounds of formulas 1 or 2 according to presented invention show good crystallinity and stability.
The crystalline compounds of formulas 1 or 2 or 3,
Figure imgf000012_0001
m is between 1 and 7 ^ '
can be used for the preparation of Carfilzomib or a derivative thereof, wherein the derivative has a general formula:
Figure imgf000012_0002
wherein R means rest of the molecule. The examples of such derivatives can be found for example in WO2005105827, WO2006017842, WO2009045497, WO2015032621
applications.
In subsequent step c. Carfilzomib or a salt thereof is prepared by reaction of a compound of formula 1 or 2 or 3 with a compound of formula:
Figure imgf000013_0001
in a solvent in the presence of a coupling agent.
The reaction can be performed in an organic solvent selected from alcohols (for example methanol, ethanol, propanol, butanol) or haloalkanes (for example dichloromethane, chloroform) or acetates (for example ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, propyl acetate) or ethers (for example diethyl ether, methyl tert-butyl ether) or tetrahydrofurane or dimethylformamide or dimethysulfoxide or acetonitrile or 1,3-Dimethyl- 3,4,5, 6-tetrahydro-2(lH)-pyrimidinone (DMPU) or in a combination thereof. The organic solvent can be also combined with water.
The reaction is performed in the presence of a coupling agent. Examples of coupling agents are DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), HOBt (1- hydroxy-benzotriazole), HOAt (l-hydroxy-7-aza-benzotriazole), BOP (benzotriazol-1- yloxy)tris(dimethylamio)phosphonium hexafluorophosphate), PyBOP (benzotriazol-1- yloxy)tris(pyrrolidino)phosphonium hexafluorophosphat, PyBroP (bromo)tris(pyrrolidino) phosphonium hexafluorophosphate), BroP (bromo)tris(dimethylamio)phosphonium hexafluorophosphate), HBTU (2-(lH-benzotriazole-l-yl)- 1, 1,3 ,3-tetramethyluronium hexafluorophosphate) , CDI (Ι, -Carbonyldiimidazole), ED AC (N-(3-Dimethylamino- propyl)-N'-ethylcarbodiimide hydrochloride or a cyclic alkyltriphosphonate anhydride of general formula:
Figure imgf000013_0002
wherein A is C1-C3 alkyl group, preferably propyl. The compound, wherein A is propyl, is commercially available, e.g. under trade name Allesan CAP.
Both the cyclic and the linear triphosphates of the above formula are well soluble in water and in various organic solvents and can thus be easily removed from the reaction product. They are stable, non-toxic compounds with low sensitization potential, which may be handled by standard means. The amidation reaction proceeds generally at ambient and/or lower than ambient temperature.
The reaction proceeds in the presence of a base, preferably an organic base. Examples of the organic base are triethylamine and DIPEA (diisopropylethylamine), in particular DIPEA.
The reaction temperature is typically from -20°C and 0°C. The reaction time is about 2 and 10 hours. The amount of coupling agent with respect to compound of formula 2 is advantageously from 1 to 10, preferably from 1 to 5 molar equivalents. The reaction progress might be monitored by a suitable analytical technique, e.g. by HPLC or GC.
Carfilzomib can be isolated from a mixture by any isolation technique, for example by an addition of an anti-solvent (for example acetonitrile, methanol, ethanol, ethyl acetate, acetone, water or a mixture thereof), allowing the solution to cool, reducing the volume of the solution (e.g., by distilling the solution), or any combination thereof. Carfilzomib can be isolated in an amorphous or crystalline state.
Carfilzomib can be optionally isolated in form of a salt thereof. Preferably Carfilzomib is isolated as a salt with a compound of formula CF3(CF2)mCOOH, wherein m is between 1 and 7. More preferably Carfilzomib is isolated as a salt with a compound of formula
CF3CF2COOH or CF3(CF2)2COOH.
The solid salt form of Carfilzomib is prepared by a process comprising dissolving Carfilzomib in a solvent and addition of a compound of general formula CF3(CF2)mCOOH, wherein m is between 1 and 7, preferably of formula CF3CF2COOH or CF3(CF2)2COOH into the solution. The solvent can be for example an alcohol, such as methanol, ethanol, isopropanol, propanol or an ether, such as tert-butyl-methyl ether, diethyl ether, THF or acetonitrile or acetone or an acetate, such as ethyl acetate or toluene or a mixture thereof or a mixture thereof with water.
The advantage of compounds of formula CF3(CF2)mCOOH in comparing to compounds disclosed in prior art is that the compound of formula CF3(CF2)mCOOH, wherein m is between 1 and 7, preferably of formula CF3CF2COOH or CF3(CF2)2COOH do not react with the epoxyketone part of the Carfilzomib molecule. As a result Carfilzomib salt is obtained in better yield and purity. Solid salts of Carfilzomib with compounds of formula CF3CF2COOH or CF3(CF2)2COOH also show good crystallinity and stability and can be used for example for purification of Carfilzomib.
The molar ration between Carfilzomib and the acid can be between 1: 1 to 1: 10, preferably between 1: 1 and 1:3.
The compound of formula CF3(CF2)mCOOH can be added into Carfilzomib solution at a temperature between -10°C and 30°C, preferably between 0°C and 10°C.
After the compound of formula CF3(CF2)mCOOH is added, the mixture can be heated at a temperature between 0°C and the boiling point of the solvent, preferably it is heated at the room temperature.
The reaction time after compound of formula CF3(CF2)mCOOH is added can be between 1 and 10 hours, preferably it is between 1 and 3 hours.
The salt of Carfilzomib can be isolated from a mixture by any isolation technique, for example by an addition of an anti- solvent (for example acetonitrile, methanol, ethanol, ethyl acetate, acetone, water or a mixture thereof), allowing the solution to cool, reducing the volume of the solution (e.g., by distilling the solution), or any combination thereof. The salt of Carfilzomib can be isolated in an amorphous or crystalline state. Obtained solid Carfilzomib or a salt thereof can be washed with an organic solvent, with a mixture of organic solvents or a mixture of organic solvent(s) and water. Preferably acetonitrile, methanol, ethanol, ethyl acetate, acetone or combination thereof is used.
Obtained salts of Carfilzomib can be subsequently transformed into Carfilzomib after dissolving in a solvent and addition of a base.
Carfilzomib obtainable by described process may be formulated into pharmaceutical compositions, for instance to powders for infusion, and may be used in medicine, for instance in a treatment of multiple myeloma.
The invention will be further described with reference to the following non-limiting examples.
EXAMPLES
Example 1
Figure imgf000016_0001
The compound Prot-5a (5 g) was dissolved in dichloromethane (76 ml). The mixture was cooled down to 0°C. The solution was stirred under argon and pentafluoropropanoic acid (49 g, 0.3mol) was added. The mixture was warmed to 25°C and it was stirred for 4 hrs. Then the mixture was distilled off on rotavap and the residue was dissolved in 76 ml of dichloromethane. The mixture was distilled off on rotavap and the residue was dissolved in 76 ml of dichloromethane. The mixture was distilled off on rotavap. The residue was mixed with 28 ml methyl-tert butyl ether/heptane mixture (1: 1) and it was cooled down to -10°C. White crystals were filtered off and washed with 38 ml of methyl-tert butyl ether/heptane mixture (1: 1). The yield of obtained compound of formula 1 was 93% of theoretical yield with purity 94%. Example 2
Figure imgf000017_0001
The compound Prot-5a (5 g) was dissolved in dichloromethane (76 ml). The mixture was cooled down to 0°C. The solution was stirred under argon and heptafluorobutyric acid (43 g, 0.2 mol) was added. The mixture was warmed to 23°C and it was stirred for 2 hrs. Then the mixture was distilled off on rotavap and the residue was dissolved in 76 ml of dichloromethane. The mixture was distilled off on rotavap and the residue was dissolved in 76 ml of dichloromethane. The mixture was distilled off on rotavap. The residue was mixed with methyl-tert butyl ether/heptane mixture (38 ml/38 ml) and it was cooled down to -10°C. White crystals were filtered off washed with 47 ml of methyl-tert butyl ether/heptane mixture (1: 1). The yield of obtained compound of formula 5 was 94% of the theoretical yield with purity 96%.
Example 3
Figure imgf000017_0002
4.5 g of compound 1 was dissolved in 126 ml DMF, together with 5.9 g HBTU, 2.1 g HOBt and 5.93 g compound of formula 6. The mixture was cooled to -5°C and 2.7 ml of diethylamine were added dropwise. The mixture was stirred at -5°C for 1.5 hour. To the mixture 90 ml of saturated aqueous NaHC03 solution were added. To the mixture 500 ml of ethyl acetate were added, the layers were separated. The organic layer was twice extracted with 135 ml of saturated aqueous solution of NaHC03 and with 90 ml of brine. The organic layer was dried over MgS04.
The organic layer was concentrated to provide Carfilzomib in 86% of the theoretical yield.
Example 4
Figure imgf000018_0001
4.5 g of compound 2 was dissolved in 126 ml DMF, together with 5.1 g HBTU, 1.8 g HOBt and 5.2 g compound of formula 6. The mixture was cooled to -5°C and 2.4 ml of diethylamine were added dropwise. The mixture was stirred at -5°C for 1.5 hour. To the mixture 90 ml of saturated aqueous NaHC03 solution were added. To the mixture 500 ml of ethyl acetate were added, the layers were separated. The organic layer was twice extracted with 135 ml of saturated aqueous solution of NaHC03 and with 90 ml of brine. The organic layer was dried over MgS04. The organic layer was concentrated to provide Carfilzomib in 88% yield.
Example 5
Figure imgf000019_0001
4.5 g of compound 1 and 5.93 g compound of formula 6 were dissolved in 60 ml dichloromethane. The mixture was cooled to -15°C and 5.4 g of N-methylmorpholine was added. To the mixture 6.41 g of compound of formula 8 was added. The mixture was stirred at -10°C for 1.5 hour. The mixture was warmed to 20-25°C and 60 ml of water was added. The layers were separated and the organic layer was washed with 55 ml of brine. The organic layer was dried over anhydrous sodium sulfate.
The organic layer was concentrated to provide Carfilzomib in a very high yield.
Example 6
1 g of Carfilzomib obtained in Example 5 was dissolved in a mixture of 5 ml of acetonitrile and 7.5 ml of tetrahydrofuran. The mixture was cooled down at 5°C and 0.15 ml of CF3CF2COOH was added dropwise. The reaction mixture was stirred at 5°C for 15 minutes. Then it was heated at room temperature (25°C) and stirred at this temperature for 1.5 hours. The reaction mixture was concentrated and the rest was dissolved in 6.5 ml of methanol. To the solution 4 ml of water were added and the mixture was heated at 60°C and stirred at this temperature for 45 minutes. Then the mixture was cooled down at room temperature and stirred at this temperature for 3 hours. The solid was filtered off to provide Carfilzomib salt in a very high yield and purity. The XRPD of obtained solid corresponds to XRPD spectrum depicted in Figure 5 and to following peak list:
Figure imgf000020_0001
Example 7
1 g of Carfilzomib obtained in Example 5 was dissolved in a mixture of 5 ml of acetonitrile and 7.5 ml of tetrahydrofuran. The mixture was cooled down at 5°C and 0.30 ml of compound of formula CF3(CF2)2COOH was added dropwise. The reaction mixture was stirred at 5°C for 15 minutes. Then it was heated at room temperature (25 °C) and stirred at this temperature for 3.5 hours. The reaction mixture was concentrated and the rest was dissolved in 6.5 ml of methanol. To the solution 4 ml of water were added and the mixture was heated at 55°C and stirred at this temperature for 45 minutes. Then the mixture was cooled down at room temperature and stirred at this temperature for 3 hours. The solid was filtered off to provide Carfilzomib salt in a very high yield and purity.

Claims

A process for preparation of Carfilzomib of formula:
Figure imgf000021_0001
salt thereof, the process comprising steps
Reacting a compound of formula:
Figure imgf000021_0002
wherein PG is a protecting group
with a compound of formula CF3(CF2)mCOOH. wherein m is between 1 and
7. in an organic solvent to obtain compound of formula (3),
Figure imgf000021_0003
Optionally isolating of a solid form of compound of formula (3);
Reacting of compound of formula (3) with compound of formula:
Figure imgf000021_0004
in a solvent in the presence of a coupling agent to provide Carfilzomib; d. Optionally isolating a solid form of Carfilzomib or a salt thereof.
The process according to claim 1 wherein the compound of formula (3) is compound of formula (1) or (2):
Figure imgf000022_0001
The process according to claim 2 wherein the compound of formula (1) is isolated as a solid compound characterized by XRPD pattern having 2Θ values
8.64°. 17.26°. 22.26°. 26.0° (+0.2).
The process according to claim 2 wherein the compound of formula (2) is isolated as a solid compound characterized by XRPD pattern having 2Θ values 8.10°. 12.96°. 16.96°. 22.49° (+0.2).
The process according to any one of claims 1 to 4 wherein the step a. is done in an organic solvent selected from dichloromethane or ethylacetate or isopropyl acetate or butyl acetate or isobutyl acetate or propyl acetate or diethyl ether or methyl tert-butyl ether or a combination thereof.
The process according to any one of claims 1 to 5 wherein the isolation step c.
comprises distilling off the mixture and addition of a second solvent mixture.
The process according to claim 6 wherein the second solvent mixture is a mixture of methyl tert-butyl ether and heptane.
The process according to any one of claims 1 to 7 wherein coupling agent of step c. is compound of formula:
Figure imgf000022_0002
wherein A is C1-C3 alkyl group.
9. The process according to claim 8 wherein A is propyl group.
10. The process according to any one of claims 1 to 9 wherein Carfilzomib is isolated as a salt with compound of formula CF3(CF2)mCOOH. wherein m is between 1 and 7.
11. The process according to claim 10 wherein Carfilzomib is isolated as a salt with
compounds CF3CF2COOH or CF3(CF2)2COOH.
PCT/EP2017/069241 2016-08-02 2017-07-28 Process for making carfilzomib WO2018024645A1 (en)

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Citations (4)

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