WO2024057332A1 - An improved process for the preparation of erdafitinib and its pharmaceutically acceptable salts & polymorphs thereof - Google Patents
An improved process for the preparation of erdafitinib and its pharmaceutically acceptable salts & polymorphs thereof Download PDFInfo
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- WO2024057332A1 WO2024057332A1 PCT/IN2023/050376 IN2023050376W WO2024057332A1 WO 2024057332 A1 WO2024057332 A1 WO 2024057332A1 IN 2023050376 W IN2023050376 W IN 2023050376W WO 2024057332 A1 WO2024057332 A1 WO 2024057332A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- erdafitinib
- solvents
- reaction mass
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 229950004444 erdafitinib Drugs 0.000 title claims description 56
- OLAHOMJCDNXHFI-UHFFFAOYSA-N n'-(3,5-dimethoxyphenyl)-n'-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-n-propan-2-ylethane-1,2-diamine Chemical compound COC1=CC(OC)=CC(N(CCNC(C)C)C=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 OLAHOMJCDNXHFI-UHFFFAOYSA-N 0.000 title claims description 44
- 150000003839 salts Chemical class 0.000 title description 6
- -1 N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl]ethane-1,2-diamine compound Chemical class 0.000 claims abstract description 55
- 150000001875 compounds Chemical class 0.000 claims description 75
- 239000002904 solvent Substances 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 14
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- 239000003446 ligand Substances 0.000 claims description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 208000023747 urothelial carcinoma Diseases 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to an improved process for the preparation of N- (3,5dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l-methyl-lH-pyrazol-4-yl) quinoxalin-6-yl]ethane-l,2-diamine compound of formula- 1 which is represented by the following structural formula:
- the present invention also relates to salts of compound of formula- 1 and its crystalline forms as well as its process for the preparation.
- the drug compound N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l- methyl-lH-pyrazol-4-yl)quinoxalin-6-yl]ethane-l, 2-diamine is commonly known as “Erdafitinib”.
- the Erdafitinib is a fibroblast growth factor receptor (FGFR) kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.
- FGFR fibroblast growth factor receptor
- Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
- a single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC) which have been used to distinguish polymorphic forms.
- the first aspect of the present invention is to provide an improved process for the preparation of Erdafitinib compound of formula- 1.
- the second aspect of the present invention is to provide a crystalline form of Erdafitinib HC1 compound of formula- la hereinafter designated as “Form-N” and its process for the preparation.
- the third aspect of the present invention is to provide an improved process for the preparation of crystalline form-A of Erdafitinib compound of formula- 1.
- FIG.1 Illustrates the characteristic PXRD pattern of crystalline form-N of Erdafitinib HC1 (Formula- la).
- FIG.2 Illustrates the characteristic PXRD pattern of crystalline form-A of Erdafitinib. Detailed description of the Invention:
- suitable solvent refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents” such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxye thane, tetrahydrofuran, 1,4-dioxane, monoxime, dioxime and the like; "ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N, N- dime thy lace tamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl
- anti-solvent refers to a solvent which is used to precipitate the solid from a solution.
- suitable acid refers to organic acids or inorganic acids.
- the “inorganic acid” is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acid” is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalen
- suitable base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert- butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethyl
- the first aspect of the present invention is to provide an improved process for the preparation of Erdafitinib compound of formula- 1, comprising of: a) Treating 7-Bromo-lH-quinoxalin-2-one compound of formula-2 with thionyl chloride
- Formula-8 in presence of potassium hydroxide as a base, tetrabutylammonium bromide (TBAB) as a catalyst in a suitable solvent to provide N-(3,5- dimethoxyphenyl)-N’ -( 1 -methylethyl)-N- [3-( 1 -methyl- lH-pyrazol-4-yl) quinoxalin-6-yl] ethane- 1,2-diamine crude compound of formula- 1, followed by treating the obtained compound with IPA.HC1 to provide Erdafitinib HCl salt compound of formula- la, optionally purifying the obtained compound with a suitable solvent, e) treating the compound of formula- la with sodium hydroxide in a suitable solvent to provide Erdafitinib compound of formula- 1.
- TBAB tetrabutylammonium bromide
- the suitable solvent is selected from alcoholic solvents, polar- aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
- the preferred embodiment of the present invention is to provide an improved process for the preparation of Erdafitinib compound of formula- 1, comprising of: a) Treating 7-Bromo-lH-quinoxalin-2-one compound of formula-2 with thionyl chloride in presence of N, N-dimethylformamide to provide 7-Bromo-2- chloroquinoxaline compound of formula-3, purifying the obtained compound with 15% ethyl acetate in hexane to obtain compound of formula-3 with high purity and yield, b) reacting the compound of formula-3 with l-Methylpyrazole-4-boronic acid pinacol ester compound of formula-4 in presence of Sodium carbonate as a base, tetrakis(triphenyl phosphine)palladium [Pd(PPh3)4] as catalyst and triphenyl phosphine as ligand in dimethyl sulfoxide (DMSO) solvent to provide 7-Bromo-2-(l -methyl- lH-
- the second aspect of the present invention is to provide a crystalline form-N of Erdafitinib HC1 salt compound of formula- la, which is characterized by: i) Its powder X-ray diffractogram having peaks at about 6.2, 8.7, 13.0, 14.6, 21.4, 21.8 and 26.8 ⁇ 0.2 degrees 2-theta. ii) Its powder X-ray diffraction pattern as shown in figure- 1.
- the present invention also provides a process for the preparation of crystalline Form-N of Erdafitinib HC1 salt compound of formula- la, comprising of: a) Adding isopropyl alcohol to N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)- N-[3-( 1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-6-yl]ethane- 1 ,2-diamine crude compound of formula- 1 , b) heating and stirring the reaction mixture, c) adding IPA.HC1 to the reaction mass, d) cooling and stirring the reaction mixture, e) adding a suitable solvent to the reaction mass, f) filtering, washing and drying the compound to get the crystalline form-N of Erdafitinib HC1 salt compound of formula- 1 a.
- the suitable solvent is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents or mixtures thereof.
- the preferred embodiment of the present invention provides a process for the preparation of crystalline Form-N of Erdafitinib HC1 salt compound of formula- la, comprising of: a) Adding isopropyl alcohol to N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)- N- [3 -( 1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1 ,2-diamine crude compound of formula- 1 , b) heating and stirring the reaction mixture, c) adding IPA.HC1 to the reaction mass, d) cooling and stirring the reaction mixture, e) adding acetone & dichloromethane to the reaction mass, f) filtering, washing with acetone and drying the compound to get the crystalline form-N of Erdafitinib HC1 salt compound of formula- la.
- the third aspect of the present invention is to provide a process for the preparation of crystalline Form-A of Erdafitinib compound of formula- 1 , comprising of: a) Adding a suitable solvent to Erdafitinib HC1 compound of formula- 1 a, b) neutralizing the reaction mass with a suitable base, c) adding a suitable solvent and heating the reaction mass, d) stirring and cooling the reaction mixture, e) filtering, washing the wet solid with a suitable solvent and drying the compound to get the crystalline Form-A of Erdafitinib compound of formula- 1.
- the suitable base is sodium hydroxide.
- the suitable solvents are selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
- the preferred embodiment of the present invention is to provide a process for the preparation of crystalline Form- A of Erdafitinib compound of formula- 1, comprising of: a) Adding ethyl acetate to Erdafitinib HC1 compound of formula- 1 a, b) neutralizing the reaction mass with sodium hydroxide, c) adding aqueous acetone and heating the reaction mass, d) stirring and cooling the reaction mixture, e) filtering, washing the wet solid with aqueous acetone and drying the compound to get the crystalline Form-A of Erdafitinib compound of formula- 1.
- the compound of formula-3 is prepared in absence of solvent thereby maintenance time reduced from 17 hrs to 2-3 hrs by performing neat reaction.
- the process of the present invention does not require chromatographic purification techniques like column chromatography, preparative HPLC or preparative TLC in any stage of the process. 3.
- the maintenance time reduced from 17 -20 hrs to 8-10 hrs by using Xantphos as ligand in place of Rac-BiNap.
- the present invention involves the usage of low cost reagents & solvents which reduce the cost of production and also best suitable for commercial scale process.
- Example-1 Preparation of 7-Bromo-2-chloroquinoxaline (Formula-3):
- Example-2 Preparation of 7-Bromo-2-(l-methyl-lH-pyrazol-4yl) quinoxaline (Formula-5):
- Pd(PPh3)4 (3.8g) into reaction mass and again bubbled with N2 for 10-15 mins. Heated the reaction mass temperature to 85-90°C and stirred for 18 hours at same temperature. Cooled the reaction mass temperature to 25-35°C and stirred for 90-120 mins at same temperature and then filtered the reaction mass.
- Example-3 Preparation of N-(3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4-yl) quinoxaline-6-amine (Formula-7):
- Example-5 Preparation of Erdafitinib HC1 salt compound of Formula-la
- Example-6 Preparation of Erdafitinib Crystalline form-A:
Abstract
The present invention relates to an improved process for the preparation of N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl]ethane-1,2-diamine compound of formula-1 which is represented by the following structural formula: Formula-1.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF ERDAFITINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS & POLYMORPHS
THEREOF
Field of the invention:
The present invention relates to an improved process for the preparation of N- (3,5dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l-methyl-lH-pyrazol-4-yl) quinoxalin-6-yl]ethane-l,2-diamine compound of formula- 1 which is represented by the following structural formula:
Formula- 1
The present invention also relates to salts of compound of formula- 1 and its crystalline forms as well as its process for the preparation.
Background of the Invention:
The drug compound N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l- methyl-lH-pyrazol-4-yl)quinoxalin-6-yl]ethane-l, 2-diamine is commonly known as “Erdafitinib”. The Erdafitinib is a fibroblast growth factor receptor (FGFR) kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.
Erdafitinib has been approved by USFDA on 12 April 2019 and sold under the brand name “Balversa”.
US8895601 disclosed a process for the preparation of Erdafitinib. The process described in US8895601 having many drawbacks such as process involves more number of steps, column purifications and provides the final compound with low yield and purity. Hence, the said process is not suitable for commercial scale process.
Therefore, there remains a need to provide a cost effective and commercially viable process for the preparation Erdafitinib.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC) which have been used to distinguish polymorphic forms.
As of the date, the PXRD of Erdafitinib HC1 was not characterized and disclosed in the prior-art. The present inventors have characterized and disclosed the PXRD of Erdafitinib HC1 and designated as crystalline “Form-N”.
Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of Erdafitinib compound of formula- 1.
The second aspect of the present invention is to provide a crystalline form of Erdafitinib HC1 compound of formula- la hereinafter designated as “Form-N” and its process for the preparation.
The third aspect of the present invention is to provide an improved process for the preparation of crystalline form-A of Erdafitinib compound of formula- 1.
Brief description of the Drawings:
FIG.1 : Illustrates the characteristic PXRD pattern of crystalline form-N of Erdafitinib HC1 (Formula- la).
FIG.2: Illustrates the characteristic PXRD pattern of crystalline form-A of Erdafitinib.
Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxye thane, tetrahydrofuran, 1,4-dioxane, monoxime, dioxime and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N, N- dime thy lace tamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane/methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution.
As used herein the present invention the term “suitable acid” refers to organic acids or inorganic acids. The “inorganic acid” is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acid” is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like or mixtures thereof.
As used herein the present invention the term “suitable base” refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert- butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.
The first aspect of the present invention is to provide an improved process for the preparation of Erdafitinib compound of formula- 1, comprising of: a) Treating 7-Bromo-lH-quinoxalin-2-one compound of formula-2 with thionyl chloride
Formula-2 in presence of N, N-dimethylformamide as a catalyst in absence of solvent to provide 7-Bromo-2-chloroquinoxaline compound of formula-3, optionally purifying the obtained compound with a suitable solvent,
Formula-3 b) reacting the compound of formula-3 with l-Methylpyrazole-4-boronic acid pinacol ester compound of formula-4
Formula-4 in presence of Sodium carbonate as a base, tetrakis(triphenyl phosphine)palladium [Pd(PPh3)4] as catalyst and triphenyl phosphine as ligand in a suitable solvent to provide 7-Bromo-2-(l -methyl- lH-pyrazol-4yl) quinoxaline compound of formula-5, optionally purifying the obtained compound with a suitable solvent,
Formula-5 c) reacting the compound of formula-5 with 3,5-Dimethoxyaniline compound of formula-6
Formula-6 in presence of Cesium carbonate as a base, Palladium(II)acetate as a catalyst, Xantphos as a ligand in a suitable solvent to provide N-(3,5-
dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxaline-6-amine compound of formula-7, optionally purifying the obtained compound with a suitable solvent,
d) reacting the compound of formula-7 with N-(2-chloroethyl)-2- propanamine.HCl compound of formula-8,
Formula-8 in presence of potassium hydroxide as a base, tetrabutylammonium bromide (TBAB) as a catalyst in a suitable solvent to provide N-(3,5- dimethoxyphenyl)-N’ -( 1 -methylethyl)-N- [3-( 1 -methyl- lH-pyrazol-4-yl) quinoxalin-6-yl] ethane- 1,2-diamine crude compound of formula- 1, followed by treating the obtained compound with IPA.HC1 to provide Erdafitinib HCl salt compound of formula- la, optionally purifying the obtained compound with a suitable solvent,
e) treating the compound of formula- la with sodium hydroxide in a suitable solvent to provide Erdafitinib compound of formula- 1.
Wherein, in step-a, b, c, d & e) the suitable solvent is selected from alcoholic solvents, polar- aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
The preferred embodiment of the present invention is to provide an improved process for the preparation of Erdafitinib compound of formula- 1, comprising of: a) Treating 7-Bromo-lH-quinoxalin-2-one compound of formula-2 with thionyl chloride in presence of N, N-dimethylformamide to provide 7-Bromo-2- chloroquinoxaline compound of formula-3, purifying the obtained compound with 15% ethyl acetate in hexane to obtain compound of formula-3 with high purity and yield, b) reacting the compound of formula-3 with l-Methylpyrazole-4-boronic acid pinacol ester compound of formula-4 in presence of Sodium carbonate as a base, tetrakis(triphenyl phosphine)palladium [Pd(PPh3)4] as catalyst and triphenyl phosphine as ligand in dimethyl sulfoxide (DMSO) solvent to provide 7-Bromo-2-(l -methyl- lH-pyrazol-4yl)quinoxaline compound of formula-5, purifying the obtained compound with 20% ethyl acetate in hexane to obtain compound of formula-5 with high purity and yield, c) reacting the compound of formula-5 with 3,5-Dimethoxyaniline compound of formula-6 in presence of Cesium carbonate as a base, Palladium(II)acetate as a catalyst, Xantphos as a ligand in 1 ,2-dimethoxyethane solvent to provide N- (3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxaline-6-amine compound of formula-7, purifying the obtained compound with 25% tetrahydrofuran in ethyl acetate solvent to obtain compound of formula-7 with high purity, d) reacting the compound of formula-7 with N-(2-chloroethyl)-2- propanamine.HCl compound of formula-8 in presence of potassium hydroxide
as a base, tetrabutylammonium bromide (TBAB) as a catalyst in aqueous tetrahydrofuran solvent to provide N-(3,5-dimethoxyphenyl)-N’-(l- methylethyl)-N-[3-( 1 -methyl- lH-pyrazol-4-yl)quinoxalin-6-yl]ethane- 1 ,2- diamine crude compound of formula- 1, followed by treating the obtained compound with IPA.HC1 in isopropyl alcohol solvent to provide Erdafitinib HC1 salt compound of formula- la which was purified with acetone and dichloromethane to obtain compound of formula- la with high purity, e) treating the compound of formula- 1 a with sodium hydroxide in ethyl acetate to provide Erdafitinib compound of formula- 1, isolating the obtained compound with aqueous acetone to provide the pure Erdafitinib compound of formula-I.
The second aspect of the present invention is to provide a crystalline form-N of Erdafitinib HC1 salt compound of formula- la, which is characterized by: i) Its powder X-ray diffractogram having peaks at about 6.2, 8.7, 13.0, 14.6, 21.4, 21.8 and 26.8± 0.2 degrees 2-theta. ii) Its powder X-ray diffraction pattern as shown in figure- 1.
Further, the present invention also provides a process for the preparation of crystalline Form-N of Erdafitinib HC1 salt compound of formula- la, comprising of: a) Adding isopropyl alcohol to N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)- N-[3-( 1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-6-yl]ethane- 1 ,2-diamine crude compound of formula- 1 , b) heating and stirring the reaction mixture, c) adding IPA.HC1 to the reaction mass, d) cooling and stirring the reaction mixture, e) adding a suitable solvent to the reaction mass, f) filtering, washing and drying the compound to get the crystalline form-N of Erdafitinib HC1 salt compound of formula- 1 a.
Wherein in step-a) & e), the suitable solvent is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents or mixtures thereof.
The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-N of Erdafitinib HC1 salt compound of formula- la, comprising of: a) Adding isopropyl alcohol to N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)- N- [3 -( 1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1 ,2-diamine crude compound of formula- 1 , b) heating and stirring the reaction mixture, c) adding IPA.HC1 to the reaction mass, d) cooling and stirring the reaction mixture, e) adding acetone & dichloromethane to the reaction mass, f) filtering, washing with acetone and drying the compound to get the crystalline form-N of Erdafitinib HC1 salt compound of formula- la.
The third aspect of the present invention is to provide a process for the preparation of crystalline Form-A of Erdafitinib compound of formula- 1 , comprising of: a) Adding a suitable solvent to Erdafitinib HC1 compound of formula- 1 a, b) neutralizing the reaction mass with a suitable base, c) adding a suitable solvent and heating the reaction mass, d) stirring and cooling the reaction mixture, e) filtering, washing the wet solid with a suitable solvent and drying the compound to get the crystalline Form-A of Erdafitinib compound of formula- 1.
Wherein in step-b), the suitable base is sodium hydroxide.
In step- a) & c), the suitable solvents are selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
The preferred embodiment of the present invention is to provide a process for the preparation of crystalline Form- A of Erdafitinib compound of formula- 1, comprising of: a) Adding ethyl acetate to Erdafitinib HC1 compound of formula- 1 a, b) neutralizing the reaction mass with sodium hydroxide, c) adding aqueous acetone and heating the reaction mass, d) stirring and cooling the reaction mixture, e) filtering, washing the wet solid with aqueous acetone and drying the compound to get the crystalline Form-A of Erdafitinib compound of formula- 1.
The 7-Bromo-lH-quinoxalin-2-one compound of formula-2 and 1- Methylpyrazole-4-boronic acid pinacol ester compound of formula-4 & 3,5- Dimethoxyaniline compound of formula-6 are prepared from the processes known in the art.
Advantages of the present invention:
1. The compound of formula-3 is prepared in absence of solvent thereby maintenance time reduced from 17 hrs to 2-3 hrs by performing neat reaction.
2. The process of the present invention does not require chromatographic purification techniques like column chromatography, preparative HPLC or preparative TLC in any stage of the process.
3. In the process for preparing compound of formula-7, the maintenance time reduced from 17 -20 hrs to 8-10 hrs by using Xantphos as ligand in place of Rac-BiNap.
4. The preparation of HC1 salt compound of formula- 1 a, isolating and purification of salt provides Erdafitinib with high purity and yield.
5. The present invention involves the usage of low cost reagents & solvents which reduce the cost of production and also best suitable for commercial scale process.
PXRD method of analysis:
PXRD analysis of the crystalline form of Erdafitinib and its HC1 salt were carried out using Panlytical Expert Pro DY3248 X-ray powder diffractometer using Cu-Ka radiation of 10 wavelength 1.5406 A° and at continuous scan speed of 0.037min.
The process for the preparation of Erdafitinib compound of formula- 1 is schematically represented as below:
Scheme-I:
HCl salt: Formula-la
The best mode of carrying out the present invention was illustrated by the below 5 mentioned examples. These examples provide as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:
10 Example-1: Preparation of 7-Bromo-2-chloroquinoxaline (Formula-3):
Into a 4-neck RBF charged 7-Bromo-lH-quinoxalin-2-one compound of formula-2 (250 g) and thionyl chloride (1500 mL) and DMF (8.12 g). Heated the reaction mass to 70-75°C and stirred for 2-3 hours at same temperature and then cooled to 25-30°C. Subsequently, Charged DM Water (7500mL) into 4-Neck RB flask and 15 cooled to 5 °C and slowly added the obtained thionyl chloride reaction mass and then
stirred for 20-30 mins at same temperature. Filtered the compound and transferred into another 4-neck RBF and then charged 2500mL of DM Water and stirred for 20-30 mins at 25-30°C and filtered the reaction mass. Charged 15% Ethyl acetate in Hexane (2500 mL) and obtained crude into another 4N RBF and heated to 50-60°C and then stirred for 45-60 mins at same temperature. Cooled the reaction mass temperature to 25-30°C and then stirred for 45-60 mins at same temperature. Filtered the reaction mass and washed with 15% Ethyl acetate in hexane(500mL) and then dried to provide the title compound 7-Bromo-2-chloroquinoxaline (Formula-3) (Yield:21 Igms).
Example-2: Preparation of 7-Bromo-2-(l-methyl-lH-pyrazol-4yl) quinoxaline (Formula-5):
DM Water (500 mL) and Na2COs (108.8g) and DMSO (2400 mL) were charged into 4N RBF and then charged 7-Bromo-2-chloroquinoxaline (Formula-3) (200g) and l-Methylpyrazole-4-boronic acid pinacol ester (Formula-4) (188g, Lot-I) and Triphenylphosphine (8.62g) into reaction mass and then bubbled the reaction mass with N2 for 10-15 mins. Charged Pd(PPh3)4 (3.8g) into reaction mass and again bubbled with N2 for 10-15 mins. Heated the reaction mass temperature to 85-90°C and stirred for 18 hours at same temperature. Cooled the reaction mass temperature to 25-35°C and stirred for 90-120 mins at same temperature and then filtered the reaction mass.
Charged DM water (2000 mL) and above obtained solid mass into 4N RBF and stirred for 20-30 mins at 25-35°C and then filtered. Charged methylene chloride (3000 mL) and obtained crude into another 4N RBF, heated the reaction mass temperature to 35-40 °C and stirred for 20-30 mins at same temperature. Transferred the reaction mass into a separating funnel in hot condition, settled and collected the organic layer and then distilled off. Charged Methanol (1600mL) and obtained solid into another 4N RBF. Heated the reaction mass temperature to 60-65°C and stirred for 45-60 mins at same temperature and then cooled to 25-30°C and stirred for 45-60 mins. Filtered the reaction mass and transferred into another 4N RBF and charged 20% Ethyl acetate in hexane (2000 mL), heated the reaction mass temperature to 50-60 °C and stirred for
45-60 mins. Cooled the reaction mass temperature to 25-30 °C and stirred for 45-60 mins at same temperature. Filtered the reaction mass and washed with 20% Ethyl acetate in hexane (200mL) and then dried to provide the title compound 7-Bromo-2- (1 -methyl- lH-pyrazol-4yl) quinoxaline (Formula-5) (Yield: 163gms with above 99% purity).
Example-3: Preparation of N-(3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4-yl) quinoxaline-6-amine (Formula-7):
7-Bromo-2-(l -methyl- lH-pyrazol-4yl) quinoxaline (Formula-5) (150 g), 1,2- Dimethoxyethane (2250 mF) and 3, 5 -Dimethoxy aniline (Formula-6)( 103.30 g) were charged into 4N RBF and charged Cs2C03(202.80g) and Xantphos (5.4g) into reaction mass and then bubbled the reaction mass with N2 for 10-15 mins. Charged Pd(OAc)2( 1.05g) into reaction mass and again bubbled with N2 for 10-15 mins. Heated the reaction mass temperature to 78-82°C and stirred for 8-9 hours at same temperature. Cooled the reaction mass temperature to 50°C and charged DM Water (4500 mF) and then cooled to 25-30°C. Stirred for 45-60 mins at same temperature and then filtered the reaction mass.
Charged Ethyl acetate (3000 mF) and above obtained wet solid mass into 4N RBF and heated to 63 -67 °C and then stirred the reaction mass at same temperature for 20-30 mins. Transferred the reaction mass into separating funnel in hot condition and collected the organic layer, filtered, and then distilled off completely. Charged 25% THF in Ethyl acetate (1500 mF) and obtained crude was transferred into another 4N RBF, heated the reaction mass temperature to 60-65°C and stirred for 45-60 mins at same temperature. Cooled the reaction mass temperature to 25-30°C and stirred for 45- 60 mins. Filtered the reaction mass and washed with 25% THF in Ethyl acetate and then dried to provide the title compound N-(3,5-dimethoxyphenyl)-3-(l- methylpyrazol-4-yl)quinoxaline-6-amine (Formula-7) (Yield: 139gms with above 99% purity).
Example-4: Preparation of N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l- methyl-lH-pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine crude (Formula-1)
Into a 4N RBF charged KOH (388g), DM water (62.5mL), THF (3125 mL), N- (3,5-dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxaline-6-amine (Formula- 7)(125 g) and Tetrabutylammonium bromide (TBAB) (27.86g). Heated the reaction mass temperature to 50-55°C and stirred for 60-75mins. Charged N-(2-chloroethyl)-2- propanamine.HCl (Formula-8) (120.3g) and stirred for 12-13 hours at same temperature. Cooled the reaction mass temperature to 25-35°C and charged DM water (1250mL) and stirred for 20-30mins and then transferred the reaction mass into a separating funnel and collected organic layer. Charged organic layer into another 4N RBF and charged Carbon (12.5g) and then stirred for 20-30mins. Filtered the reaction mass on a hyflo bed and distilled off solvent from filtrate to provide the title compound N-(3,5dimethoxyphenyl)-N’-( l-methylethyl)-N-[3-(l -methyl- lH-pyrazol-4-yl) quinoxaline-6-yl]ethane-l,2-diamine crude (Formula-1 crude). (Yield: 168 gms; Purity: 96% by HPLC)
Example-5: Preparation of Erdafitinib HC1 salt compound of Formula-la
Charged IPA (lOOmL) and above obtained crude (Formula- 1) into 4N RBF and heated the reaction mass temperature to 60-65°C and then stirred for 10-15 mins. Added IPA. HC1 (191.3g) to the reaction mass at 60-65°C and stirred for 30-45mins at same temperature. Cooled the reaction mass to 25 -35 °C and stirred for 45-60 mins and then filtered and washed with acetone (500mL). Charged obtained HC1 salt and Acetone (1875mL) into 4NRBF and heated the reaction mass temperature to 50-55°C and then stirred for 30-45 mins. Cooled the reaction mass temperature to 25-35°C and stirred for 30-45 mins and then filtered and washed with acetone (500mL). Charged obtained wet material and Methylene chloride (750mL) into 4N RBF and stirred the reaction mass at 25-35°C for 30-45 mins and then filtered and washed with acetone (500mL). (Yield: 210 gms; Purity: 99.7 % by HPLC)
The PXRD of Erdafitinib HC1 salt compound of formula- la is illustrated in figure- 1.
Example-6: Preparation of Erdafitinib Crystalline form-A:
Charged above obtained compound of Formula- 1 a wet material to DM water in 4N RBF and charged Ethyl acetate (1875mE). Adjusted the reaction mass pH to 8.5- 9.5 by using aq.NaOH solution stirred the reaction mass for 10-15 mins. Transferred the reaction mass into a separating funnel, settled and separated the organic layer (lot- I) and aqueous layer. Charged the collected aqueous layer into 4N RBF and charged ethyl acetate (625mE) and stirred for 10-15 mins. Transferred the reaction mass into a separating funnel, settled and separated the organic layer (lot-II). Combine two lots of organic layers and transferred into 4N RBF and charged DM water (625mE) and then stirred for 10-15 mins. Separated the organic layer and distilled off completely.
Charged Acetone(lOOOmE) into the above Erdafitinib, heated to 50-55°C and stirred for 10-15 mins at same temperature. Added DM water (2500mE) into reaction mass over a period of 45-60 mins at 50-55°C and stirred for 20-30 mins at same temperature. Cooled the reaction mass to 25-35 and stirred for 3-4 hours at same temperature. Filtered the reaction mass and washed with DM water (500mE) and then dried to provide the title compound Erdafitinib crystalline form-A (Yield: 114gms; Purity: 99.8 % by HPEC).
The PXRD of Erdafitinib compound of formula- 1 is illustrated in figure-2.
Claims
1. An improved process for the preparation of Erdafitinib compound of formula- 1 ,
comprising of: a) Treating 7-Bromo-lH-quinoxalin-2-one (Formula-2) with thionyl chloride
Formula-2 in presence of N, N-dimethylformamide as a catalyst in absence of a solvent to provide 7-Bromo-2-chloroquinoxaline (Formula-3), optionally purifying the obtained compound with a suitable solvent,
Formula-3 b) reacting the compound of formula-3 with l-Methylpyrazole-4-boronic acid pinacol ester (Formula-4)
Formula-4
in presence of Sodium carbonate as a base, tetrakis(triphenyl phosphine)palladium [Pd(PPh3)4] as catalyst and triphenyl phosphine as ligand in a suitable solvent to provide 7-Bromo-2-(l -methyl- lH-pyrazol-4yl) quinoxaline (Formula-5), optionally purifying the obtained compound with a suitable solvent,
c) reacting the compound of formula-5 with 3,5-Dimethoxyaniline (Formula-6)
in presence of Cesium carbonate as a base, Palladium(II)acetate as a catalyst, Xantphos as a ligand in a suitable solvent to provide N-(3,5-dimethoxy phenyl)-3-( 1 -methylpyrazol-4-yl)quinoxaline-6-amine (Formula-7), optionally purifying the obtained compound with a suitable solvent,
Formula-7 d) reacting the compound of formula-7 with N-(2-chloroethyl)-2- propanamine.HCl (Formula-8),
Formula-8 in presence of potassium hydroxide as a base, tetrabutylammonium bromide (TBAB) as a catalyst in a suitable solvent to provide N-(3,5- dimethoxyphenyl)-N’ -( 1 -methylethyl)-N- [3-( 1 -methyl- lH-pyrazol-4-yl) quinoxalin-6-yl] ethane- 1,2-diamine crude (Formula-1), followed by treating the obtained compound with IPA.HC1 to provide Erdafitinib HC1 salt compound of Formula- la, optionally purifying the obtained compound with a suitable solvent,
Formula- 1 a e) treating the compound of formula- la with sodium hydroxide in a suitable solvent to provide Erdafitinib compound of formula- 1.
2. The process as claimed in claim- 1, wherein,
In step-a, b, c, d & e) the suitable solvent is selected from alcoholic solvents, polar- aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
3. The process as claimed in claim- 1, comprising of: a) Treating 7-Bromo-lH-quinoxalin-2-one of formula-2 with thionyl chloride in presence of N, N-dimethylformamide as a catalyst in absence of a solvent to
provide 7-Bromo-2-chloroquinoxaline (Formula-3), purifying the obtained compound with 15% ethyl acetate in hexane to obtain compound of formula-3 with high purity, b) reacting the compound of formula-3 with l-Methylpyrazole-4-boronic acid pinacol ester
(Formula-4) in presence of sodium carbonate as a base, tetrakis(triphenyl phosphine)palladium [Pd(PPh3)4] as catalyst and triphenyl phosphine as ligand in dimethyl sulfoxide(DMSO) solvent to provide 7-Bromo- 2-(l -methyl- lH-pyrazol-4yl)quinoxaline (Formula-5), purifying the obtained compound with 20% ethyl acetate in hexane to obtain compound of formula-5 with high purity, c) reacting the compound of formula-5 with 3,5-Dimethoxyaniline of formula-6 in presence of Cesium carbonate as a base, Palladium(II)acetate as a catalyst, Xantphos as a ligand in 1,2-dimethoxy ethane solvent to provide N-(3,5- dimethoxyphenyl)-3-(l-methylpyrazol-4-yl)quinoxaline-6-amine (Formula-7), purifying the obtained compound with 25% tetrahydrofuran in ethyl acetate solvent to obtain compound of formula-7 with high purity, d) reacting the compound of formula-7 with N-(2-chloroethyl)-2- propanamine.HCl of formula-8 in presence of potassium hydroxide as a base, tetrabutylammonium bromide (TBAB) as a catalyst in aqueous tetrahydrofuran solvent to provide N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l- methyl- lH-pyrazol-4-yl)quinoxalin-6-yl]ethane- 1 ,2-diamine crude (Formula- 1), followed by treating the obtained compound with IPA.HC1 in isopropyl alcohol solvent to provide Erdafitinib HC1 salt compound of Formula- 1 a which was purified with mixture of acetone and dichloromethane to obtain compound of formula- la with high purity, e) treating the compound of formula- 1 a with sodium hydroxide in ethyl acetate to provide Erdafitinib compound of formula- 1 , purifying the obtained compound with aqueous acetone to provide pure Erdafitinib compound of formula-I.
The process as claimed in claim- 1, wherein the N-(3,5-dimethoxyphenyl)-3-(l- methylpyrazol-4-yl)quinoxaline-6-amine (Formula-7)
Formula-7 is prepared by reacting the compound of formula-5 with 3,
5-Dimethoxyaniline of formula-6 in presence of Cesium carbonate as a base, Palladium(II)acetate as a catalyst, Xantphos as a ligand in 1 ,2-dimethoxyethane solvent. A novel crystalline form-N of Erdafitinib HC1 salt compound of formula- la, which is characterized by: i) Its powder X-ray diffractogram having peaks at about 6.2, 8.7, 13.0, 14.
6, 21.4, 21.8 and 26.8± 0.2 degrees 2-theta. ii) Its powder X-ray diffraction pattern as shown in figure- 1. A process for the preparation of crystalline Form-N of Erdafitinib HC1 compound of formula-la as claimed in claim-5, comprising of: a) Adding isopropyl alcohol to N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)-N- [3 -( 1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1 ,2-diamine (Formula- 1 crude), b) heating and stirring the reaction mixture, c) adding IPA.HC1 to the reaction mass, d) cooling and stirring the reaction mixture, e) adding a suitable solvent to the reaction mass, f) filtering, washing and drying the compound to get the crystalline form-N of Erdafitinib HC1 salt compound (Formula- la).
7. The process as claimed in claim-6, comprising of: a) Adding isopropyl alcohol to N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)-N- [3 -( 1 -methyl- 1 H-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1 ,2-diamine (Formula- 1 crude), b) heating and stirring the reaction mixture, c) adding IPA.HC1 to the reaction mass, d) cooling and stirring the reaction mixture, e) adding acetone & dichloromethane to the reaction mass, f) filtering, washing with acetone and drying the compound to get the crystalline form-N of Erdafitinib HC1 (Formula- la).
8. A process for the preparation of crystalline Form- A of Erdafitinib compound of formula- 1, comprising of: a) Adding a suitable solvent to Erdafitinib HC1 compound (Formula- la), b) neutralizing the reaction mass with a suitable base, c) adding a suitable solvent and heating the reaction mass, d) stirring and cooling the reaction mixture, e) filtering, washing and drying the compound to get the crystalline Form-A of Erdafitinib compound of formula- 1.
9. The process as claimed in claim-8, wherein,
In step-b), the suitable base is sodium hydroxide.
In step-a) & c), the suitable solvents are selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
10. The process as claimed in claim-8, comprising of: a) Adding ethyl acetate to Erdafitinib HC1 compound (Formula- la), b) neutralizing the reaction mass with sodium hydroxide,
c) adding aqueous acetone and heating the reaction mass, d) stirring and cooling the reaction mixture, e) filtering, washing and drying the compound to get the crystalline Form-A of Erdafitinib compound of formula- 1.
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| CN113024517A (en) * | 2019-12-09 | 2021-06-25 | 武汉九州钰民医药科技有限公司 | Method for preparing erdastinib |
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| Title |
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| VINOGRADOVA S. V., V. A. PANKRATOVV. V. KORSHAK, AND L. I. KOMAROVA: "INVESTIGATION OF THE REACTION OF THIONYL CHLORIDE WITH DIMETHYLFORMAMIDE", BULLETIN OF THE ACADEMY OF SCIENCES OF THE USSR DIVISION OF CHEMICAL SCIENCE, vol. 20, no. 3, 1 January 1971 (1971-01-01), pages 450 - 455, XP093151387, DOI: 10.1007/bf00852028 * |
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