WO2022168115A1 - A process for the preparation of larotrectinib or its salts - Google Patents
A process for the preparation of larotrectinib or its salts Download PDFInfo
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- WO2022168115A1 WO2022168115A1 PCT/IN2022/050085 IN2022050085W WO2022168115A1 WO 2022168115 A1 WO2022168115 A1 WO 2022168115A1 IN 2022050085 W IN2022050085 W IN 2022050085W WO 2022168115 A1 WO2022168115 A1 WO 2022168115A1
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- formula
- larotrectinib
- phenyls
- alkyls
- solvent
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 title claims abstract description 21
- 229950003970 larotrectinib Drugs 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 title claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- PXHANKVTFWSDSG-QLOBERJESA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide;sulfuric acid Chemical compound OS(O)(=O)=O.C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 PXHANKVTFWSDSG-QLOBERJESA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 9
- -1 -Cl Chemical class 0.000 claims description 8
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 8
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 8
- 239000012454 non-polar solvent Substances 0.000 claims description 8
- 239000003880 polar aprotic solvent Substances 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000004210 ether based solvent Substances 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical group 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 239000003759 ester based solvent Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- GYCKQBWUSACYIF-UHFFFAOYSA-N Ethyl salicylate Chemical compound CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 229940005667 ethyl salicylate Drugs 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- AFHQSQTUSWXNCL-UHFFFAOYSA-N pyrimidin-5-ol Chemical compound OC1=CN=CN=C1.OC1=CN=CN=C1 AFHQSQTUSWXNCL-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- QPMSJEFZULFYTB-WCCKRBBISA-N (3s)-pyrrolidin-3-ol;hydrochloride Chemical compound Cl.O[C@H]1CCNC1 QPMSJEFZULFYTB-WCCKRBBISA-N 0.000 description 1
- LCDCPQHFCOBUEF-UHFFFAOYSA-N 1-Pyrrolidinecarboxamide Natural products NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 description 1
- PNTNLXBVYHOZQI-CQSZACIVSA-N 5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-amine Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)N)=CC(F)=CC=C1F PNTNLXBVYHOZQI-CQSZACIVSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PXXNTAGJWPJAGM-VCOUNFBDSA-N Decaline Chemical compound C=1([C@@H]2C3)C=C(OC)C(OC)=CC=1OC(C=C1)=CC=C1CCC(=O)O[C@H]3C[C@H]1N2CCCC1 PXXNTAGJWPJAGM-VCOUNFBDSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention provides a process for the preparation of an intermediate compound of Formula IV comprising the steps of: a) converting Formula II into a Formula IV ; and b) isolating Formula IV.
- R is-SCLRi; -CO-R2; Ri is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I.
Abstract
The present invention provides a process for the preparation of Larotrectinib or its pharmaceutically acceptable salts with a key intermediate of Formula IV by using Formula IIa.
Description
A PROCESS FOR THE PREPARATION OF LAROTRECTINIB OR ITS SALTS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 202141004943 filed on February 05, 2021.
FIELD OF THE INVENTION
The present disclosure generally relates to the field of pharmaceutical sciences and more specifically relates process for the preparation of an intermediate compound of Formula IV, which is a useful intermediate for Larotrectinib or its pharmaceutically acceptable salts. It also provides a process for the preparation of amorphous Larotrectinib or its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Larotrectinib sulfate, chemically known as (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)-l- pyrrolidinyl] pyrazolo [ 1 , 5 - a] pyrimidin- 3 -yl } - 3 -hydroxy- 1 -pyrrolidinec arboxamide sulfate having the structure shown in Formula-I, is a kinase inhibitor.
Larotrectinib sulfate is approved and is being marketed under the brand name Vitrakvi® for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory alternative treatments.
United States Pat. No. US 8513263 discloses Larotrectinib, its pharmaceutically acceptable salt and process for the preparation of same.
United States Pat. No. US 9127013 discloses Larotrectinib sulfate and a process for the preparation of amorphous form of Larotrectinib sulfate in methanol, followed by concentration of methanol by the distillation.
The present invention provides a process for the preparation of Larotrectinib sulfate which is cost effective and industrially viable.
OBJECT AND SUMMARY OF THE INVENTION
In one object, the present invention provides a process for the preparation of an intermediate compound of Formula IV comprising the steps of: a) converting Formula II into a Formula IV ; and
b) isolating Formula IV. wherein R is-SCLRi; -CO-R2; Ri is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I.
In another object, the present invention provides a novel intermediate compound of Formula Ila.
wherein R is-SO2Ri; -CO-R2; Ri is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I.
In one more embodiment, the present invention provides a process for the preparation of amorphous Larotrectinib sulfate comprising the steps of: a) taking larotrectinib in a solvent selected from polar aprotic solvent and nonpolar solvents or mixtures thereof; b) adding sulfuric acid; and c) isolating amorphous Larotrectinib sulfate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of Larotrectinib or its pharmaceutically acceptable salts using a novel intermediate of Formula Ila. Also, provides a process for the preparation of amorphous larotrectinib sulfate.
In one embodiment of the present invention provide a process for the preparation of an intermediate of Formula IV comprising the steps of: a) converting Formula II into a Formula IV ; and
b) isolating Formula IV.
wherein R is-SChRi; -CO-R2; Ri is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I.
Within the context of the present invention, R is-SChRl; -CO-R2; Rl is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I. Substitutions are selected from halo includes -F, -Cl,-Br, -I, nitro, amino, alkyloxy, Alkyl includes methyl, ethyl, propyl, butyl, iso propyl, isobutyl, t-butyl.
In one embodiment, Formula II is converted into Formula IV by reacting Formula II preferably with a suitable leaving group containing -SO2R1 in presence of a base and solvent to give Formula Ila. The suitable base is organic base includes, but not limited to trialkyl amines include, but not limited to triethyl amine, diisopropyl ethyl amine, dimethyl amine, dimethyl amino pyridine, trimethyl amine, , DBU and Inorganic bases includes, but not limited to hydroxides such KOH, NaOH, LiOH, carbonates Na2COs, K2CO3 and bicarbonates such as KHCO3, NaHCOs; preferably diisopropyl ethyl amine.
The suitable solvent for the reaction is selected from polar solvents includes, but not limited to dichloromethane, tetrahydrofuran, acetone, dimethyl formamide, dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, isopropyl acetate, n-butyl acetate, dimethyl sulfoxide; non polar solvents includes, but not limited to toluene, methyl isobutyl ketone, methyl ethyl ketone, anisole; preferably dichloromethane.
In another embodiment, the Formula Ila resulting from the above embodiment is optionally isolated and reacted with Formula III to give Formula IV.
The preparation of Formula IV using the intermediate of formula Ila a cost-effective process.
In one more embodiment, the Formula IV may be further converted into Larotrectinib or its pharmaceutically acceptable salts as per the process known in the literature WO 2010048314 and WO 2017201241.
The present invention also provides a novel intermediate of Formula Ila.
In one embodiment R is tosyl, acyl.
Yet another embodiment, the process of preparing Larotrectinib or its pharmaceutically acceptable salts as per the present invention depicted in scheme-I.
In another embodiment, the obtained Larotrectinib or its pharmaceutically acceptable salts can be further converted into suitable polymorphic forms or their solid dispersions.
Yet another embodiment, the present invention provides a process for the preparation of amorphous Larotrectinib sulfate comprising the steps of: a) taking larotrectinib in a solvent selected from polar aprotic solvent and nonpolar solvents or mixtures thereof;
b) adding sulfuric acid; and c) isolating amorphous Larotrectinib sulfate.
According to the present invention, larotrectinib is taken into a solvent selected from polar aprotic solvent and non-polar solvents or mixtures thereof. The polar aprotic solvent includes, but not limited to dimethyl formamide, dichloromethane, dimethyl sulfoxide, acetonitrile, ketonic solvents, ester solvents and ether solvents. Ketonic solvents includes, but not limited to methyl isobutyl ketone, acetone, methyl ethyl ketone, di iso butyl ketone. Ester solvents includes, but not limited to ethyl acetate, n- butyl acetate, tert- butyl acetate, ethyl salicylate, ether solvents include, but not limited to tetrahydrofuran, 1,4-doixane, diethyl ether, diisopropyl ether, dimethyl ether, diisopropyl ether; The non-polar solvents include, but not limited to toluene, diethyl ether, hexane, heptane, pentane, cyclohexane, decaline and anisole etc.
To the above larotrectinib mixture added sulfuric acid, preferably the sulfuric acid is in a suitable solvent selected from polar aprotic solvent includes, but not limited to dimethyl formamide, dichloromethane, dimethyl sulfoxide, acetonitrile, ketonic solvents, ester solvents and ether solvents. Ketonic solvents includes, but not limited to methyl isobutyl ketone, acetone, methyl ethyl ketone, di iso butyl ketone. Ester solvents includes, but not limited to ethyl acetate, n-butyl acetate, tert- butyl acetate, ethyl salicylate, ether solvents include, but not limited to tetrahydrofuran, 1,4- doixane, diethyl ether, diisopropyl ether, dimethyl ether, diisopropyl ether; preferably methyl isobutyl ketone and tetrahydrofuran filtered to isolate amorphous Larotrectinib sulfate.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
EXAMPLES
Preparation of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3-nitropyrazolo[l,5- a] pyrimidine IV:
25 g of 3-nitropyrazolo[l,5-a]pyrimidin-5-ol of Formula II, 26.98 g of p-toluene sulfonyl chloride and 25.11g of diisopropyl ethyl amine were taken in 100 ml of dichloromethane and stirred it at ambient temperature. To the reaction mixture, 25.43 g of (R)-difluorophenyl pyrrolidine and 25 ml dichloromethane mixture was added and continued stirring for 3 hrs. After completion of the reaction, the reaction mixture was quenched by adding 125 ml of water and 10 ml aq. ammonia. The reaction mixture was filtered through hyflo and washed with 25 ml of dichloromethane. The dichloromethane layer was separated and washed with water (125ml X 2), concentrated volatiles at vacuuo to yield 3-Nitropyrazolo[l,5-a]pyrimidin-5-ol of Formula IV. Weight: 46g.
Preparation of (R) -5- (2- (2,5 -difluorophenyl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5 - a]pyrimidin-3-amine V:
34.95 g ammonium chloride in 175 ml water solution was added to of slurry of 35 g Formula IV and 34.91g of Zn-dust in 175 ml of methanol at 35-40°C. The reaction mixture was heated to 50-60 °C for 2 hrs. After completion of the reaction, the reaction mixture was cooled to ambient temperature. To the reaction mixture, charged 175 ml of ethyl acetate and 70 ml of aqueous ammonia. The reaction mixture was filtered through hyflo and washed hyflo with 175 ml of ethyl acetate to remove inorganic materials. The ethyl acetate layer separated. The aqueous layer was back extracted with ethyl acetate and combined with ethyl acetate layer washed with water and 10% brine. Ethyl acetate layer was treated with 3.5 g of activated carbon, filtered and concentrated at vacuuo to yield solid of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin- l-yl)pyrazolo[l,5-a]pyrimidin-3-amine of Formula V. Weight 30g.
Preparation of Larotrectinib:
Solution of 5g Formula V and 25 ml of dichloromethane was added to slurry of 2.82 g l,l'-carbonyldiimidazole and 50 ml of dichloromethane at -10 to 0°C. The reaction mixture was stirred for 4 hrs. To the reaction mixture were added 2.36g (S)-3- hydroxypyrrolidine hydrochloride and 2.25 g of triethyl amine and allowed to warm
the reaction mixture to ambient temperature. After completion of the reaction, added 10% of citric acid aqueous solution and was separated organic layer. The organic layer was washed with water, then treated with 0.25g of activated carbon and filtered. Distilled out the volatiles at vacuuo to yield Larotrectinib crude. Weight 6.6g.
Preparation of amorphous Larotrectinib sulfate:
5 g of Larotrectinib, 150 ml of THF and 150 ml toluene were stirred at ambient temperature. To the reaction mixture was added solution of 1.09g cone, sulfuric acid in 25ml THF and stirred for 1-2 hrs. The solid was filtered and washed with the mixture of 20ml THF/Toluene (1:1). The resulting product was dried in vacuum oven
14 hrs at 40-42°C. to obtained amorphous Larotrectinib sulfate. Weight 5.92g.
Preparation of amorphous Larotrectinib sulfate:
0.5 g of Larotrectinib and 30 ml methyl isobutyl ketone (MIBK) were stirred at ambient temperature. To the reaction mixture was added solution of 0.108g cone. sulfuric acid in 2.5ml MIBK and stirred for 1-2 hrs. The solid was filtered and dried in vacuum oven 14 hrs at ambient temperature to obtained amorphous Larotrectinib sulfate. Weight 0.45g.
Claims
1. A process for the preparation of amorphous Larotrectinib sulfate comprising the steps of: a) taking larotrectinib in a solvent selected from polar aprotic solvent and non-polar solvents or mixtures thereof; b) adding sulfuric acid; and c) isolating amorphous Larotrectinib sulfate.
2. The process as claimed in claim 1, wherein the polar aprotic solvents is selected from ketonic solvents and ether solvents.
3. The process as claimed in claim 2, wherein the ketonic solvent is methyl isobutyl ketone and ether solvent is tetrahydrofuran
4. The process as claimed in claim 1, wherein the non-polar solvent is toluene.
5. The process as claimed in claim 1, wherein the mixture of solvents is tetrahydrofuran and toluene.
6. A process for the preparation of an intermediate compound of Formula IV comprising the steps of: a) converting Formula II into a Formula IV ; and
b) isolating Formula IV. wherein R is-SCLRl; -CO-R2; R1 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I.
The process as claimed in claim 6, wherein the conversion of Formula II to Formula IV carried in presence of a base and solvent. The process as claimed in claim 7, wherein the base is selected from organic base or inorganic base and the solvent is selected from polar solvent or nonpolar solvent or mixtures thereof. An intermediate compound of Formula Ila.
wherein R is-SChRi; -CO-R2; Ri is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I. The process as claimed in the proceeding claims, wherein the formula Ila and Formula IV can be converted into Larotrectinib or its pharmaceutically acceptable salts.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010048314A1 (en) | 2008-10-22 | 2010-04-29 | Array Biopharma Inc. | SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS |
| WO2016077841A1 (en) * | 2014-11-16 | 2016-05-19 | Array Biopharma, Inc. | Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate |
| WO2017201241A1 (en) | 2016-05-18 | 2017-11-23 | Mark Reynolds | Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010048314A1 (en) | 2008-10-22 | 2010-04-29 | Array Biopharma Inc. | SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS |
| US8513263B2 (en) | 2008-10-22 | 2013-08-20 | Array Biopharma Inc. | Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors |
| US9127013B2 (en) | 2008-10-22 | 2015-09-08 | Array Biopharma, Inc. | Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds |
| WO2016077841A1 (en) * | 2014-11-16 | 2016-05-19 | Array Biopharma, Inc. | Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate |
| WO2017201241A1 (en) | 2016-05-18 | 2017-11-23 | Mark Reynolds | Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide |
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