WO2024075131A1 - Co-crystal of upadacitinib and diacetyl-d-tartaric acid and process for the preparation thereof - Google Patents
Co-crystal of upadacitinib and diacetyl-d-tartaric acid and process for the preparation thereof Download PDFInfo
- Publication number
- WO2024075131A1 WO2024075131A1 PCT/IN2022/051056 IN2022051056W WO2024075131A1 WO 2024075131 A1 WO2024075131 A1 WO 2024075131A1 IN 2022051056 W IN2022051056 W IN 2022051056W WO 2024075131 A1 WO2024075131 A1 WO 2024075131A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- acetate
- upadacitinib
- suitable solvent
- Prior art date
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- WYQFJHHDOKWSHR-MNOVXSKESA-N (3S,4R)-3-ethyl-4-(1,5,7,10-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),3,7,9,11-pentaen-12-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide Chemical compound CC[C@@H]1CN(C(=O)NCC(F)(F)F)C[C@@H]1C1=CN=C2N1C(C=CN1)=C1N=C2 WYQFJHHDOKWSHR-MNOVXSKESA-N 0.000 title claims abstract description 73
- 229950000088 upadacitinib Drugs 0.000 title claims abstract description 71
- 239000013078 crystal Substances 0.000 title claims abstract description 50
- UIKHKLFBHLPAPO-HTQZYQBOSA-N (2r,3r)-2,3-diacetyl-2,3-dihydroxybutanedioic acid Chemical compound CC(=O)[C@@](O)(C(O)=O)[C@@](O)(C(C)=O)C(O)=O UIKHKLFBHLPAPO-HTQZYQBOSA-N 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000008569 process Effects 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 90
- -1 (S)(R)Diacetyl-D-tartaric acid Chemical compound 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 38
- 239000002904 solvent Substances 0.000 claims description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 27
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 20
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 18
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 14
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 14
- XLLIQLLCWZCATF-UHFFFAOYSA-N 2-methoxyethyl acetate Chemical compound COCCOC(C)=O XLLIQLLCWZCATF-UHFFFAOYSA-N 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 11
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 11
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 11
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 11
- 229940011051 isopropyl acetate Drugs 0.000 claims description 11
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 11
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 10
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229940035429 isobutyl alcohol Drugs 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 6
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 6
- 238000011065 in-situ storage Methods 0.000 claims description 6
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 claims description 5
- 239000012296 anti-solvent Substances 0.000 claims description 5
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- WYMDDFRYORANCC-UHFFFAOYSA-N 2-[[3-[bis(carboxymethyl)amino]-2-hydroxypropyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)CN(CC(O)=O)CC(O)=O WYMDDFRYORANCC-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- APTNXGQTESXKBG-UHFFFAOYSA-N n,n-diethylethanamine;n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(CC)CC.CCN(C(C)C)C(C)C APTNXGQTESXKBG-UHFFFAOYSA-N 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims 1
- 238000001144 powder X-ray diffraction data Methods 0.000 claims 1
- 238000000634 powder X-ray diffraction Methods 0.000 abstract description 20
- 238000006243 chemical reaction Methods 0.000 description 16
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 14
- 229960001270 d- tartaric acid Drugs 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 3
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 3
- 235000019797 dipotassium phosphate Nutrition 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- DNISEZBAYYIQFB-WDSKDSINSA-N (2s,3s)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-WDSKDSINSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 229960005137 succinic acid Drugs 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- FMCAFXHLMUOIGG-JTJHWIPRSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-JTJHWIPRSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- UUDLQDCYDSATCH-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;hydrate Chemical compound O.OC(=O)C(O)C(O)C(O)=O UUDLQDCYDSATCH-UHFFFAOYSA-N 0.000 description 1
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VJDVHRAORKIHCS-WBVHZDCISA-N 8-((3r,4s)-4-ethylpyrrolidin-3-yl)-3-tosyl-3h-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine Chemical compound CC[C@@H]1CNC[C@@H]1C1=CN=C2N1C(C=CN1S(=O)(=O)C=3C=CC(C)=CC=3)=C1N=C2 VJDVHRAORKIHCS-WBVHZDCISA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
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- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-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
- 239000004012 Tofacitinib Substances 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- AVMNFQHJOOYCAP-UHFFFAOYSA-N acetic acid;propanoic acid Chemical compound CC(O)=O.CCC(O)=O AVMNFQHJOOYCAP-UHFFFAOYSA-N 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- MCBXXQJEBJJFFW-VWNXMTODSA-N benzyl (3S,4R)-3-ethyl-4-[5-(4-methylphenyl)sulfonyl-1,5,7,10-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),3,7,9,11-pentaen-12-yl]pyrrolidine-1-carboxylate Chemical compound C1=CC=2N3C([C@H]4CN(C[C@H]4CC)C(=O)OCC=4C=CC=CC=4)=CN=C3C=NC=2N1S(=O)(=O)C1=CC=C(C)C=C1 MCBXXQJEBJJFFW-VWNXMTODSA-N 0.000 description 1
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- ZTUJDPKOHPKRMO-UHFFFAOYSA-N hydron;2,2,2-trifluoroethanamine;chloride Chemical compound Cl.NCC(F)(F)F ZTUJDPKOHPKRMO-UHFFFAOYSA-N 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000010977 unit operation Methods 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/16—Acetic acid esters of dihydroxylic compounds
Definitions
- the present invention relates to a Co-crystal of Upadacitinib.
- the present invention relates to a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), characterized by X-ray diffraction pattern (PXRD) comprising the peaks at about 5.3, 6.1, 7.4, 16.5 ⁇ 0.2° 2 ⁇ and further peaks additional at about 9.7, 10.6, 12.5, 14.3, 15.9, 21.3 and 24.8° ⁇ 0.2° 2 ⁇ ” and process for the preparation thereof.
- DATA Upadacitinib and Diacetyl-D-tartaric acid
- PXRD X-ray diffraction pattern
- Upadacitinib Diacetyl-D-tartaric acid (DATA) BACKGROUND OF THE INVENTION
- Upadacitinib is the adopted name of drug compound having a chemical name: (3S,4R)-3-Ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2- trifluoroethyl)- pyrrolidine-l-carboxamide compound of Formula-Ia and structure as below.
- Formula-Ia Upadacitinib also known as ABT-494, is potent and selective JAK inhibitor approved for rheumatoid arthritis (RA).
- Upadacitinib is approximately 74-fold selective for JAK1 over JAK2 in cellular assays dependent on specific, relevant cytokines. Upadacitinib demonstrates efficacy in rat arthritis models.
- ACR20 American College of Rheumatology 20 percent improvement criteria
- Patients were randomized to receive immediate-release Upadacitinib at 3, 6, 12, or 18 mg twice daily or matching placebo. The researchers found that significantly more patients receiving Upadacitinib achieved an ACR20 response (53 to 71 percent) versus placebo (34 percent).
- Upadacitinib may spare JAK2 and JAK3 dependent signaling.
- US RE47221 discloses a process for the preparation of Upadacitinib of Formula- Ia as illustrated in the Scheme-I below.
- the compound of Formula-II is deprotected in the presence of trifluoroacetic acid/HCl in 1,4-dioxane solvent to obtain compound of Formula-III, which is further reacted with benzyl-2,5- dioxopyrrolidine-1-yl-carbonate to obtain compound of Formula-IV followed by reaction with HBr/oxalyl chloride in the presence of trimethylsilyldiazomethane to obtain compound of Formula-V.
- Condensation of compound of Formula-V with compound of Formula-VI in the presence of NaH in DMF to obtain compound of Formula-VII, which further undergoes cyclization in the presence of dithaiophosphetane to obtain compound of Formula-VIII.
- the described upadacitinib salts include a tartrate hydrate, various hydrochloride solvates designated Form AA, Form BB and Form CC as well as crystalline forms of L-Maleate salt designated Form AAA and Form BBB, respectively.
- Crystalline Form-C Hemihydrate of Upadacitinib disclosed in US 9951080 is characterized by X-ray diffraction pattern (PXRD) comprising the peaks at 7.7, 7.9, 9.6, 10.3, 13.4, 13.9, 15.1, 15.5, 15.9, 17.0, 17.2, 17.8, 18.1, 18.3, 19.3, 19.7, 20.5, 20.9, 21.7, 21.9, 22.2, 23.5, 24.4, 24.9, 28.2 and 29.5° 2 ⁇ .
- PXRD X-ray diffraction pattern
- US ‘ 080 further discloses that the peaks at 7.9, 10.3, 13.4, 15.1, 15.5, 17, 20.9 and 21.7 are major characteristic peaks for Crystalline Form-C Hemihydrate of Upadacitinib.
- Crystalline Form-D Anhydrous of Upadacitinib disclosed in US 9951080 is characterized by X-ray diffraction pattern (PXRD) comprising the peaks at 4.0, 8.0, 9.7, 14.2, 14.5, 19.0 and 20.3° 2 ⁇ .
- US ‘080 further discloses that the peaks at 4.0, 9.7, 14.2, 14.5, 19.0 and 20.3° 2 ⁇ . are major characteristic peaks for Crystalline Form-D anhydrous of Upadacitinib.
- US 20220002306 A1 discloses a Crystalline form CSI of Upadacitinib (acetic acid solvate).
- US 20210380596 A1 discloses a Crystalline Form-CSII of Upadacitinib (Anhydrate).
- EP 3891151 A1 discloses a Crystalline Phosphate salt of Upadacitinib.
- WO 2020115213 A1 discloses acetic acid solvate of Upadacitinib.
- CN 112110929 A1 discloses Crystalline Forms of CM-I and CM-II of Upadacitinib.
- CN 112409362 A1 discloses Crystalline Forms of Upadacitinib intermediate.
- US 20220041611 A1 discloses crystal form-A of the Di-p-toluoyl-L-tartrate of Upadacitinib, oxalate of Upadacitinib and PTSA salt of Upadacitinib.
- WO 2021/244323 A1 discloses Crystal form CSIV of Upadacitinib (Sebacic acid Co-crystal) and Crystal form CSV of Upadacitinib (Glutaric acid Co-crystal).
- US 20220204519 A discloses a Crystal form CSVI of Upadacitinib (Succinic acid Co-crystal) and Crystal form CSVII of Upadacitinib (Adipic acid Co-crystal).
- IN 202041025283 A discloses a crystalline Form-US of Upadacitinib and succinic acid (co-crystal).
- IN 202041052794 A discloses a Crystalline Form-UF of Upadacitinib and fumaric acid.
- the above prior art references disclose various polymorphic forms of Upadacitinib free base. None of the prior art discloses co-crystals of Upadacitinib and Diacetyl- D-tartaric acid (DATA).
- the inventors of the present invention have developed a novel co-crystal of Upadacitinib and Diacetyl-D-tartaric acid which is more stable and suitable for making formulation.
- the present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), characterized by powder X-ray diffraction pattern (PXRD) comprising the peaks at about 5.3, 6.1, 7.4, 16.5 ⁇ 0.2° 2 ⁇ and further peaks at about 9.7, 10.6, 12.5, 14.3, 15.9, 21.3 and 24.8° ⁇ 0.2° 2 ⁇ ” and process for the preparation thereof.
- DATA Upadacitinib and Diacetyl-D-tartaric acid
- PXRD powder X-ray diffraction pattern
- the present invention further provides Co-crystal of Upadacitinib and Diacetyl-D- tartaric acid (DATA) characterized in that its powder X-ray powder diffraction pattern is basically the same as that of FIG.1.
- the present invention also provides a process for preparing the compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), Formula-I Diacetyl-D-tartaric acid (DATA) comprising the steps of: a) reacting compound of Formula-Va, Formula-Va with compound of Formula-VI Formula-VI in presence of a base in a suitable solvent to produce compound of Formula- XIII.
- DPTA (+)-Di-p-toluoyl-D-tartaric Acid
- CDI Carbonyldiimidazole
- SCXRD Single Crystal X-ray Diffraction
- Figure 2 Illustrates the PXRD diagram of compound of Formula-I which is a co- crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA).
- DATA Upadacitinib and Diacetyl-D-tartaric acid
- the present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, characterized by powder X-ray diffraction pattern (PXRD) comprising the peaks at about 5.3, 6.1,7.4, 9.7, 10.6, 12.5, 14.3, 15.9, 16.5, 21.3 and 24.8° ⁇ 0.2° 2 ⁇ ” and process for the preparation thereof.
- PXRD powder X-ray diffraction pattern
- the present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, characterized by powder X-ray diffraction pattern (PXRD) comprising the peaks at about 5.3, 6.1, 7.4, 16.5 ⁇ 0.2° 2 ⁇ and further the peaks at about 9.7, 10.6, 12.5, 14.3, 15.9, 21.3 and 24.8° ⁇ 0.2° 2 ⁇ ” and process for the preparation thereof.
- the present invention further provides a Co-crystal of Upadacitinib and Diacetyl- D-tartaric acid characterized in that its X-ray powder diffraction pattern is basically the same as that of FIG.1.
- the present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, characterized by powder X-ray diffraction pattern (PXRD), wherein the peak at 7.9 and 10.3 are absent in the PXRD of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid in the present invention.
- PXRD powder X-ray diffraction pattern
- the present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, characterized by powder X-ray diffraction pattern (PXRD), wherein the peak at 4.0 is absent in the PXRD of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid in the present invention.
- the present invention further provides Co-crystal comprises Upadacitinib and Diacetyl-D-tartaric acid within the same crystalline phase in a molar ratio of 1: 0.5.
- SCXRD Single Crystal X-ray Diffraction
- the co-crystal may be present in crystalline form.
- the present invention also provides a process for preparing the compound of Formula-I of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), comprising the steps of: a) reacting compound of Formula-Va, with compound of Formula-VI in presence of a base in a suitable solvent to produce compound of Formula- XIII. b) cyclizing the compound of Formula-XIII in-situ in presence of Trifluoroacetic anhydride (TFAA) in a suitable solvent to produce compound of Formula-XIV.
- TFAA Trifluoroacetic anhydride
- the base used in Step-a) is an organic or inorganic base.
- the organic base is selected from N,N-diisopropylamine, N,N-diisopropylethylamine triethylamine, N,N- dimethylamine, trimethylamine, pyridine;
- the inorganic base is selected from sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof. preferably sodium hydride.
- the solvent used in step a) is an organic solvent, for example an aprotic polar solvent comprises N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof preferably dimethylformamide; alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
- an aprotic polar solvent comprises N,N-dimethylformamide, dimethylsulfoxide, aceton
- the reaction may be performed from -60 ° C to 60 ° C for 30 min to 48 hours and then compound of Formula-XIII can be obtained by a usual procedure.
- the obtained compound-XIII can be used in the next reaction directly without isolation.
- the solvent used in step b) is an organic solvent, for example an aprotic polar solvent.
- Appropriate aprotic polar solvents can comprise N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixtures thereof, preferably dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
- step c) can be an inorganic acid comprising HCl, HBr in water or in organic solvents Methanol, Isopropyl alcohol acetic acid preferably HBr in acetic acid.
- the solvent used in step c) is an organic solvent, for example an aprotic polar solvent comprises N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof, preferably dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, 2-Ethoxyethyl acetate or mixture thereof organic acid comprises Formic acid, Acetic acid Propionic acid or mixture thereof preferably Acetic acid
- the organic acid used in step c) is selected from tartaric acid, Dibenzoyl-D-tartaric acid, Di-p-toluoyl-D-tartaric acid, Dia
- the base used in step d) is selected from triethylamine, N,N-diisopropylamine, N,N- diisopropylethylamine, N,N-dimethylamine, trimethylamine, pyridine or mixture thereof.
- the solvent used in step d) is an organic solvent, for example an aprotic polar solvent comprises dichloromethane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, or mixture thereof, preferably dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
- an aprotic polar solvent comprises dichloromethane, N,N-dimethylformamide, dimethyl
- the reaction may be performed from 0 ° C to 60 ° C for 30 min to 48hours and then compound of Formula-XVI can be obtained by a usual procedure.
- the obtained compound-XVI can be used in the next reaction directly without isolation.
- the base used in step e) is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof.
- the suitable solvent used in step e) is selected from tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water or mixture thereof preferably tetrahydrofuran;
- the reaction may be performed from 0 ° C to 60 ° C for 30 min to 48 hours and then compound of Formula-XVII can be obtained by a usual procedure.
- the suitable solvent used in step f) is an organic solvent, for example an alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ester comprises ethyl acetate, methyl acetate, n-butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
- an alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof
- ester comprises ethyl acetate, methyl acetate, n-butyl acetate, isopropyl acetate, methoxy
- the anti-solvent used in step f) is selected from ethyl acetate, methyl acetate, n- butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
- n-butyl acetate Preferably n-butyl acetate.
- the reaction may be performed from 0 ° C to 60 ° C for 30 min to 48hours and then compound of Formula-I of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA).
- Advantages of present invention 1.
- the above reaction scheme is straightforward; minimizes the unit operation, and isolates the intermediate as filterable solid. 2. Controlling of racemization and achieving required chemical and chiral purity. 3.
- EXAMPLE-1 PREPARATION OF (3R,4S)-3-[2-[[(1,1-DIMETHYLETHOXY) CARBONYL][5-[(4-METHYLPHENYL)SULFONYL]-5H-PYRROLO[2,3-b] PYRA-ZIN-2-YL]AMINO]ACETYL]-4-ETHYL-1-PYRROLIDINE CARBOXYLICACID PHENYL METHYL ESTER OF FORMULA-XIII.
- the reaction mixture was quenched with a mixture of acetic acid (38.6 g, 1.0 m.eq) and DMF (40 mL) mixture after the reaction was completed by HPLC.
- the product was extracted with toluene twice (2.5 L, 1.25 L) and the combined organic layers were washed with sodium chloride (1.25 L).
- the organic layer is concentrated and co-distilled with acetonitrile to get Compound of Formula-XIII as a syrupy mass.
- the resulted syrupy mass dissolved in acetonitrile (2.5 L) and used for next step.
- EXAMPLE-2 PREPARATION OF (3S,4R)-3-ETHYL-4-[3-[(4-METHYL PHENYL)SULFONYL]-3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]PYRAZIN-8-YL]-1- PYRROLIDINE CARBOXYLIC ACID PHENYLMETHYL ESTER OF FORMULA-XIV.
- trifluoroacetic anhydride 270.3 g, 1.28 moles
- reaction mixture was agitated at 25-30°C for 2 hours, after which the mass was diluted with DM water and washed three times with MTBE (5000 mL). Then the aqueous layer is back- extracted with dichloromethane (2*1250 mL) after pH adjustment by using aqueous ammonia (500 mL) at 0-10°C. The combined organic layers were washed with DM water (1250 mL) and the organic layers were concentrated under reduced pressure.
- EXAMPLE-04 PREPARATION OF (3S,4R)-3-ETHYL-4-[5-(P-TOLYL SULFONYL)-1,5,7,10-TETRAZATRICYCLO[7.3.0.02,6]DODECA-2(6),3,7,9, 11-PENTAE-N-12-YL]-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1- CARBOXAMIDE OF FORMULA-XVI.
- EXAMPLE-05 PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a] PYRROLO[2,3-e]PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROMETHYL)- PYRROLIDINE-1-CARBOXAMIDE, SODIUM P-TOLUENESULFONATE OF FORMULA-XVII.
- EXAMPLE-06 PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2- a]PYRROLO[2,3-e]PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROMETHYL)- PYRROLIDINE-1-CARBOXAMIDE,(+)DIACETYL-D-TARTARICACID (1:0.5) OF FORMULA-I.
- Compound of Formula-XVII (290g) was added to ethyl acetate (2250 mL) and agitated for 10 minutes before adding DM water (1125 mL) and stirring for another 30 mins.
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Abstract
5 The present invention relates to a Co-crystal of Upadacitinib. More particularly, the present invention relates to a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), characterized by powder X-ray diffraction pattern (PXRD) comprising the peaks at about 5.3, 7.4, 9.7, 10.6, 12.5, 14.3, 15.9, 16.6, 21.3 and 24.8° ± 0.2° 2θ" and process for the 10 preparation thereof. (S)(R)Diacetyl-D-tartaric acid (DATA) Formula-I
Description
CO-CRYSTAL OF UPADACITINIB AND DIACETYL-D-TARTARIC ACID AND PROCESS FOR THE PREPARATION THEREOF FIELD OF THE INVENTION The present invention relates to a Co-crystal of Upadacitinib. More particularly, the present invention relates to a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), characterized by X-ray diffraction pattern (PXRD) comprising the peaks at about 5.3, 6.1, 7.4, 16.5 ± 0.2° 2θ and further peaks additional at about 9.7, 10.6, 12.5, 14.3, 15.9, 21.3 and 24.8° ± 0.2° 2θ” and process for the preparation thereof.
Upadacitinib Diacetyl-D-tartaric acid (DATA) BACKGROUND OF THE INVENTION Upadacitinib is the adopted name of drug compound having a chemical name: (3S,4R)-3-Ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2- trifluoroethyl)- pyrrolidine-l-carboxamide compound of Formula-Ia and structure as below. Formula-Ia
Upadacitinib, also known as ABT-494, is potent and selective JAK inhibitor approved for rheumatoid arthritis (RA). Upadacitinib is approximately 74-fold
selective for JAK1 over JAK2 in cellular assays dependent on specific, relevant cytokines. Upadacitinib demonstrates efficacy in rat arthritis models. Researchers found that the proportion of patients meeting the American College of Rheumatology 20 percent improvement criteria (ACR20) at week 12 was higher with Upadacitinib than placebo (62 to 80 percent versus 46 percent). Patients were randomized to receive immediate-release Upadacitinib at 3, 6, 12, or 18 mg twice daily or matching placebo. The researchers found that significantly more patients receiving Upadacitinib achieved an ACR20 response (53 to 71 percent) versus placebo (34 percent). Preliminary evidence suggests that compared to Tofacitinib, Upadacitinib may spare JAK2 and JAK3 dependent signaling. US RE47221 discloses a process for the preparation of Upadacitinib of Formula- Ia as illustrated in the Scheme-I below. First, the compound of Formula-II is deprotected in the presence of trifluoroacetic acid/HCl in 1,4-dioxane solvent to obtain compound of Formula-III, which is further reacted with benzyl-2,5- dioxopyrrolidine-1-yl-carbonate to obtain compound of Formula-IV followed by reaction with HBr/oxalyl chloride in the presence of trimethylsilyldiazomethane to obtain compound of Formula-V. Condensation of compound of Formula-V with compound of Formula-VI in the presence of NaH in DMF to obtain compound of Formula-VII, which further undergoes cyclization in the presence of dithaiophosphetane to obtain compound of Formula-VIII. Deprotection of compound of Formula-VIII in the presence of HBr to obtain compound of Formula- IX followed by reacting with 2,2,2-trifluoroethanamine in the presence of CDI in DMF to obtain compound of Formula-X. Further, deprotection of compound of Formula-X in the presence of sodium hydroxide followed by resolution using chiral preparative HPLC to obtain Upadacitinib of Formula-(Ia). The synthetic procedure is illustrated in Scheme-I as below:
Oxalyl chloride/ THF/ 1,4-Dioxane/ Benzyl 2,5-dioxopyrrolidine- Trimethylsilyl- HCl 1-yl-carbonate diazomethane/HBr Step-I . HCl Step-II Step-III (II) (III) (IV) (V) NaH/DMF Step-IV (VI) HBr Dithaiophosphetane CDI/DMF Step-VI Step-VII Step-V (X) (IX) (VIII) Step-VIII 1. NaOH 2. Chiral preparative HPLC (VII) Upadacitinib of Formula-Ia Scheme-I US9951080 also discloses a process for the preparation of Upadacitinib of Formula- Ia as shown in Scheme II below, by the condensation of compound of Formula-Va with compound of Formula-VIa in the presence of lithium tert butoxide to obtain compound of Formula-VIIa, which undergoes cyclization in the presence of Trifluoroacetic anhydride (TFAA) in pyridine followed by deprotection in the presence of sodium hydroxide to obtain compound of Formula-XI. Further, deprotection of compound of Formula-XI in presence of HCl in EtOH/ EtOAc produces compound of Formula-XII. And, compound of Formula-XII is further reacted with 2,2,2-trifluoroethanamine in the presence of CDI, KOH and Dipotassium phosphate (K2HPO4) to obtain Upadactinib of Formula-Ia. The synthetic procedure is illustrated in Scheme-II as below:
LiOtBu 1. TFAA/ Pyridine DMA 2. NaOH Step-I Step-II (VIa) (IV) (Va) (XI) Step-III HCl/ EtOH/ EtOAc (VIIa) .2HCl CDI/ K2HPO4 Step-IV (XII) Upadacitinib (Formula-Ia) Scheme-II US 9951080 discloses various solid-state forms of upadacitinib free base such as Form- A (Isopropyl aetate/ water solvate), Form-B (hydrate), Form-C (Hemihydrate) and Form-D (Anhydrous) and different acid addition salts of upadacitinib were disclosed in US9951080. The described upadacitinib salts include a tartrate hydrate, various hydrochloride solvates designated Form AA, Form BB and Form CC as well as crystalline forms of L-Maleate salt designated Form AAA and Form BBB, respectively. Crystalline Form-C Hemihydrate of Upadacitinib disclosed in US 9951080 is characterized by X-ray diffraction pattern (PXRD) comprising the peaks at 7.7, 7.9, 9.6, 10.3, 13.4, 13.9, 15.1, 15.5, 15.9, 17.0, 17.2, 17.8, 18.1, 18.3, 19.3, 19.7, 20.5, 20.9, 21.7, 21.9, 22.2, 23.5, 24.4, 24.9, 28.2 and 29.5° 2θ. US ‘ 080 further discloses that the peaks at 7.9, 10.3, 13.4, 15.1, 15.5, 17, 20.9 and 21.7 are major characteristic peaks for Crystalline Form-C Hemihydrate of Upadacitinib.
Crystalline Form-D Anhydrous of Upadacitinib disclosed in US 9951080 is characterized by X-ray diffraction pattern (PXRD) comprising the peaks at 4.0, 8.0, 9.7, 14.2, 14.5, 19.0 and 20.3° 2θ. US ‘080 further discloses that the peaks at 4.0, 9.7, 14.2, 14.5, 19.0 and 20.3° 2θ. are major characteristic peaks for Crystalline Form-D anhydrous of Upadacitinib. US 20220002306 A1 discloses a Crystalline form CSI of Upadacitinib (acetic acid solvate). US 20210380596 A1 discloses a Crystalline Form-CSII of Upadacitinib (Anhydrate). EP 3891151 A1 discloses a Crystalline Phosphate salt of Upadacitinib. WO 2020115213 A1 discloses acetic acid solvate of Upadacitinib. CN 112110929 A1 discloses Crystalline Forms of CM-I and CM-II of Upadacitinib. CN 112409362 A1 discloses Crystalline Forms of Upadacitinib intermediate. US 20220041611 A1 discloses crystal form-A of the Di-p-toluoyl-L-tartrate of Upadacitinib, oxalate of Upadacitinib and PTSA salt of Upadacitinib. WO 2021/244323 A1 discloses Crystal form CSIV of Upadacitinib (Sebacic acid Co-crystal) and Crystal form CSV of Upadacitinib (Glutaric acid Co-crystal). US 20220204519 A discloses a Crystal form CSVI of Upadacitinib (Succinic acid Co-crystal) and Crystal form CSVII of Upadacitinib (Adipic acid Co-crystal). IN 202041025283 A discloses a crystalline Form-US of Upadacitinib and succinic acid (co-crystal). IN 202041052794 A discloses a Crystalline Form-UF of Upadacitinib and fumaric acid. The above prior art references disclose various polymorphic forms of Upadacitinib free base. None of the prior art discloses co-crystals of Upadacitinib and Diacetyl-
D-tartaric acid (DATA). The inventors of the present invention have developed a novel co-crystal of Upadacitinib and Diacetyl-D-tartaric acid which is more stable and suitable for making formulation. SUMMARY OF THE INVENTION The present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), characterized by powder X-ray diffraction pattern (PXRD) comprising the peaks at about 5.3, 6.1, 7.4, 16.5 ± 0.2° 2θ and further peaks at about 9.7, 10.6, 12.5, 14.3, 15.9, 21.3 and 24.8° ± 0.2° 2θ” and process for the preparation thereof. The present invention further provides Co-crystal of Upadacitinib and Diacetyl-D- tartaric acid (DATA) characterized in that its powder X-ray powder diffraction pattern is basically the same as that of FIG.1. The present invention also provides a process for preparing the compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), Formula-I
Diacetyl-D-tartaric acid (DATA) comprising the steps of: a) reacting compound of Formula-Va, Formula-Va
with compound of Formula-VI
Formula-VI in presence of a base in a suitable solvent to produce compound of Formula- XIII. Formula-XIII
b) cyclizing the compound of Formula-XIII in-situ in presence of Trifluoroacetic anhydride (TFAA) in a suitable solvent to produce compound of Formula-XIV. Formula-XIV
c) deprotecting the compound of Formula-XIV in-situ in presence of an acid in a suitable solvent followed by treating with (+)-Di-p-toluoyl-D-tartaric Acid (DPTA) in an alcohol solvent to produce compound of Formula-XV. Formula-XV
d) reacting the compound of Formula-XV with 2,2,2-trifluoroethanamine or it’s salt in presence of Carbonyldiimidazole (CDI) and a base in a suitable solvent to produce compound of Formula-XVI. Formula-XVI
e) deprotecting the compound of Formula-XVI in presence of a base in a suitable solvent followed by treating with p-Toluenesulfonic acid to produce a compound of Formula-XVII. XVII
f) treating the compound of Formula-XVII with Diacetyl-D-Tartaric acid in a suitable solvent followed by adding anti-solvent and precipitation the compound of Formula-I. DESCRIPTION OF THE DRAWINGS: Figure 1: Illustrates the Single Crystal X-ray Diffraction (SCXRD) diagram of compound of Formula-I which is a co-crystal of Upadacitinib and Diacetyl-D- tartaric acid (DATA). Figure 2: Illustrates the PXRD diagram of compound of Formula-I which is a co- crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA). DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, characterized by powder X-ray
diffraction pattern (PXRD) comprising the peaks at about 5.3, 6.1,7.4, 9.7, 10.6, 12.5, 14.3, 15.9, 16.5, 21.3 and 24.8° ± 0.2° 2θ” and process for the preparation thereof. The present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, characterized by powder X-ray diffraction pattern (PXRD) comprising the peaks at about 5.3, 6.1, 7.4, 16.5 ± 0.2° 2θ and further the peaks at about 9.7, 10.6, 12.5, 14.3, 15.9, 21.3 and 24.8° ± 0.2° 2θ” and process for the preparation thereof. The present invention further provides a Co-crystal of Upadacitinib and Diacetyl- D-tartaric acid characterized in that its X-ray powder diffraction pattern is basically the same as that of FIG.1. In another embodiment, the present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, characterized by powder X-ray diffraction pattern (PXRD), wherein the peak at 7.9 and 10.3 are absent in the PXRD of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid in the present invention. In another embodiment, the present invention provides a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, characterized by powder X-ray diffraction pattern (PXRD), wherein the peak at 4.0 is absent in the PXRD of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid in the present invention. The present invention further provides Co-crystal comprises Upadacitinib and Diacetyl-D-tartaric acid within the same crystalline phase in a molar ratio of 1: 0.5. Single Crystal X-ray Diffraction (SCXRD) for Upadacitinib and Diacetyl-D- tartaric acid (1:0.5) co-crystal: SCXRD measurements of the Upadacitinib and Diacetyl-D-tartaric acid crystallized in the monoclinic Crystal system with the C2 Space group and consists
of four Upadacitinib molecules with two molecules of Diacetyl-D-tartaric acid (DATA) co-former (1:0.5) in the asymmetric unit as shown below as Figure-1.
Fig-1: Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii. Hydrogen bonds are shown by dashed lines. Table 1. Crystal data and structure refinement for Upadacitinib diacetyl-D-tartaric acid co-crystal. Identification code Upadacitinib diacetyl-D-
crystal Empirical formula 2(C17H19F3N6O), C8H10O8 Formula weight 994.92 Temperature 294(2) K Wavelength 0.71073 A Crystal system Monoclinic Space group C2 Unit cell dimensions a = 25.1095(5) Ao α= 90°.
b = 23.3596(5) Ao β= 108.9710(8)°. c = 20.3721(4) Ao γ = 90°. Volume 11300.2(4) A3 Z 8 Density (calculated) 1.170 Mg/m3 Absorption coefficient 0.098 mm-1 F(000) 4144 Crystal size 0.220 x 0.180 x 0.090 mm3 θ range for data collection 1.057 to 25.000° Index ranges -29<=h<=29, -27<=k<=27, -24<=1<=24 Reflections collected 105460 Independent reflections 19888 [R(int) = 0.0774] Completeness to θ = 25.000° 100.0% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7461 and 0.6055 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 19888 / 159 / 1270 Goodness-of-fit on F2 1.076 Final R indices [I>26(I)] R1 = 0.1041, wR2 = 0.2558 R indices (all data) R1 = 0.1533, wR2 = 03091 Absolute structure parameter 0.3(3) Extinction coefficient 0.0046(6) Largest diff. peak and hole 0.726 and -0.902 e. Ao -3 Measurement Bruker D8 QUEST PHOTON-III Detector Software Used SHELXTL-PLUS Refinement: The X-ray data for Upadacitinib diacetyl-D-tartaric acid was collected at a room temperature on a Bruker D8 QUEST instrument with an IµS Mo microsource (λ=0.7107) and a PHOTON-III detector. The raw data frames were reduced and
corrected for absorption effects using Bruker Apex 3 software suite programs. The structure was solved using the intrinsic phasing method and was further refined with the SHELXL program and expanded using Fourier techniques. Anisotropic displacement parameters were included for all non-hydrogen atoms. All N, O, and C bounded H atoms were positioned geometrically and treated as riding on their parent C atoms. The solvent molecules were not identified in different Fourier maps; hence, the squeeze command was applied to remove the solvent contribution to crystal structure. The absolute configuration has been assigned by reference to an unchanged chiral in the synthetic procedure. The hydrogen-bonding interactions in the crystal structure of Upadacitinib diacetyl-D-tartaric acid are shown below in Table-2. Table-3: Hydrogen bonds for Upadacitinib diacetyl-D-tartaric acid co-crystal [Ao and °].
In another embodiment of the present invention, the co-crystal may be present in crystalline form or amorphous form. More preferably, the co-crystal may be present in crystalline form.
The present invention also provides a process for preparing the compound of Formula-I of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), comprising the steps of: a) reacting compound of Formula-Va, with compound of Formula-VI in presence of a base in a suitable solvent to produce compound of Formula- XIII. b) cyclizing the compound of Formula-XIII in-situ in presence of Trifluoroacetic anhydride (TFAA) in a suitable solvent to produce compound of Formula-XIV. c) deprotecting the compound of Formula-XIV in-situ in presence of an acid in a suitable solvent followed by treating with (+)-Di-p-toluoyl-D-tartaric Acid (DPTA) in an alcohol solvent to produce compound of Formula-XV. d) reacting the compound of Formula-XV with 2,2,2-trifluoroethanamine or its salt in presence of Carbonyldiimidazole (CDI) and a base in a suitable solvent to produce compound of Formula-XVI. e) deprotecting the compound of Formula-XVI in presence of a base in a suitable solvent followed by treating with p-Toluenesulfonic acid acid to produce compound of Formula-XVII. f) treating the compound of Formula-XVII with Diacetyl-D-Tartaric acid in a suitable solvent followed by adding anti-solvent to produce compound of Formula-I. The base used in Step-a) is an organic or inorganic base. The organic base is selected from N,N-diisopropylamine, N,N-diisopropylethylamine triethylamine, N,N- dimethylamine, trimethylamine, pyridine; the inorganic base is selected from sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof. preferably sodium hydride. The solvent used in step a) is an organic solvent, for example an aprotic polar solvent comprises N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof preferably dimethylformamide; alcohol
comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof. The reaction may be performed from -60°C to 60° C for 30 min to 48 hours and then compound of Formula-XIII can be obtained by a usual procedure. The obtained compound-XIII can be used in the next reaction directly without isolation. The solvent used in step b) is an organic solvent, for example an aprotic polar solvent. Appropriate aprotic polar solvents can comprise N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixtures thereof, preferably dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof. preferably Acetonitrile. The reaction may be performed from 30°C to 90° C for 30 min to 48hours and then compound of Formula-XIV can be obtained by a usual procedure. The obtained compound-XIVcan be used in the next reaction directly without isolation. The acid used in step c) can be an inorganic acid comprising HCl, HBr in water or in organic solvents Methanol, Isopropyl alcohol acetic acid preferably HBr in acetic acid. The solvent used in step c) is an organic solvent, for example an aprotic polar solvent comprises N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof, preferably dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl
acetate, 2-Ethoxyethyl acetate or mixture thereof organic acid comprises Formic acid, Acetic acid Propionic acid or mixture thereof preferably Acetic acid The organic acid used in step c) is selected from tartaric acid, Dibenzoyl-D-tartaric acid, Di-p-toluoyl-D-tartaric acid, Diacetyl-D-tartaric acid or mixture thereof preferably Di-p-toluoyl-D-tartaric acid The reaction may be performed from 0°C to 60° C for 30 min to 48 hours and then compound of Formula-XV can be obtained by a usual procedure. The base used in step d) is selected from triethylamine, N,N-diisopropylamine, N,N- diisopropylethylamine, N,N-dimethylamine, trimethylamine, pyridine or mixture thereof. The solvent used in step d) is an organic solvent, for example an aprotic polar solvent comprises dichloromethane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, or mixture thereof, preferably dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof. The reaction may be performed from 0°C to 60° C for 30 min to 48hours and then compound of Formula-XVI can be obtained by a usual procedure. The obtained compound-XVI can be used in the next reaction directly without isolation. The base used in step e) is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof. The suitable solvent used in step e) is selected from tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, water or mixture thereof preferably tetrahydrofuran;
The reaction may be performed from 0°C to 60° C for 30 min to 48 hours and then compound of Formula-XVII can be obtained by a usual procedure. The suitable solvent used in step f) is an organic solvent, for example an alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ester comprises ethyl acetate, methyl acetate, n-butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof. The anti-solvent used in step f) is selected from ethyl acetate, methyl acetate, n- butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof. Preferably n-butyl acetate. The reaction may be performed from 0°C to 60° C for 30 min to 48hours and then compound of Formula-I of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA). Advantages of present invention: 1. The above reaction scheme is straightforward; minimizes the unit operation, and isolates the intermediate as filterable solid. 2. Controlling of racemization and achieving required chemical and chiral purity. 3. Prepared stable co-crystal with Diacetyl-D-Tartaric acid (DATA). The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES: EXAMPLE-1: PREPARATION OF (3R,4S)-3-[2-[[(1,1-DIMETHYLETHOXY) CARBONYL][5-[(4-METHYLPHENYL)SULFONYL]-5H-PYRROLO[2,3-b] PYRA-ZIN-2-YL]AMINO]ACETYL]-4-ETHYL-1-PYRROLIDINE CARBOXYLICACID PHENYL METHYL ESTER OF FORMULA-XIII. DMF (1.0 L) was charged and cooled to 0-5°C in a round bottom flask and added sodium hydride (26.1 g, 1.1 m.eq). Compound of Formula-VI (250.0 g, 1.0 m.eq) was added to the above NaH/DMF (1.0 L) mixture over 30-60 mins and stirred for 30 mins. at 0-5°C. The resultant mixture was cooled to -20 to -30°C and added a solution of compound of Formula-Va (250.7 g, 1.1 m.eq in DMF (0.5 L)) over 30-60 mins. The mixture was then agitated for two hrs at -20 to -30°C. The reaction mixture was quenched with a mixture of acetic acid (38.6 g, 1.0 m.eq) and DMF (40 mL) mixture after the reaction was completed by HPLC. The product was extracted with toluene twice (2.5 L, 1.25 L) and the combined organic layers were washed with sodium chloride (1.25 L). The organic layer is concentrated and co-distilled with acetonitrile to get Compound of Formula-XIII as a syrupy mass. The resulted syrupy mass dissolved in acetonitrile (2.5 L) and used for next step. EXAMPLE-2: PREPARATION OF (3S,4R)-3-ETHYL-4-[3-[(4-METHYL PHENYL)SULFONYL]-3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]PYRAZIN-8-YL]-1- PYRROLIDINE CARBOXYLIC ACID PHENYLMETHYL ESTER OF FORMULA-XIV. To a solution of Compound of Formula-XIII in acetonitrile, trifluoroacetic anhydride (270.3 g, 1.28 moles) was added the mixture was warmed to 70-75°C and stirred for 4 hours. After completing the reaction on seen by HPLC, the mixture was cooled to 65- 70°C and concentrated, yielding a syrupy mass of Compound of Formula-XIV (500ml), which was used for next step without further isolation. EXAMPLE-3: PREPARATION OF 8-[(3R,4S)-4-ETHYL-3-PYRROLIDINYL]-3- [(4-METHYLPHENYL)SULFONYL]-3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]
PYRAZINE, (2S,3S)-2,3-BIS[(4-METHYLBENZOYL)OXY]-BUTANEDIOIC ACID (1:0.5) OF FORMULA-XV A solution of Compound of Formula-XIV in acetic acid (832 g, 3.21 moles) was added to HBr in acetic acid (832 g, 3.21 moles) maintain temperature of 0-10°C. The reaction mixture was agitated at 25-30°C for 2 hours, after which the mass was diluted with DM water and washed three times with MTBE (5000 mL). Then the aqueous layer is back- extracted with dichloromethane (2*1250 mL) after pH adjustment by using aqueous ammonia (500 mL) at 0-10°C. The combined organic layers were washed with DM water (1250 mL) and the organic layers were concentrated under reduced pressure. The resulting crude compound was dissolved in methanol (2125 mL), added the Di-p- toluoyl-D-Tartaric acid (136.7g, 0.35 moles) in methanol (2125 mL), and maintained for 30 minutes at 25-30°C followed by 2 hours at 50-55°C. The salt was agitated at 20- 30°C, then 0-5°C and the solid was filtered to yield pure Compound of Formula-XV (198.2g). Yield 51%; HPLC purity is 99.33%, and Chiral HPLC purity is 99.87%. EXAMPLE-04: PREPARATION OF (3S,4R)-3-ETHYL-4-[5-(P-TOLYL SULFONYL)-1,5,7,10-TETRAZATRICYCLO[7.3.0.02,6]DODECA-2(6),3,7,9, 11-PENTAE-N-12-YL]-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1- CARBOXAMIDE OF FORMULA-XVI. To a cooled 0-5°C suspension of 2,2,2-Trifluoroethylamine hydrochloride (75.73g, 1.5 m.eq) dichloromethane (900 mL), added the CDI (90.8g 1.5 m.eq) followed by triethylamine (56.6 g, 1.5 m.eq). The reaction was maintained at 0-5°C for 2-2.5 hrs, and then added a solution of Formula-XV. After completing the reaction on seen by HPLC, added the pre-cooled DM water (1125 mL, 10°C), mix for 30 minutes, and separate the organic layer with aqueous hydrochloric acid and sodium bicarbonate. Separated the organic layer, concentrated under reduced pressure resulting compound of Formula-XVI as a syrup, and dissolved in THF (2250 ml). Note: Compound of formula-XV free base solution was (225g 1.0 m.eq) was prepared by liberating salt with sodium hydroxide solution (112 mL. 1.5 m.eq) and extracting with Dichloromethane (2250 mL) and used for next step without further isolation.
EXAMPLE-05: PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a] PYRROLO[2,3-e]PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROMETHYL)- PYRROLIDINE-1-CARBOXAMIDE, SODIUM P-TOLUENESULFONATE OF FORMULA-XVII. To a solution of compound Formula-XVI in THF (2250 mL) added 50% sodium hydroxide solution (104.52g, 3.5 m.eq) at 25-30°C, maintained the reaction mixture at 50-55°C for 60-75 min, upon completion of the reaction by HPLC, cooled the reaction mixture to 25-30°C and maintained for 3-3.5h at 25-30°C. The precipitated solid was filtered and washed with THF (450 mL), dried under suction to yield compound of Formula-XVII (290g), which was used for next step without any further isolation or purification. EXAMPLE-06: PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2- a]PYRROLO[2,3-e]PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROMETHYL)- PYRROLIDINE-1-CARBOXAMIDE,(+)DIACETYL-D-TARTARICACID (1:0.5) OF FORMULA-I. Compound of Formula-XVII (290g) was added to ethyl acetate (2250 mL) and agitated for 10 minutes before adding DM water (1125 mL) and stirring for another 30 mins. The organic layer was separated, the aqueous layer was successively extracted with Ethyl acetate (1125 mL), and the combined organic layer was washed with sodium bicarbonate solution and DM water (1125 mL). After charcoal treatments concentrated under reduced pressure. Co-distilled twice with Isopropyl alcohol. Thereafter added isopropyl alcohol (337.5 mL), stirred for 15 minutes, then added (+)-Diacetyl-D- tartaric acid (48 g) in n-Butyl acetate (450 mL) solution, stirred for 90 minutes. Thereafter added n-Butyl acetate (10800 mL) agitated for 20-21h, resulting solid was filtered, washed with n-Butyl acetate (450 mL), suction dried under vacuum for 30 min and dried under vacuum to obtain Compound of Formula-I of Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid of Formula-I. Yield: 75%. HPLC purity: 99.97%.
Claims
We Claim: 1. A Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA). 2. A Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid (DATA), characterized by a PXRD pattern comprising the peaks at about 5.3, 6.1, 7.4 and 16.5°± 0.
2° 2θ. 3. The co-crystal as claimed in claim 2, further characterized by one or more additional peaks at about 9.7, 10.6, 12.5, 14.3, 15.9, 21.
3 and 24.8° ± 0.2° 2θ.
4. A process for preparing a compound of Formula-I, which is a Co-crystal of Upadacitinib and Diacetyl-D-tartaric acid, Formula-I
Diacetyl-D-tartaric acid comprising the steps of: a) reacting compound of Formula-Va, Formula-Va
with compound of Formula-VI, Formula-VI
in presence of a base in a suitable solvent to produce compound of Formula- XIII. 1
Formula-XIII b) cyclizing the compound of Formula-XIII in-situ in presence of Trifluoroacetic anhydride (TFAA) in a suitable solvent to produce compound of Formula-XIV. Formula-XIV
c) deprotecting the compound of Formula-XIV in-situ in presence of an acid in a suitable solvent followed by treating with (+)-Di-p-toluoyl-D-tartaric Acid (DPTA) in an alcohol solvent to produce compound of Formula-XV. Formula-XV
d) reacting the compound of Formula-XV with 2,2,2-trifluoroethanamine or it’s salt in presence of Carbonyldiimidazole (CDI) and a base in a suitable solvent to produce compound of Formula-XVI. 2
Formula-XVI e) deprotecting the compound of Formula-XVI in presence of a base in a suitable solvent followed by treating with p-Toluenesulfonic acid to produce compound of Formula-XVII. f) treating the compound of Formula-XVII with Diacetyl-D-Tartaric acid (DATA) in a suitable solvent followed by adding anti-solvent and precipitation the compound of Formula-I.
5. The process as claimed in claim 4, wherein, In step-a) the base used is selected from the group consisting of diisopropylamine, diisopropylethylamine triethylamine, N,N-dimethylamine, trimethyl amine, pyridine, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate and mixtures thereof; In step a) the suitable solvent used is selected from the group consisting of dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol, 2-methoxyethanol, acetone, methylisobutylketone, 2-pentanone, ethyl methyl ketone, diethyl ketone, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate and 2-methoxyethyl acetate, and mixtures thereof.
6. The process as claimed in claim 4, wherein, In step-b) the suitable solvent used is selected from the group consisting of N,N- dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butyl alcohol, isoamylalcohol, 2-methoxyethanol, acetone, methyl isobutyl 3
ketone, 2-pentanone, ethyl methyl ketone, diethyl ketone, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate, and mixtures thereof.
7. The process as claimed in claim 4, wherein, In step c) the acid used is selected from HCl or HBr in an aqueous or in an organic solvent selected from the group consisting of methanol, isopropyl alcohol and acetic acid and mixtures thereof; In step c) the suitable solvent used is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol and 2-methoxyethanol and mixtures thereof.
8. The process as claimed in claim 4, wherein, In step d) the base used is selected from the group consisting of triethylamine, diisopropylamine, diisopropylethylamine, dimethylamine, trimethyl amine, and pyridine; In step d) the suitable solvent used is selected from the group consisting of dichloromethane, dimethylformamide, dimethylsulfoxide, acetonitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert- butylalcohol, isoamylalcohol, 2-methoxyethanol, acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, 2-methoxyethyl acetate, and mixtures thereof.
9. The process as claimed in claim 4, wherein, In step e) the base used is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate and mixtures thereof; In step e) the suitable solvent used is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide and acetonitrile and mixtures thereof. 4
10. The process as claimed in claim 4, wherein, In step f) the suitable solvent used is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol, ethyl acetate, methyl acetate, n-butyl acetate, isopropyl acetate, and methoxy ethyl acetate; In step f) the anti-solvent used is selected from the group consisting of ethyl acetate, methyl acetate, n-butyl acetate, isopropyl acetate and 2-methoxyethyl acetate and mixtures thereof. 5
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WO2017066775A1 (en) * | 2015-10-16 | 2017-04-20 | Abbvie Inc. | PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]-PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND SOLID STATE FORMS THEREOF |
WO2020224633A1 (en) * | 2019-05-09 | 2020-11-12 | 苏州鹏旭医药科技有限公司 | Upadacitinib salt compound and preparation method therefor |
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WO2017066775A1 (en) * | 2015-10-16 | 2017-04-20 | Abbvie Inc. | PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]-PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND SOLID STATE FORMS THEREOF |
WO2020224633A1 (en) * | 2019-05-09 | 2020-11-12 | 苏州鹏旭医药科技有限公司 | Upadacitinib salt compound and preparation method therefor |
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