WO2011050159A1 - Compositions and processes - Google Patents
Compositions and processes Download PDFInfo
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- WO2011050159A1 WO2011050159A1 PCT/US2010/053540 US2010053540W WO2011050159A1 WO 2011050159 A1 WO2011050159 A1 WO 2011050159A1 US 2010053540 W US2010053540 W US 2010053540W WO 2011050159 A1 WO2011050159 A1 WO 2011050159A1
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- 238000000034 method Methods 0.000 title claims abstract description 89
- 239000000203 mixture Substances 0.000 title claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims description 104
- SCUMWVJJSLLWHQ-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,3-dimethylindazol-6-amine Chemical compound C1=CC2=C(C)N(C)N=C2C=C1NC1=CC=NC(Cl)=N1 SCUMWVJJSLLWHQ-UHFFFAOYSA-N 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 239000011541 reaction mixture Substances 0.000 claims description 22
- 230000002194 synthesizing effect Effects 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 19
- 239000002245 particle Substances 0.000 claims description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 17
- PVNVSSNARYHLRF-UHFFFAOYSA-N 2,3-dimethylindazol-6-amine Chemical compound C1=C(N)C=CC2=C(C)N(C)N=C21 PVNVSSNARYHLRF-UHFFFAOYSA-N 0.000 claims description 15
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 claims description 15
- 238000009826 distribution Methods 0.000 claims description 13
- 239000012022 methylating agents Substances 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 9
- 235000015096 spirit Nutrition 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 7
- 239000000543 intermediate Substances 0.000 abstract description 28
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003798 L01XE11 - Pazopanib Substances 0.000 abstract description 6
- 229960000639 pazopanib Drugs 0.000 abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 239000012455 biphasic mixture Substances 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- DVGMRZQSSNNTFY-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-n,2,3-trimethylindazol-6-amine Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C1=CC=NC(Cl)=N1 DVGMRZQSSNNTFY-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- MQHIQUBXFFAOMK-UHFFFAOYSA-N pazopanib hydrochloride Chemical compound Cl.C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 MQHIQUBXFFAOMK-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-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-IWFBPKFRSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 229940044613 1-propanol Drugs 0.000 description 1
- -1 2-(trimethylsilyl)ethyl Chemical group 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- 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
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- RGKFSIOGIJNWPQ-UHFFFAOYSA-N 5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide;hydrate;hydrochloride Chemical compound O.Cl.C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 RGKFSIOGIJNWPQ-UHFFFAOYSA-N 0.000 description 1
- KTPBKMYOIFHJMI-UHFFFAOYSA-N 5-amino-2-methylbenzenesulfonamide Chemical compound CC1=CC=C(N)C=C1S(N)(=O)=O KTPBKMYOIFHJMI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- GVXHFOKUYBWKLF-UHFFFAOYSA-O CC(NC)=C(C=CC(N(C)c1nc(N(C(C=CC2=C(C)[NH2+]C)=CC2=N)c2ccnc(Cl)n2)ncc1)=C1)C1=N Chemical compound CC(NC)=C(C=CC(N(C)c1nc(N(C(C=CC2=C(C)[NH2+]C)=CC2=N)c2ccnc(Cl)n2)ncc1)=C1)C1=N GVXHFOKUYBWKLF-UHFFFAOYSA-O 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- TXUNTXQWEARYOT-UHFFFAOYSA-N Cc1c(ccc(N(C)c2nc(N(c3cc4n[n](C)c(C)c4cc3)c3ccnc(Cl)n3)ncc2)c2)c2n[n]1C Chemical compound Cc1c(ccc(N(C)c2nc(N(c3cc4n[n](C)c(C)c4cc3)c3ccnc(Cl)n3)ncc2)c2)c2n[n]1C TXUNTXQWEARYOT-UHFFFAOYSA-N 0.000 description 1
- SVNKYHODKSWCIB-UHFFFAOYSA-N Cc1c(ccc(Nc2nc(Cl)ncc2)c2)c2n[nH]1 Chemical compound Cc1c(ccc(Nc2nc(Cl)ncc2)c2)c2n[nH]1 SVNKYHODKSWCIB-UHFFFAOYSA-N 0.000 description 1
- 241001427367 Gardena Species 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 229940009976 deoxycholate Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 108010075324 emt protein-tyrosine kinase Proteins 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000007415 particle size distribution analysis Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000011057 process analytical technology Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to compositions that are useful in the manufacture of pharmaceuticals as well as processes for preparing such compositions.
- Pazopanib is a highly bio-available, multi- tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-l, -2, -3, platelet-derived factor receptor (PDGFR) - ⁇ , - ⁇ , cytokine receptor (cKit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms).
- VEGFR vascular endothelial growth factor receptor
- PDGFR platelet-derived factor receptor
- Itk interleukin-2 receptor inducible T-cell kinase
- Lck leukocyte-specific protein tyrosine kinase
- c-Fms transmembrane glycoprotein receptor tyrosine kinase
- Pazopanib was recently approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma; thus adding to the other FDA-approved VEGF pathway inhibitors, sunitinib, bevacizumab (in combination with interferon) and sorafinib for this same indication.
- FDA Food and Drug Administration
- a composition includes a compound of formula (X):
- a composition includes a compound of formula (X):
- a composition includes a compound of formula (XII :
- a composition includes a compound of formula (XII):
- N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine includes combining N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and a base selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4- pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine to less than 2 % is less than 8 hours in a solution of an organic solvent and a methylating agent, and heating the reaction mixture to a temperature up to and including reflux for at least 4 hours to provide the compound of formula (XII).
- Figures la and lb illustrate UV and temperature profiles of two reactions in the synthesis of Intermediate 1 heated at different rates
- Figures 2a and 2b illustrate pH and temperature profiles of two reactions run with different particle size distributions of sodium bicarbonate.
- the present invention relates to the synthesis of intermediates that are useful in the manufacture of pazopanib.
- Pazopanib has the following chemical structure:
- D10 means that size in microns below which 10% of the particles lie D[v,0.1].
- D50 means that size in microns below which 50% of the particles lie D[v,0.5].
- D90 means that size in microns below which 90% of the particles lie D[v,0.9].
- the term “D99” means that size in microns below which 99% of the particles lie D[v,0.99].
- the percentage of a compound in a composition that includes Compound X is expressed as % area as determined by HPLC Method 1 as described herein, unless otherwise specified.
- the percentage of a compound in a composition that includes Compound XII is expressed as % area as determined by HPLC Method 3 as described herein, unless otherwise specified.
- particle size distribution is determined by the sieve cut method, which will be understood by those skilled in the art to mean that the smallest diameter sieve on which all particles are retained.
- a particle size distribution of > 250 ⁇ means that a 250 ⁇ sieve is the smallest diameter sieve on which all particles are retained.
- a composition includes a compound of formula (X):
- the amount of the compound of formula (XI) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.40 % and an upper limit of 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73,
- a composition includes a compound of formula (X):
- the amount of the compound of formula (XI) is between a lower limit of 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, or 1.40 % and an upper limit of 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66
- the amount of the compound of formula (X) is at least 96.0, 96.1, 96.2, 96.3, 96.4, 96.5, 96.6, 96.7, 96.8, 96.9, 97.0, 97.1, 97.2, 97.3, 97.4, 97.5, 97.6, 97.7, 97.8, 97.9 or 98.0 %.
- the particle size distribution is between a lower limit of 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 ⁇ and an upper limit of 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150 ⁇ .
- the base is selected to ensure that the pH of the mixture is less than 7 for no more than 180, 175, 170, 165, 160, 155, 150, 145, 140, 135, 130, 125, 120, 115, or 110 minutes.
- bases include sodium carbonate, sodium hydroxide, barium carbonate, sodium bicarbonate, and di-isopropylethyl amine.
- a process for synthesizing a compound of formula (X) includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with a base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 300 to provide the compound of formula (X).
- a base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 300, 275, 250, 225, 200, 175, 150, 125, 100, or 75.
- bases include sodium carbonate, sodium hydroxide, barium carbonate, sodium bicarbonate, and di-isopropylethyl amine.
- the solvent is ethanol.
- the solvent is industrial methylated spirits ((IMS is a mixture of 95% Ethanol, 4.5% Methanol and 0.5% water).
- the solvent is selected from the group consisting of toluene, DMF, acetonitrile, THF, isopropyl acetate, 1-propanol, ethanol, and 2- ethoxyethanol.
- suitable protic solvents may be used.
- the combining is performed at room temperature.
- other temperatures may be used that provide for safe reaction conditions.
- the resulting reaction mixture is stirred and heated to reflux for 6, 8, 10 or more hours.
- the resulting reaction mixture is stirred and heated to > 45°C for 20, 24, 28, 32, 36, 40, 44, 48 or more hours.
- the slurry is cooled to 45-55 °C.
- other temperatures would work as well. Water is then added to maintain the temperature between 55 and 70 °C. The reaction mixture is then stirred at that temperature for 45 minutes to 1.5 hours.
- the hold time is provided to ensure the product has enough time to crystallize out, and one of skill in the art will appreciate that other hold times will work.
- the reaction mixture is then cooled to 5 -10 °C. One of skill in the art will understand that various temperatures such as 25 or 50°C will work.
- the mixture is stirred for 45 minutes to 1.5 hours.
- the hold time is provided to ensure the product has enough time to crystallize out, and one of skill in the art will appreciate that other hold times will work.
- the product is isolated by filtration and the filter cake is washed with water (2 X 8.25 L) and ethyl acetate (1 X 4.95 L). The wet cake is dried under vacuum at 60 °C to provide A compound of formula (X).
- a composition includes a compound of formula (XII :
- the total amount of the compounds of formulae (XIII), (XIV), and/or (XV) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.
- the amount of the compound of formulae (XIII) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.40 % and an upper limit of 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70,
- the amount of the compound of formula (XIV) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.40 % and an upper limit of 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.
- the amount of the compound of formula (XV) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.40 % and an upper limit of 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.
- the amount of the compound of formula (XII) is at least 98.0, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.7, 98.8, 98.9, or 99.0 %.
- the D99 is > 350 ⁇ . In other embodiments, the D99 is > 400 ⁇ . In still other embodiments, the D99 is >450 ⁇ . In yet other embodiments, the D99 is > 500 ⁇ .
- the heating is for at least 8, 9, or 10 hours.
- the D99 is ⁇ 200 ⁇ . In other embodiments, the D99 is ⁇ 150 ⁇ . In still other embodiments, the D99 is ⁇ 125 ⁇ . In yet other embodiments, the D99 is ⁇ 100 ⁇ . In other embodiments, the D99 is ⁇ 90 ⁇ .
- the heating is for at least 4, 5, or 6 hours.
- N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine includes combining N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and a base selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4- pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine to less than 2 % w/w is less than 8 hours in a solution of organic solvent and a methylating agent, and heating the reaction mixture to a temperature up to and including reflux for at least 4 hours to provide the compound of formula (XII).
- the base is selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine to less than 0.2% w/w is less than 8 hours. In other embodiments, the base is selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4-pyrimidinyl)- 2,3-dimethyl-2H-indazol-6-amine to less than 0.2% w/w is less than 7 hours.
- Suitable bases include CS 2 CO 3 , K 2 CO 3 , and long straight-chain tertiary amine bases without hindered functioinalities, such as tributyl amine, and triethyl amine.
- the heating is for at least 5 hours. In other embodiments, the heating is for at least 6 hours.
- various organic solvents may be used, including, but not limited to, dimethylformamide (DMF), and high-boiling non-protic solvents such as N- methyl pyrrolidone (NMP), dimethyl acetamide (DMAc), and dimethyl sulfoxide (DMSO).
- NMP N- methyl pyrrolidone
- DMAc dimethyl acetamide
- DMSO dimethyl sulfoxide
- Toluene and 1-butyronitrile are two solvents that do not work well.
- various methylating agents such as dimethyl carbonate (DMC), N-methyl pyrrolidone, and dimethyl sulfoxide can be used as can various other combos, such as CH 3 I/CS 2 CO 3 and TEA/DMC.
- DMC dimethyl carbonate
- N-methyl pyrrolidone N-methyl pyrrolidone
- dimethyl sulfoxide can be used as can various other combos, such as CH 3 I/CS 2 CO 3 and TEA/DMC.
- the reaction mixture is heated to a temperature of from 100 °C to reflux.
- the reaction mixture is cooled to less than 105 °C. In some embodiments, the reaction mixture is cooled to 55-70 °C. Water is charged slowly to the mixture to form a biphasic mixture. The biphasic mixture is stirred for less than 4 hours. In some embodiments, the biphasic mixture is stirred for 1 hour. Then layers are settled for extraction. The bottom aqueous layer is removed to waste. In some embodiments, water is charged over ⁇ 1 hour (though other times can be used) to the organic layer maintaining the reaction temperature between 55-70 °C. After addition the mixture is slowly cooled.
- the mixture is slowly cooled to 5-10 °C, but other temperatures such as 25 °C can be used.
- the suspension is stirred for 2 hours. In some embodiments, the suspension is stirred at 5-10 °C, but other temperatures such as 25 °C can be used.
- the product is isolated by filtration and then the filter cake is washed with water, followed by cold 1 : 1 industrial methylated spirits: water. The wet cake is dried under vacuum at 55-60 °C to afford a compound of formula (XII).
- T r retention time
- RP reverse phase
- DCM dichloromethane
- DCE dichloroethane
- TIPS triisopropylsilyl
- TBS t-butyldimethylsilyl
- IMS industrial methylated spirits
- sodium bicarbonate > 250 ⁇ , sieved, commercially available from Spectrum, located in Gardena, California
- the solution is stirred and heated to reflux for 8 hours.
- the slurry is cooled to 50 °C, and water (5.5 L) is added to maintain the temperature between 55 and 70 °C.
- the reaction is then stirred at that temperature for one hour, and then cooled the reaction mixture to 5 -10 °C and stirred for 1 hour.
- RRT relative retention times
- IMS industrial methylated spirits
- sodium bicarbonate > 70-105 ⁇ , sieved, commercially available from Glaxo Wellcome Manufacturing, Jurong, Singapore
- the solution is stirred and heated to reflux for 8 hours.
- the slurry is cooled to 50 °C, and water (5.5 L) is added to maintain the temperature between 55 and 70 °C.
- the reaction is then stirred at that temperature for one hour, and then cooled the reaction mixture to 5 -10 °C and stirred for 1 hour.
- RRT relative retention times
- Figures 2a and 2b show the pH profile during procedures similar to procedures la and lb. Note that pH drops quickly as the reactor is heated, because HC1 is a by-product of the main reaction this profile indicates that the reaction is progressing during heatup. As more evidence of reaction during heatup, Figures la and lb show UV overlaid with the temperature profile for two different heating rates; note the significant difference in initial rate of reaction. Note: on Figures la and lb, the 2,3-dimethyl-2H-indazole-6-amine curve is indicated by ⁇ and the line that corresponds thereto, the 2,4-dichloropyrimidine curve is indicated by and the line that corresponds thereto, and the compound X curve is indicated by o and the line that corresponds thereto. The plain curve indicates temperature.
- RRT relative retention times
- N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine (Intermediate 1) (1.31 kg, 4.78 mol, 1 equiv) and potassium carbonate having a D99 as described below of ⁇ 100 ⁇ (1.96 kg, 14.3 mol, 3 equiv) (commercially available from Albemarle, Baton Rouge, Louisiana) is suspended in a solution of dimethylformamide (4.3 L) and dimethyl carbonate (2.2 L) under a nitrogen atmosphere. The reaction mixture is heated to reflux (> 110 °C) and stirred for 6-7 hours. The reaction mixture is cooled to 55-70 °C and waster is charged (2.6 L) slowly to the mixture.
- N-(2-chloro-4-pyrimidinyl)-N,2,3-trimethyl-2H-indazol-6-amine (Intermediate 2) (1.66 kg, 5.8 mol, 1.0 equiv) and 5-amino-2-methyl benzenesulfonamide (Starting Material 3 (SM3)) (commercially available from Asymchem Laboratories (Fuxin) Co., Ltd, PR China and from Sumitomo Seika Chemicals Co. Ltd, Japan) (1.19 kg, 6.4 mol, 1.1 equiv) is suspended in 19.9 L of methanol. The mixture is heated to reflux and stirred until complete dissolution is observed.
- SM3 Starting Material 3
- the mixture is charged with 4M HCl in 1, 4-dioxane (30.0 mL, 0.116 mol, 0.02 equiv) between 60-65 °C.
- the mixture is stirred at reflux for 12 hours.
- the reaction is deemed complete when the amount IM2 is less than or equal to 0.05% w/w by HPLC.
- the mixture is cooled to 20-25 °C and stirred for 1 hour.
- the product is isolated by filtration and the filter cake is washed with acetonitrile (2 X 5.8 L). The wet cake is dried under vacuum at 50-60 °C to afford Intermediate 3.
- the monohydrate slurry is cooled to -5 to +5 °C at less than 0.5 °C/min.
- the suspension is held at that temperature (-5 to +5 °C) for up to 36 hours.
- the product is isolated using a filter dryer with jacket temperature set at to 0 °C.
- the slurry is settled for at least 30 minutes prior to filtration.
- Mother liquors are removed using 1-2 barg of nitrogen pressure.
- the cake is washed with 5.6 L of premixed aqueous acetonitrile (75 vol % acetonitrile) at 0-5 °C (held rinse in the reactor until cooled to 0-5 °C).
- the wash is held on the cake for 30 minutes prior to filtration at 1-2 barg nitrogen pressure.
- the cake is deliquored at 1-2 barg nitrogen pressure, with the filter dried jacket at 25°C and the cake is smoothed cake as necessary. After the cake is deliquored, the jacket temperature was increased to 65 °C on the filter drier and vacuum dry the
- the conversion liquors are filtered using 1-2 barg nitrogen pressure.
- the cake is deliquored with the jacket at 65 °C using 1-2 barg nitrogen pressure and is smoothed as necessary. Vacuum is applied with the jacket at 60 °C and the contents are agitated until the loss on drying (LOD) was obtained ⁇ 0.5% to afford the Final Product.
- LOD loss on drying
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Abstract
Methods of making intermediates useful in the synthesis of pazopanib and compositions of such intermediates are described.
Description
COMPOSITIONS AND PROCESSES
FIELD OF THE INVENTION
The present invention relates to compositions that are useful in the manufacture of pharmaceuticals as well as processes for preparing such compositions.
BACKGROUND OF THE INVENTION
Pazopanib is a highly bio-available, multi- tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-l, -2, -3, platelet-derived factor receptor (PDGFR) -α, -β, cytokine receptor (cKit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). Pazopanib was recently approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma; thus adding to the other FDA-approved VEGF pathway inhibitors, sunitinib, bevacizumab (in combination with interferon) and sorafinib for this same indication.
Processes by which pazopanib and its intermediates can be synthesized have been described in US Patent No. 7,105,530 as well as in the published PCT application WO03/106416.
SUMMARY OF THE INVENTION
and 0.05 - 1.0 % of a com ound of formula (XI):
According to another aspect of the present invention, a composition includes a compound of formula (X):
According to still another aspect of the present invention, a process for synthesizing a compound of formula X):
includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with sodium bicarbonate having a particle size distribution of > 250 μιη to provide the compound of formula (X).
According to yet another aspect of the present invention, a process for synthesizing a compound of formula X):
includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with sodium bicarbonate having a particle size distribution of 50 μιη to 150 μιη to provide the compound of formula (X).
According to another aspect of the present invention, a process for synthesizing a compound of formula (X):
includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with a base selected to ensure that the pH of the mixture is less than 7 for no more than 180 minutes to provide the compound of formula (X).
According to still another aspect of the present invention, a process for synthesizing a compound of formula X):
includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with a base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 300 to provide the compound of formula
(X).
According to yet another aspect of the present invention, a composition includes a compound of formula (XII :
and a total percentage of 0.05 - 1.0 % of compounds of formulae (XIII), (XIV), and/or
(XV):
According to another aspect of the present invention, a composition includes a compound of formula (XII):
total percentage of 1.01 - 3% of compounds of formulae (XIII), (XIV), and/or
According to still another aspect of the present invention, a process for synthesizing a compound of formula XII):
includes suspending N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and potassium carbonate having a D99 of > 300 μιη in a solution of an organic solvent and a methylating agent, and heating the reaction mixture to a temperature up to and including reflux for at least 8 hours to provide the compound of formula (XII).
According to yet another aspect of the present invention, a process for synthesizing a compound of formula XII):
includes suspending N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and potassium carbonate having a D99 of < 200 μιη in a solution of an organic solvent and a methylating agent, and heating the reaction mixture to a temperature up to and including reflux for at least 4 hours to provide the compound of formula (XII).
According to another aspect of the present invention, a process for synthesizing a compound of formula (XII :
includes combining N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and a base selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4- pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine to less than 2 % is less than 8 hours in a solution of an organic solvent and a methylating agent, and heating the reaction mixture
to a temperature up to and including reflux for at least 4 hours to provide the compound of formula (XII).
BRIEF DESCRIPTION OF THE DRAWINGS
Figures la and lb illustrate UV and temperature profiles of two reactions in the synthesis of Intermediate 1 heated at different rates; and
Figures 2a and 2b illustrate pH and temperature profiles of two reactions run with different particle size distributions of sodium bicarbonate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the synthesis of intermediates that are useful in the manufacture of pazopanib. Pazopanib has the following chemical structure:
and has the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide.
As used herein, the term "between" includes both endpoints unless otherwise stated.
As used herein, the term "D10" means that size in microns below which 10% of the particles lie D[v,0.1].
As used herein, the term "D50" means that size in microns below which 50% of the particles lie D[v,0.5].
As used herein, the term "D90" means that size in microns below which 90% of the particles lie D[v,0.9].
As used herein, the term "D99" means that size in microns below which 99% of the particles lie D[v,0.99].
As used herein, the percentage of a compound in a composition that includes Compound X is expressed as % area as determined by HPLC Method 1 as described herein, unless otherwise specified.
As used herein, the percentage of a compound in a composition that includes Compound XII is expressed as % area as determined by HPLC Method 3 as described herein, unless otherwise specified.
As used herein, particle size distribution is determined by the sieve cut method, which will be understood by those skilled in the art to mean that the smallest diameter sieve on which all particles are retained. For example, a particle size distribution of > 250μιη means that a 250μιη sieve is the smallest diameter sieve on which all particles are retained.
In some embodiments, the amount of the compound of formula (XI) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.40 % and an upper limit of 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or 1.0 %.
In some embodiments, the amount of the compound of formula (X) is at least 98.0, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.7, 98.8, 98.9, or 99.0 %.
According to another aspect of the present invention, a composition includes a compound of formula (X):
In some embodiments, the amount of the compound of formula (XI) is between a lower limit of 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, or 1.40 % and an upper limit of 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0%.
In some embodiments, the amount of the compound of formula (X) is at least 96.0, 96.1, 96.2, 96.3, 96.4, 96.5, 96.6, 96.7, 96.8, 96.9, 97.0, 97.1, 97.2, 97.3, 97.4, 97.5, 97.6, 97.7, 97.8, 97.9 or 98.0 %.
According to another aspect of the present invention, a process for synthesizing a compound of formula (X):
includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with sodium bicarbonate having a particle size distribution of > 250 μιη to provide the compound of formula (X).
According to yet another aspect of the present invention, a process for
includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with sodium bicarbonate having a particle size distribution of 50 μιη to 150 μιη to provide the compound of formula (X).
In some embodiments, the particle size distribution is between a lower limit of 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 μιη and an upper limit of 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150 μιη.
According to still another aspect of the present invention, a process for
includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with a base selected to ensure that the pH of the mixture is less than 7 for no more than 180 minutes to provide the compound of formula (X).
In some embodiments, the base is selected to ensure that the pH of the mixture is less than 7 for no more than 180, 175, 170, 165, 160, 155, 150, 145, 140, 135, 130, 125, 120, 115, or 110 minutes. One of ordinary skill in the art of chemical manufacturing processes can select suitable bases. Exemplary bases include sodium carbonate, sodium hydroxide, barium carbonate, sodium bicarbonate, and di-isopropylethyl amine.
According to another aspect of the present invention, a process for synthesizing a compound of formula (X):
includes combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with a base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 300 to provide the compound of formula (X).
In some embodiments, a base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 300, 275, 250, 225, 200, 175, 150, 125, 100, or 75. One of ordinary skill in the art of chemical manufacturing processes can select suitable bases. Exemplary bases include sodium carbonate, sodium hydroxide, barium carbonate, sodium bicarbonate, and di-isopropylethyl amine.
In embodiments according to the foregoing aspects of the processes for synthesizing compound (X), the solvent is ethanol. In other embodiments, the solvent is industrial methylated spirits ((IMS is a mixture of 95% Ethanol, 4.5% Methanol and 0.5% water). In still other embodiments, the solvent is selected from the group consisting of toluene, DMF, acetonitrile, THF, isopropyl acetate, 1-propanol, ethanol, and 2- ethoxyethanol. As one of skill in the art will appreciate, suitable protic solvents may be used.
In embodiments according to the foregoing aspects of the processes for synthesizing compound (X), the combining is performed at room temperature. As one skill in the art will understand, other temperatures may be used that provide for safe reaction conditions. In some embodiments, the resulting reaction mixture is stirred and heated to reflux for 6, 8, 10 or more hours. In other embodiments, the resulting reaction mixture is stirred and heated to > 45°C for 20, 24, 28, 32, 36, 40, 44, 48 or more hours. In some embodiments, the slurry is cooled to 45-55 °C. As one of skill in the art will appreciate, other temperatures would work as well. Water is then added to maintain the temperature between 55 and 70 °C. The reaction mixture is then stirred at that temperature for 45 minutes to 1.5 hours. The hold time is provided to ensure the product has enough time to crystallize out, and one of skill in the art will appreciate that other hold times will work. The reaction mixture is then cooled to 5 -10 °C. One of skill in the art will understand that various temperatures such as 25 or 50°C will work. The mixture is stirred for 45 minutes to 1.5 hours. The hold time is provided to ensure the product has enough time to crystallize out, and one of skill in the art will appreciate that other hold
times will work. The product is isolated by filtration and the filter cake is washed with water (2 X 8.25 L) and ethyl acetate (1 X 4.95 L). The wet cake is dried under vacuum at 60 °C to provide A compound of formula (X).
According to yet another aspect of the present invention, a composition includes a compound of formula (XII :
total percentage of 0.05 - 3.0 % of compounds of formulae (XIII), (XIV), and/or
In some embodiments according to this aspect of the present invention, the total amount of the compounds of formulae (XIII), (XIV), and/or (XV) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66,
0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, or 1.40 % and an upper limit of 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0%.
In some embodiments according to this aspect of the present invention, the amount of the compound of formulae (XIII) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.40 % and an upper limit of 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or 1.0 %
In some embodiments according to this aspect of the present invention, the amount of the compound of formula (XIV) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.40 % and an upper limit of 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76,
0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or 1.0 %
In some embodiments according to this aspect of the present invention, the amount of the compound of formula (XV) is between a lower limit of 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, or 0.40 % and an upper limit of 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, or 1.0 %
In some embodiments according to this aspect of the present invention, the amount of the compound of formula (XII) is at least 98.0, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.7, 98.8, 98.9, or 99.0 %.
According to still another aspect of the present invention, a process for synthesizing a compound of formula XII):
includes suspending N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and potassium carbonate having a D99 of > 300 μιη in a solution of an organic solvent and a methylating agent. The reaction mixture is heated to a temperature up to and including reflux for at least 8 hours to provide the compound of formula (XII).
In some embodiments according to this aspect of the present invention, the D99 is > 350 μιη. In other embodiments, the D99 is > 400 μιη. In still other embodiments, the D99 is >450 μιη. In yet other embodiments, the D99 is > 500 μιη.
In some embodiments according to this aspect of the present invention, the heating is for at least 8, 9, or 10 hours.
According to yet another aspect of the present invention, a process for
includes suspending N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and potassium carbonate having a D99 of < 200 μιη in a solution of an organic solvent and a methylating agent, and heating the reaction mixture to a temperature up to and including reflux for at least 4 hours to provide the compound of formula (XII).
In some embodiments according to this aspect of the present invention, the D99 is < 200 μιη. In other embodiments, the D99 is < 150 μιη. In still other embodiments, the D99 is < 125 μιη. In yet other embodiments, the D99 is < 100 μιη. In other embodiments, the D99 is < 90 μιη.
In some embodiments according to this aspect of the present invention, the heating is for at least 4, 5, or 6 hours.
According to another aspect of the present invention, a process for synthesizing a compound of formula (XII :
includes combining N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and a base selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4- pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine to less than 2 % w/w is less than 8 hours in a solution of organic solvent and a methylating agent, and heating the reaction mixture to a temperature up to and including reflux for at least 4 hours to provide the compound of formula (XII).
In some embodiments, the base is selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine to less than 0.2% w/w is less than 8 hours. In other embodiments, the base is selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4-pyrimidinyl)- 2,3-dimethyl-2H-indazol-6-amine to less than 0.2% w/w is less than 7 hours. Suitable
bases include CS2CO3, K2CO3, and long straight-chain tertiary amine bases without hindered functioinalities, such as tributyl amine, and triethyl amine.
In some embodiments, the heating is for at least 5 hours. In other embodiments, the heating is for at least 6 hours.
In embodiments according to the foregoing aspects of the processes for synthesizing compound (XII), various organic solvents may be used, including, but not limited to, dimethylformamide (DMF), and high-boiling non-protic solvents such as N- methyl pyrrolidone (NMP), dimethyl acetamide (DMAc), and dimethyl sulfoxide (DMSO). Toluene and 1-butyronitrile are two solvents that do not work well.
In embodiments according to the foregoing aspects of the processes for synthesizing compound (XII), various methylating agents, such as dimethyl carbonate (DMC), N-methyl pyrrolidone, and dimethyl sulfoxide can be used as can various other combos, such as CH3I/CS2CO3 and TEA/DMC. Dimethyl sulfate and
formaldehyde/formic acid will not work for this reaction. In some embodiments, 1, 2, or 3 to 2, 3, 4, or 5 equivalents of potassium carbonate is used. In some embodiments, the methylating agent is used to excess. In other embodiments, 2, 3, or 4 to 4, 5, 6, or 7 equivalents of the methylating agent is used. Equivalents are determined relative to Compound X.
In embodiments according to the foregoing aspects of the processes for synthesizing compound (XII), a nitrogen atmosphere can be used, although this is not required.
In embodiments according to the foregoing aspects of the processes for synthesizing compound (XII),the reaction mixture is heated to a temperature of from 100 °C to reflux.
In embodiments according to the foregoing aspects of the processes for synthesizing compound (XII), the reaction mixture is cooled to less than 105 °C. In some embodiments, the reaction mixture is cooled to 55-70 °C. Water is charged slowly to the mixture to form a biphasic mixture. The biphasic mixture is stirred for less than 4 hours. In some embodiments, the biphasic mixture is stirred for 1 hour. Then layers are settled for extraction. The bottom aqueous layer is removed to waste. In some embodiments, water is charged over ~1 hour (though other times can be used) to the organic layer
maintaining the reaction temperature between 55-70 °C. After addition the mixture is slowly cooled. In some embodiments, the mixture is slowly cooled to 5-10 °C, but other temperatures such as 25 °C can be used. The suspension is stirred for 2 hours. In some embodiments, the suspension is stirred at 5-10 °C, but other temperatures such as 25 °C can be used. The product is isolated by filtration and then the filter cake is washed with water, followed by cold 1 : 1 industrial methylated spirits: water. The wet cake is dried under vacuum at 55-60 °C to afford a compound of formula (XII).
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
EXAMPLES
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:
g (grams); mg (milligrams);
L (liters); mL (milliliters);
μΐ, (microliters); psi (pounds per square inch);
M (molar); mM (millimolar);
N (Normal) Kg (kilogram)
i. v. (intravenous); Hz (Hertz);
MHz (megahertz); mol (moles);
mmol (millimoles); RT (room temperature);
min (minutes); h (hours);
mp (melting point); TLC (thin layer chromatography);
Tr (retention time); RP (reverse phase);
DCM (dichloromethane); DCE (dichloroethane);
DMF (N,N-dimethylformamide); HO Ac (acetic acid);
TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);
TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);
HPLC (high pressure liquid chromatography);
THF (tetrahydrofuran); DMSO (dimethylsulfoxide);
EtOAc (ethyl acetate);DME (1 ,2-dimethoxyethane);
EDTA ethylenediaminetetraacetic acid
FBS fetal bovine serum
IMDM Iscove's Modified Dulbecco's medium
PBS phosphate buffered saline
RPMI Roswell Park Memorial Institute
RIPA buffer *
RT room temperature
* 150 mM NaCl, 50 mM Tris-HCl, pH 7.5, 0.25% (w/v) -deoxycholate, 1% NP- 40, 5 mM sodium orthovanadate, 2 mM sodium fluoride, and a protease inhibitor cocktail.
Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions conducted under an inert atmosphere at room temperature unless otherwise noted.
The following examples describe the syntheses of intermediates useful in the synthesis of the compound of formula (I) as well as the synthesis of the compound of formula (I) and the hydrochloride salt and monohydrate monohydrochloride salt thereof:
Intermediate 1
Synthesis of Intermediate 1 (N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6- amine) (Intermediate 1)
Procedure la
To a solution of 2,3-dimethyl-2H-indazol-6-amine (Starting Material 1 (SMI)) (commercially available from Dottikon Exclusive Synthesis AG, Switzerland and from Divi's Laboratories Limited, India) (1.1 kg, 6.8 mol, 1.0 equiv) and 2,4- dichloropyrimidine (Starting Material 2 (SM2)) (commercially available from Suven Life Sciences Limited, India and from Piramal Healthcare Limited, India) (1.22 kg, 8.1. mol, 1.2 equiv) in 11 L of industrial methylated spirits (IMS is a mixture of 95% Ethanol, 4.5% Methanol and 0.5%> water) is charged sodium bicarbonate (> 250 μιη, sieved, commercially available from Spectrum, located in Gardena, California) (1.26 kg, 15.0 mol, 2.2 equiv) at room temperature. The solution is stirred and heated to reflux for 8 hours. The slurry is cooled to 50 °C, and water (5.5 L) is added to maintain the temperature between 55 and 70 °C. The reaction is then stirred at that temperature for one hour, and then cooled the reaction mixture to 5 -10 °C and stirred for 1 hour. The product is isolated by filtration and the filter cake is washed with water (2 X 8.25 L) and ethyl acetate (1 X 4.95 L). The wet cake is dried under vacuum at 60 °C to afford a product that is > 97.60% Intermediate 1 (IM1) and 1.08% Impurity 1 by HPLC using the method described below.
Impurity 1
HPLC Method 1
(min) (%) B
0 84 (%)
16
20 53
47
20.1 84
16
25 84
16
Flow Rate 1.0 mL per minute
Temperature 40°C
UV Detection Wavelength 242 nm
Sample Concentration 0.5 mg/mL
Injection Volume 5 μΐ^
Exemplary relative retention times (RRT) under the chromatographic conditions specified are as follows:
Procedure lb
To a solution of 2,3-dimethyl-2H-indazol-6-amine (Starting Material 1 (SMI)) (commercially available from Dottikon Exclusive Synthesis AG, Switzerland and from Divi's Laboratories Limited, India) (1.1 kg, 6.8 mol, 1.0 equiv) and 2,4- dichloropyrimidine (Starting Material 2 (SM2)) (commercially available from Suven Life Sciences Limited, India and from Piramal Healthcare Limited, India) (1.22 kg, 8.1. mol, 1.2 equiv) in 11 L of industrial methylated spirits (IMS is a mixture of 95% Ethanol, 4.5%) Methanol and 0.5%> water) is charged sodium bicarbonate (> 70-105 μιη, sieved,
commercially available from Glaxo Wellcome Manufacturing, Jurong, Singapore) (1.26 kg, 15.0 mol, 2.2 equiv) at room temperature. The solution is stirred and heated to reflux for 8 hours. The slurry is cooled to 50 °C, and water (5.5 L) is added to maintain the temperature between 55 and 70 °C. The reaction is then stirred at that temperature for one hour, and then cooled the reaction mixture to 5 -10 °C and stirred for 1 hour. The product is isolated by filtration and the filter cake is washed with water (2 X 8.25 L) and ethyl acetate (1 X 4.95 L). The wet cake is dried under vacuum at 60 °C to afford a product that is > 99.00% Intermediate 1 (IM1) and 0.19% Impurity 1 by HPLC using the method described above in Procedure la.
Reaction profiles of procedures similar to procedures la and lb were followed using offline HPLC samples run on the HPLC Method 2 to track Impurity 1 throughout the reaction progress. In addition to offline HPLC measurements of experimental reactions, various process analytical technology instruments (IR, UV, pH) were used.
HPLC Method 2
Exemplary relative retention times (RRT) under the chromatographic conditions specified are as follows:
Figures 2a and 2b show the pH profile during procedures similar to procedures la and lb. Note that pH drops quickly as the reactor is heated, because HC1 is a by-product of the main reaction this profile indicates that the reaction is progressing during heatup. As more evidence of reaction during heatup, Figures la and lb show UV overlaid with the temperature profile for two different heating rates; note the significant difference in initial rate of reaction. Note: on Figures la and lb, the 2,3-dimethyl-2H-indazole-6-amine curve is indicated by□ and the line that corresponds thereto, the 2,4-dichloropyrimidine curve is indicated by and the line that corresponds thereto, and the compound X curve is indicated by o and the line that corresponds thereto. The plain curve indicates temperature.
As shown in Figures 2a and 2b, the pH levels out in both cases and eventually increases to a basic regime, though for the fine bicarbonate (PSD 70-105 μιη), the time and "depth" in the acidic region is much smaller. This indicates that particle size distribution of the base impacts dissolution and further consumption of the acid byproduct of the reaction. This is also an indication that pH is a good way to monitor the reaction progress. In Figures 2a and 2b, note that the curve with the shaded portion indicates pH levels while the other curve indicates temperature.
In addition to the variation in the pH profiles, significant differences were seen in the purity of the offloaded Intermediate 1. As shown in Table 1 below, the more acidic the reaction, the more Impurity 1 is present in the product. Also, the higher the value of the integral of the pH profile over the duration of acidic conditions (the shaded regions in Figures 2a and 2b), the more Impurity 1 is present in the product.
Table 1
Purity results
Intermediate 2
Synthesis of N-(2-chloro-4-pyrimidinyl)-N,2,3-trimethyl-2H-indazol-6-amine (Intermediate 2) and pseudodimer (Impurity 2)
Intermediate 2
Procedure 2a
N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine (IMl) (1.31 kg, 4.78 mol, 1 equiv) and potassium carbonate having a D99 as described below of > 300 μιη (1.96 kg, 14.3 mol, 3 equiv) (commercially available from Armand Products
Company, Princeton, New Jersey) is suspended in a solution of dimethylformamide (4.3 L) and dimethyl carbonate (2.2 L) under a nitrogen atmosphere. The reaction mixture is heated to reflux (> 110 °C) and stirred for 10-12 hours. The reaction mixture is cooled to 55-70 °C and waster is charged (2.6 L) slowly to the mixture. The biphasic mixture is stirred for lh and then layers are settled for extraction. The bottom aqueous layer is removed to waste. Water is charged (13.1 L) over ~1 hr to the organic layer maintaining the reaction temperature between 55-70 °C. After addition the mixture is slowly cooled to 5-10 °C and the suspension is stirred for 2 hours at 5-10 °C. The product is isolated by filtration and then the filter cake is washed with water (2 X 5.9 L), followed by cold 1: 1 industrial methylated spirits: water (1 X 2.6 L). The wet cake is dried under vacuum at 55-60 °C to afford a product that is > 98 % Intermediate 2 (IM2), and < 2% combined impurities 2-4 as determined by HPLC and/or LC/MS.
HPLC Method 3
Exemplary relative retention times (RRT) under the chromatographic conditions specified are as follows:
Impurity 4
Procedure 2b
N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine (Intermediate 1) (1.31 kg, 4.78 mol, 1 equiv) and potassium carbonate having a D99 as described below of < 100 μιη (1.96 kg, 14.3 mol, 3 equiv) (commercially available from Albemarle, Baton Rouge, Louisiana) is suspended in a solution of dimethylformamide (4.3 L) and dimethyl carbonate (2.2 L) under a nitrogen atmosphere. The reaction mixture is heated to reflux (> 110 °C) and stirred for 6-7 hours. The reaction mixture is cooled to 55-70 °C and waster is charged (2.6 L) slowly to the mixture. The biphasic mixture is stirred for lh and then layers are settled for extraction. The bottom aqueous layer is removed to waste. Water is charged (13.1 L) over ~1 hr to the organic layer maintaining the reaction temperature between 55-70 °C. After addition the mixture is slowly cooled to 5-10 °C and the suspension is stirred for 2 hours at 5-10 °C. The product is isolated by filtration
and then the filter cake is washed with water (2 X 5.9 L), followed by cold 1: 1 industrial methylated spirits: water (1 X 2.6 L). The wet cake is dried under vacuum at 55-60 °C to afford a product that is > 98 % Intermediate 2 (IM2), and < 2% combined impurities 2-4 as determined by HPLC and/or LC/MS.
Table 2
Potassium Carbonate Particle Size Distribution Analysis (Sympatec)
* only one analysis performed
Intermediate 3
Synthesis of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-2- pyrimidinyl}amino)-2-methylbenzenesulfonamide Hydrochloride (Intermediate 3)
Intermediate 3
N-(2-chloro-4-pyrimidinyl)-N,2,3-trimethyl-2H-indazol-6-amine (Intermediate 2) (1.66 kg, 5.8 mol, 1.0 equiv) and 5-amino-2-methyl benzenesulfonamide (Starting Material 3 (SM3)) (commercially available from Asymchem Laboratories (Fuxin) Co.,
Ltd, PR China and from Sumitomo Seika Chemicals Co. Ltd, Japan) (1.19 kg, 6.4 mol, 1.1 equiv) is suspended in 19.9 L of methanol. The mixture is heated to reflux and stirred until complete dissolution is observed. At this stage, the mixture is charged with 4M HCl in 1, 4-dioxane (30.0 mL, 0.116 mol, 0.02 equiv) between 60-65 °C. The mixture is stirred at reflux for 12 hours. The reaction is deemed complete when the amount IM2 is less than or equal to 0.05% w/w by HPLC. The mixture is cooled to 20-25 °C and stirred for 1 hour. The product is isolated by filtration and the filter cake is washed with acetonitrile (2 X 5.8 L). The wet cake is dried under vacuum at 50-60 °C to afford Intermediate 3.
Intermediate 4 and Final Product
Intermediate 4 Final Product
(Pazopanib hydrochloride Form 1)
Synthesis of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-2- pyrimidinyl}amino)-2-methylbenzenesulfonamide Hydrochloride Monohydrate and 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-2-pyrimidinyl}amino)-2- methylbenzenesulfonamide Hydrochloride Form 1
Intermediate 3 (IM3) (1.4 kg, 2.95 mol, 1.0 equiv) is suspended in 6.1 L of acetonitrile/water, 1.6/1 mixture and is dissolved above 70 °C. The clear solution is filtered hot, maintaining the temperature above 55 °C throughout the filtration. The reactor and lines are rinsed with 7.35 L of acetonitrile at 20-60 °C. The filtered solution is heated at about 1 °C/min to 68-73 °C until dissolved. The clear solution is cooled to 43-47 °C at 0.5 to 1.5 °C/min. The solution is held at 43-47 °C for 90 minutes for nucleation of the monohydrate. The monohydrate slurry is cooled to -5 to +5 °C at less than 0.5 °C/min. The suspension is held at that temperature (-5 to +5 °C) for up to 36
hours. The product is isolated using a filter dryer with jacket temperature set at to 0 °C. The slurry is settled for at least 30 minutes prior to filtration. Mother liquors are removed using 1-2 barg of nitrogen pressure. The cake is washed with 5.6 L of premixed aqueous acetonitrile (75 vol % acetonitrile) at 0-5 °C (held rinse in the reactor until cooled to 0-5 °C). The wash is held on the cake for 30 minutes prior to filtration at 1-2 barg nitrogen pressure. The cake is deliquored at 1-2 barg nitrogen pressure, with the filter dried jacket at 25°C and the cake is smoothed cake as necessary. After the cake is deliquored, the jacket temperature was increased to 65 °C on the filter drier and vacuum dry the
Intermediate 4 (IM4) while agitating the cake. The vacuum is released and the jacket temperature increased to >75 °C with continued agitation until the cake temperature >55 °C is achieved. A separate vessel is charged with 8.4 L of aqueous acetonitrile (3 vol% water) and the solution is heated to > 70 °C. (28.0 g, 2.5% w/w) micronized Final Product seeds are charged to the form conversion solution. The hot seeded aqueous acetonitrile is transferred to the filter dryer and stirred continuously until XRPD testing indicates that no monohydrate is present and the spectra is concordant with the Form 1 (anhydrate) spectra. After the XRPD indicates for complete Form 1 conversion, the conversion liquors are filtered using 1-2 barg nitrogen pressure. The cake is deliquored with the jacket at 65 °C using 1-2 barg nitrogen pressure and is smoothed as necessary. Vacuum is applied with the jacket at 60 °C and the contents are agitated until the loss on drying (LOD) was obtained <0.5% to afford the Final Product.
Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.
Claims
1. A composition comprising:
a com ound of formula (X):
2. The composition according to claim 1, comprising 0.1 - 0.75% of a compound of formula (XI).
3. The composition according to claim 1 , comprising 0.1 - 0.5% of a compound of formula (XI).
4. The composition according to claim 1, comprising 0.15 - 0.35%> of a compound of formula (XI).
5. A composition comprising:
6. The composition according to claim 5, comprising 0.1 - 0.75% of a compound of formula (XI).
7. The composition according to claim 5, comprising 0.1 - 0.5% of a compound of formula (XI).
8. The composition according to claim 5, comprising 0.15 - 0.35% of a compound of formula (XI).
9. The composition according to any one of claims 5 through 8, comprising at least 98.5% of a compound of formula (X).
10. The composition according to any one of claims 5 through 8, comprising at least 99.0% of a compound of formula (X).
1 1. A composition comprising:
and
1.01 - 4%> of a compound of formula (XI):
(XI )
12. The composition according to claim 11, comprising 1.01 - 2% of a compound of formula (XI).
13. The composition according to claim 11, comprising 1.01 - 1.5% of a compound of formula (XI).
14. The composition according to claim 11, comprising 1.01 - 1.2% of a compound of formula (XI).
15. A composition comprising:
and
16. The composition according to claim 15, comprising 1.01 - 2 % of a compound of formula (XI).
17. The composition according to claim 15, comprising 1.01 - 1.5 % of a compound of formula (XI).
18. The composition according to claim 15, comprising 1.01 - 1.2 % of a compound of formula (XI).
19. The composition according to any one of claims 15 through 18, comprising at least 97.0 % of a compound of formula (X).
said process comprising:
combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with sodium bicarbonate having a particle size distribution of > 250 μιη to provide the compound of formula (X).
21. The process according to claim 20, wherein the solvent is ethanol.
22. The process according to claim 20, wherein the solvent is industrial methylated spirits.
said process comprising:
combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with sodium bicarbonate having a particle size distribution of 50 μιη to 150 μιη to provide the compound of formula (X).
24. The process according to claim 23, wherein the solvent is ethanol.
25. The process according to claim 23, wherein the solvent is industrial methylated spirits.
26. The process according to claim 23, wherein the particle size distribution is 60 μιη to 130 μιη.
27. The process according to claim 23, wherein the particle size distribution is 70 μιη to 110 μιη.
said process comprising:
combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with a base selected to ensure that the pH of the mixture is less than 7 for no more than 180 minutes to provide the compound of formula (X).
29. The process according to claim 28, wherein the base is selected to ensure that the pH of the mixture is less than 7 for no more than 150 minutes.
30. The process according to claim 28, wherein the base is selected to ensure that the pH of the mixture is less than 7 for no more than 125 minutes.
31. The process according to claim 28, wherein the base is selected to ensure that the pH of the mixture is less than 7 for no more than 110 minutes.
said process comprising:
combining 2,3-dimethyl-2H-indazol-6-amine and 2,4-dichloropyrimidine in a solvent with a base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 300 to provide the compound of formula
(X).
33. The process according to claim 32, wherein the base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 250.
34. The process according to claim 32, wherein the base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 200.
35. The process according to claim 32, wherein the base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 150.
36. The process according to claim 32, wherein the base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 100.
37. The process according to claim 32, wherein the base selected to ensure that the integral of the pH profile over the time that the mixture is less than a pH of 7 is less than 75.
38. A composition comprising:
a compound of formula XII):
and
a total percentage of 0.05 - 3.0 % of compounds of formulae (XIII), (XIV), and/or (XV):
39. The composition according to claim 38, comprising a total percentage of 0.1 - 0.75% of the compounds of formulae (XIII), (XIV), and/or (XV).
40. The composition according to claim 38, comprising a total percentage of 0.1 - 0.5% of the compounds of formulae (XIII), (XIV), and/or (XV).
41. A composition comprising:
at least 98 % of a com ound of formula (XII):
and
42. The composition according to claim 41, comprising a total percentage of 0.1 - 0.75% of the compounds of formulae (XIII), (XIV), and/or (XV).
43. The composition according to claim 41, comprising a total percentage of 0.1 - 0.5% of the compounds of formulae (XIII), (XIV), and/or (XV).
44. The composition according to any one of claims 41 through 43, comprising at least 98.5% of a compound of formula (XII).
45. The composition according to any one of claims 41 through 43, comprising at least 99.0% of a compound of formula (XII).
46. A process for synthesizin a compound of formula (XII):
suspending N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and potassium carbonate having a D99 of > 300 μιη in a solution of an organic solvent and a methylating agent; and
heating the reaction mixture to a temperature up to and including reflux for at least 8 hours to provide the compound of formula (XII).
47. The process according to claim 46, wherein the D99 is > 350 μιη.
48. The process according to claim 46, wherein the D99 is > 400 μιη.
49. The process according to claim 46, wherein the D99 is > 450 μιη.
50. The process according to claim 46, wherein the D99 is > 500 μιη.
51. The process according to any one of claims 46 through 50, wherein the heating is for at least 9 hours.
52. The process according to any one of claims 46 through 50, wherein the heating is for at least 10 hours.
53. A process for synthesizin a compound of formula (XII):
said process comprising:
suspending N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and potassium carbonate having a D99 of < 200 μιη in a solution of an organic solvent and a methylating agent; and
heating the reaction mixture to a temperature up to and including reflux for at least 4 hours to provide the compound of formula (XII).
54. The process according to claim 53, wherein the D99 is < 150 μιη.
55. The process according to claim 53, wherein the D99 is < 125 μιη.
56. The process according to claim 53, wherein the D99 is < 100 μιη.
57. The process according to claim 53, wherein the D99 is < 90 μιη.
58. The process according to any one of claims 53 through 57, wherein the heating is for at least 5 hours.
59. The process according to any one of claims 53 through 57, wherein the heating is for at least 6 hours.
60. A process for synthesizin a compound of formula (XII):
said process comprising:
combining N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine and a base selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4- pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine to less than 2 % is less than 8 hours in a solution of an organic solvent and a methylating agent; and
heating the reaction mixture to a temperature up to and including reflux for at least 4 hours to provide the compound of formula (XII).
61. The process according to claim 60, wherein the base is selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H- indazol-6-amine to less than 1 % is less than 8 hours.
62. The process according to claim 60, wherein the base is selected to ensure that the reaction time needed to reduce the level of N-(2-chloro-4-pyrimidinyl)-2,3-dimethyl-2H- indazol-6-amine to less than 1 % is less than 7 hours.
63. The process according to any one of claims 60 through 62, wherein the heating is for at least 5 hours.
64. The process according to any one of claims 60 through 62, wherein the heating is for at least 6 hours.
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Cited By (7)
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CN103232443A (en) * | 2013-02-01 | 2013-08-07 | 天津药物研究院 | Indazole derivative crystal and its preparation method and use |
CN103373963A (en) * | 2012-04-28 | 2013-10-30 | 上海医药工业研究院 | Intermediate of pazopanib hydrochloride and preparation method of intermediate of pazopanib hydrochloride |
WO2015031604A1 (en) | 2013-08-28 | 2015-03-05 | Crown Bioscience, Inc. | Gene expression signatures predictive of subject response to a multi-kinase inhibitor and methods of using the same |
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CN110878089A (en) * | 2018-09-05 | 2020-03-13 | 江苏豪森药业集团有限公司 | Preparation method of pazopanib hydrochloride |
US10626110B2 (en) | 2018-08-07 | 2020-04-21 | Formosa Laboratories, Inc. | Polymorph of pazopanib hydrochloride and preparation process thereof |
US10730859B2 (en) | 2013-11-05 | 2020-08-04 | Laurus Labs Limited | Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof |
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WO2006020564A1 (en) * | 2004-08-09 | 2006-02-23 | Smithkline Beecham Corporation | Pyrimidin derivatives for the treatment of multiple myeloma |
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WO2007064752A2 (en) * | 2005-11-29 | 2007-06-07 | Smithkline Beecham Corporation | Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema |
WO2007143483A2 (en) * | 2006-06-01 | 2007-12-13 | Smithkline Beecham Corporation | Combination of pazopanib and lapatinib for treating cancer |
TW200840581A (en) * | 2007-02-28 | 2008-10-16 | Astrazeneca Ab | Novel pyrimidine derivatives |
EP2058307A1 (en) * | 2007-11-12 | 2009-05-13 | Cellzome Ag | Methods for the identification of JAK kinase interacting molecules and for the purification of JAK kinases |
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- 2010-10-21 JP JP2012535366A patent/JP2013508396A/en active Pending
- 2010-10-21 EP EP10825666.0A patent/EP2490536A4/en not_active Withdrawn
- 2010-10-21 WO PCT/US2010/053540 patent/WO2011050159A1/en active Application Filing
- 2010-10-21 US US13/500,318 patent/US20120197019A1/en not_active Abandoned
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US20080039622A1 (en) * | 2002-02-01 | 2008-02-14 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine compounds and their uses |
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