WO2022215083A1 - Solid state forms of (s)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl) carbamate or salts and process for its preparation thereof - Google Patents
Solid state forms of (s)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl) carbamate or salts and process for its preparation thereof Download PDFInfo
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- WO2022215083A1 WO2022215083A1 PCT/IN2022/050333 IN2022050333W WO2022215083A1 WO 2022215083 A1 WO2022215083 A1 WO 2022215083A1 IN 2022050333 W IN2022050333 W IN 2022050333W WO 2022215083 A1 WO2022215083 A1 WO 2022215083A1
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- Prior art keywords
- venglustat
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- YFHRCLAKZBDRHN-MRXNPFEDSA-N [(3s)-1-azabicyclo[2.2.2]octan-3-yl] n-[2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]propan-2-yl]carbamate Chemical compound O([C@H]1C2CCN(CC2)C1)C(=O)NC(C)(C)C(N=1)=CSC=1C1=CC=C(F)C=C1 YFHRCLAKZBDRHN-MRXNPFEDSA-N 0.000 title claims abstract description 106
- 238000000034 method Methods 0.000 title claims description 58
- 238000002360 preparation method Methods 0.000 title claims description 40
- 239000007787 solid Substances 0.000 title abstract description 17
- 150000003839 salts Chemical class 0.000 title description 17
- 239000000203 mixture Substances 0.000 claims description 116
- 229950005067 venglustat Drugs 0.000 claims description 99
- 239000002904 solvent Substances 0.000 claims description 50
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 17
- SQXUKOJKIWCALK-AAXLQGCPSA-N [(3s)-1-azabicyclo[2.2.2]octan-3-yl] n-[2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]propan-2-yl]carbamate;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.O([C@H]1C2CCN(CC2)C1)C(=O)NC(C)(C)C(N=1)=CSC=1C1=CC=C(F)C=C1 SQXUKOJKIWCALK-AAXLQGCPSA-N 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 6
- 235000006408 oxalic acid Nutrition 0.000 claims description 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 229940116298 l- malic acid Drugs 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 3
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000010410 layer Substances 0.000 description 72
- 150000001875 compounds Chemical class 0.000 description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 239000012044 organic layer Substances 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 12
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 11
- 229940011051 isopropyl acetate Drugs 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 10
- 238000001144 powder X-ray diffraction data Methods 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- NQRPHVIWLGEPOQ-UHFFFAOYSA-N 2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CSC(C=2C=CC(F)=CC=2)=N1 NQRPHVIWLGEPOQ-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 229940086542 triethylamine Drugs 0.000 description 7
- -1 (S)-quinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate oxalate Chemical compound 0.000 description 6
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000005456 alcohol based solvent Substances 0.000 description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 6
- IVLICPVPXWEGCA-SSDOTTSWSA-N (3s)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@H](O)CN1CC2 IVLICPVPXWEGCA-SSDOTTSWSA-N 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 239000003759 ester based solvent Substances 0.000 description 5
- 239000004210 ether based solvent Substances 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 239000005453 ketone based solvent Substances 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 238000010908 decantation Methods 0.000 description 4
- 230000005484 gravity Effects 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000003880 polar aprotic solvent Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 102000044956 Ceramide glucosyltransferases Human genes 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 108091000114 ceramide glucosyltransferase Proteins 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- IEPJVHULVDHSMD-UHFFFAOYSA-N ethyl 2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]acetate Chemical compound CCOC(=O)CC1=CSC(C=2C=CC(F)=CC=2)=N1 IEPJVHULVDHSMD-UHFFFAOYSA-N 0.000 description 3
- 150000002305 glucosylceramides Chemical class 0.000 description 3
- 150000002339 glycosphingolipids Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- XARRDOFGRYXMLR-UHFFFAOYSA-N ethyl 2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)C1=CSC(C=2C=CC(F)=CC=2)=N1 XARRDOFGRYXMLR-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical compound CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- IVLICPVPXWEGCA-ZETCQYMHSA-N (3r)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@@H](O)CN1CC2 IVLICPVPXWEGCA-ZETCQYMHSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- OFUMROLKEGKJMS-UHFFFAOYSA-N 2-[2-(1,3-benzodioxol-5-yl)-3-[2-(cyclohexylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound O1COC2=C1C=CC(=C2)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CCCCC1 OFUMROLKEGKJMS-UHFFFAOYSA-N 0.000 description 1
- DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-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
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
- KIPMDPDAFINLIV-UHFFFAOYSA-N 2-nitroethanol Chemical compound OCC[N+]([O-])=O KIPMDPDAFINLIV-UHFFFAOYSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000003621 hammer milling Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- MXHTZQSKTCCMFG-UHFFFAOYSA-N n,n-dibenzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 MXHTZQSKTCCMFG-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003384 small molecules Chemical group 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/06—Oxalic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Definitions
- the present invention relates to solid state forms of (S)-quinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or salts and process for its preparation thereof.
- the present invention also relates to crystalline form of (S)-quinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate oxalate and process for its preparation thereof.
- Venglustat is chemically known as (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4- yl)propan-2-yl)carbamate represented by the following structural formula.
- Venglustat oxalate is chemically known as (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl) thiazol-4-yl)propan-2-yl)carbamate oxalate represented by the following structural formula.
- Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide -based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism.
- GCS glucosylceramide synthase
- Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
- Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.
- the present invention relates to solid state forms of Venglustat or its salts and process for preparation thereof.
- the present invention also relates to novel intermediate compounds useful in the preparation of Venglustat or its salts.
- the present invention also relates to Venglustat oxalate of formula- la and crystalline form of Venglustat oxalate of formula- la and process for preparation thereof.
- Figure 1 Illustrates the PXRD pattern of crystalline Form-M of Venglustat.
- Figure-2 Illustrates the PXRD pattern of amorphous Form of Venglustat.
- Figure-3 Illustrates the PXRD pattern of amorphous Form of Venglustat L-malate.
- Figure 4 Illustrates the PXRD pattern of crystalline Form-M of Venglustat oxalate.
- suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, is
- the “suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, 1,8-diaza bicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabic
- the present invention provides crystalline Form-M of Venglustat of formula- 1 characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 5.7, 11.4 and 13.9 ⁇ 0.2 degrees of 2-theta.
- XRD X-ray powder diffraction
- the crystalline Form-M of Venglustat of formula- 1 is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure- 1.
- XRD X-ray powder diffraction
- the present invention provides a process for the preparation of crystalline Form-M of Venglustat, which comprises: a) contacting Venglustat with diisopropyl ether; and b) isolating the crystalline Form-M of Venglustat.
- isolation of crystalline Form-M of Venglustat can be carried out by any methods known in the art or crystalline Form-M of Venglustat can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
- drying the crystalline Form-M of Venglustat by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
- the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- the present invention provides an amorphous form of Venglustat of formula- 1.
- the present invention provides a process for the preparation of amorphous form of Venglustat of formula- 1, which comprises: a) providing a solution of Venglustat of formula- 1 in a suitable solvent or a mixture of solvents; and b) isolating the amorphous form of Venglustat of formula- 1.
- the suitable solvent used in step-a) is selected from alcohol solvents.
- providing a solution of Venglustat comprises dissolving Venglustat in a suitable solvent at a suitable temperature of about 30°C and above.
- the solution may be filtered to make it particle free.
- isolation of amorphous form of Venglustat can be carried out by any methods known in the art or amorphous form of Venglustat can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
- drying the amorphous form of Venglustat by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
- the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- the present invention provides an amorphous form of Venglustat L-malate of formula- lb.
- the present invention provides a process for the preparation of amorphous form of Venglustat L-malate of formula-lb, which comprises: a) providing a solution of Venglustat, b) adding a solution of L-malic acid to the solution obtained in step-a), c) isolating the amorphous form of Venglustat L-malate of formula- lb.
- providing a solution of Venglustat comprises dissolving Venglustat in a suitable solvent or a mixture of solvents at a suitable temperature of about 30°C and above.
- the solution can be filtered to make it particle free.
- the suitable solvent used in step-a) and b) is selected from alcohol solvents.
- isolation of amorphous form of Venglustat L- malate of formula- lb can be carried out by any methods known in the art or amorphous form of Venglustat L-malate of formula- lb can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
- drying the amorphous form of Venglustat L- malate of formula- lb by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
- the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- the present invention provides a process for the preparation of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula-4 with methyl iodide in the presence of suitable base in a suitable solvent to provide compound of formula-3 ;
- the suitable base used in step-a) is selected from inorganic base or organic base; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
- the present invention provides a process for the preparation of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula- 11 with methyl iodide in the presence of alkali metal amides in a suitable solvent to provide compound of formula- 10; and b) converting compound of formula- 10 to Venglustat of formula- 1 or its salts.
- the suitable alkali metal amides used in step-a) is selected from sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS) and the like; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
- LDA lithium bis(trimethylsilyl)amide
- NaHMDS sodium bis(trimethylsilyl)amide
- LiHMDS lithium bis(trimethysilyl)amide
- the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or
- the present invention provides a process for the preparation of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula- 12 with compound of formula-7 to provide compound of formula- 10; and
- Formula- 12 Form -7
- Formula- 10 b) converting compound of formula- 10 to Venglustat of formula- 1 or its salts.
- the suitable solvent used in step-a) is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
- the present invention provides novel intermediate compound of formula-3 represented by the following structural formula.
- novel intermediate compound of formula-3 is useful in the preparation of Venglustat of formula- 1 or its salts.
- Venglustat or its salts obtained according to the present invention can be purified using a suitable solvent selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
- a suitable solvent selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
- the process of the present invention can be represented schematically as follows:
- the present invention provides Venglustat oxalate of formula- la.
- the present invention provides crystalline form of Venglustat oxalate of formula- la.
- first aspect of twelfth embodiment provides crystalline form of Venglustat oxalate of formula- la characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.9, 13.7 and 18.2 ⁇ 0.2 degrees of 2-theta herein after designated as Form-M.
- XRD X-ray powder diffraction
- the crystalline Form-M of Venglustat oxalate of formula- la is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure-4.
- the present invention provides a process for the preparation of crystalline Form-M of Venglustat oxalate of formula- la, which comprises: c) providing a solution of Venglustat of formula- 1 in acetone; d) adding oxalic acid to solution obtained in step-a); and e) isolating the crystalline Form-M of Venglustat oxalate of formula- la.
- Venglustat dissolved in a suitable solvent at a suitable temperature of about 30°C and above.
- the solution may be filtered to make it particle free.
- isolation of crystalline Form-M of Venglustat oxalate of formula- la can be carried out by any methods known in the art or crystalline Form-M of Venglustat oxalate of formula- la can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
- drying of the crystalline Form-M of Venglustat oxalate of formula- la by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
- the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- Venglustat of formula- 1 obtained according to the present invention is having R-isomer of Venglustat impurity less than 0.05% as measured by HPLC.
- the Venglustat used in the present invention can be obtained by any of the processes known in the art.
- Venglustat oxalate of formula- la is useful in the preparation of Venglustat free base or Venglustat malate.
- Venglustat prepared according to the present invention is micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
- Techniques that are used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization is performed before drying, or after the completion of drying of the product.
- the invention also encompasses pharmaceutical compositions comprising crystalline form of Venglustat oxalate of the present invention.
- pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- the present invention also encompasses pharmaceutical composition comprising Amorphous Venglustat and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.
- the present invention also encompasses pharmaceutical composition comprising Venglustat oxalate and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.
- the present invention also encompasses pharmaceutical composition comprising Amorphous Venglustat L-malate and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.
- compositions include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- P-XRD Method of Analysis PXRD analyses of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A°.
- Example-1 Preparation of crystalline Form-M of Venglustat.
- Tetrahydrofuran (621 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methyl propanoic acid of formula-9 (25.0 gms) at 25-30°C under nitrogen atmosphere and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethylamine (26.1 ml) and isobutyl chloroformate (18.65 ml) were slowly added to the mixture at 0-5°C and stirred for 15 minutes. Sodium azide (12.5 gms) and water (125 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours.
- (S)-Quinuclidin-3-ol (24.18 gms) was added to the mixture at 115-120°C and stirred for 17 hours. Cooled the mixture to 25-30°C. Water (250 ml) was added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer was washed with water. Water was added to organic layer at 25-30°C and stirred for 10 minutes. Aqueous hydrochloric acid solution was slowly added to the mixture at 25-30°C and stirred for 1 hour. Layers were separated and organic layer was washed with aqueous hydrochloric acid solution. Layers were separated. Combined the total aqueous layers and washed with toluene at 25-30°C.
- Example-2 Preparation of crystalline Form-M of Venglustat.
- Tetrahydrofuran (4000 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methyl propanoic acid of formula-9 (160 gms) at 25-30°C under nitrogen atmosphere and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethylamine (122 gms) and isobutyl chloroformate (125.20 gms) were slowly added to the mixture at 0-5°C and stirred for 80 minutes. Sodium azide (78.40 gms) and water (800 ml) were slowly added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 15 hours.
- (S)-Quinuclidin-3-ol (154.75 gms) was added to the mixture at 120°C and stirred for 15 hours. Cooled the mixture to 25-30°C. Water (1600 ml) was added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated and organic layer washed with water at 25-30°C. Water (4000 ml) was added to organic layer at 25-30°C. Aqueous hydrochloric acid solution was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid solution at 25-30°C. Layers were separated.
- Example-3 Preparation of amorphous form of Venglustat.
- Example-4 Preparation of amorphous form of Venglustat L-malate.
- Isopropanol 14 ml was added to Venglustat (2.0 gms) at 25-30°C and stirred for 30 minutes. Filtered the mixture through filter paper. A solution of L-malic acid (0.689 gms) in isopropanol (13 ml) was slowly added to the filtrate at 25-30°C and stirred for 23-24 hours. Distilled off the solvent completely from the mixture below 50°C. To the obtained compound, methanol (50 ml) was added at 25-30°C and stirred for 30 minutes. Filtered the mixture through filter paper and washed with methanol. Distilled off the mixture under vacuum to get the title compound. Yield: 2.45 gms.
- Example-5 Preparation of crystalline Form-M of Venglustat oxalate.
- Example-6 Preparation of crystalline Form-M of Venglustat oxalate.
- Acetone (10 ml) was added to Venglustat (500 mg) at 25-30°C and stirred for 20 minutes. Filtered the mixture to make it particle free.
- Oxalic acid solution (oxalic acid (169.8 mg) dissolved in acetone (5.0 ml)) was added to mixture at 25-30°C.
- N-heptane (15 ml) was added to mixture at 25-30°C and stirred for 90 minutes. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 500 mg; Oxalic acid content: 18.51%.
- Example-7 Preparation of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate of Formula-11.
- Ethanol (40.0 ml) was added to 4-fhiorobenzothioamide of formula-7 (10.0 gm) at 25- 30°C and stirred for 10 minutes. Raised the temperature of the mixture to 50-55°C.
- Ethyl-4- chloro acetoacetate of formula- 13 (10.0 ml) was slowly added to the mixture at 50-55°C. Raised the temperature of the mixture to 75-80°C and stirred for 6 hours. Distilled off the mixture under vacuum at 75-80°C. Water (10.0 ml) and methyl tert-butyl ether (30.0 ml) were added to the obtained compound at 25-30°C and stirred for 30 minutes.
- Example-8 Preparation of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate of Formula-10.
- Tetrahydrofuran (70.0 ml) was added to potassium tert-butoxide (8.59 gm) at 25-30°C and stirred for 3 hours. Cooled the mixture to 0-5°C.
- Ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate (5.0 gm) and tetrahydrofuran (10.0 ml) were slowly added to the mixture at 0-5°C and stirred for 90 minutes.
- Methyl iodide (10.69 gm) and tetrahydrofuran (12.0 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour.
- Example-9 Preparation of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid of Formula-9.
- Tetrahydrofuran (75.0 ml) was added to ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoate of formula- 10 (5.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 15-20°C. Lithium hydroxide (1.75 gm) and water (24.0 ml) were slowly added to the mixture at 15-20°C and stirred for 15 minutes. Raised the temperature of the mixture to 65-70°C and stirred for 12 hours. Cooled the mixture to 25-30°C. Methyl tert-butyl ether (40.0 ml) was added to the mixture at 25-30°C and stirred for 20 minutes.
- Example-10 Preparation of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid of Formula-9.
- Tetrahydrofuran 700.0 ml was added to potassium tert-butoxide (84.5 gm) at 25-30°C and stirred for 20 minutes. Cooled the mixture to 0-5°C. Ethyl 2-(2-(4-fluorophenyl)thiazol-4- yl)acetate (50.0 gm) and tetrahydrofuran (100.0 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour. Methyl iodide (106.9 gm) and tetrahydrofuran (120.0 ml) were slowly added to the mixture at 0-5°C and stirred for 10 minutes.
- Tetrahydrofuran (100.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (4.0 gm) at 25-30°C. Cooled the mixture to 0-5°C.
- Triethyl amine (3.05 gm) and isobutyl chloroformate (3.13 gm) were added to the mixture at 0-5°C and stirred for 15 minutes.
- Sodium azide (1.96) and water (20.0 ml) were added to the mixture at 0- 5°C and stirred for 10 minutes. Raised the temperature of the mixture to 25-30°C and stirred for 18 hours.
- Ethyl acetate (60.0 ml) and water (100.0 ml) were added to the mixture at 25-30°C. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Distilled off the organic layer under vacuum at below 50°C. Toluene (100.0 ml) was added to the obtained compound at 40-45°C and stirred for 30 minutes. (S)-Quinuclidin-3-ol (3.83 gm) was added to the mixture at 40-45°C. Raised the temperature of the mixture to 60-65°C and stirred for 12 hours. Distilled off the mixture under vacuum at below 50°C.
- Example-12 Preparation of Venglustat.
- Tetrahydrofuran (621.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (25.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (26.1 ml) and isobutyl chloroformate (18.65 ml) were added to the mixture at 0-5°C and stirred for 1 hour. Sodium azide (12.5) and water (125 ml) were added to the mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours.
- Toluene (625.0 ml) was added to aqueous layer at 25-30°C. Cooled the mixture to 20-25°C. Sodium hydroxide solution was slowly added to the mixture at 20-25°C. Layers were separated and extracted aqueous layer with isopropyl acetate. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 45°C and co-distilled with diisopropyl ether. Diisopropyl ether (625.0 ml) was added to the obtained compound at 25-30°C and stirred for 2 hours. Liltered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 22.0 gm.
- Example-13 Preparation of Venglustat.
- Tetrahydrofuran 4000.0 ml was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (160.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (122.0 gm) and isobutyl chloroformate (125.20 gm) were added to the mixture at 0-5°C and stirred for 90 minutes. Sodium azide (78.40 gm) and water (800.0 ml) were added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 15 hours.
- Tetrahydrofuran (125.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (5.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (3.81 gm) and isobutyl chloroformate (3.91 gm) were added to the mixture at 0-5°C and stirred for 90 minutes. Sodium azide (2.45 gm) and water (25.0 ml) were added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours.
- (R)-Quinuclidin-3-ol (4.5 gm) was added to the mixture at 115-120°C and stirred for 16 hours. Cooled the mixture to 25-30°C. Water (50.0 ml) was added to the mixture at 25-30°C and stirred for 10 minutes. Layers were separated and organic layer washed with water. Water (50.0 ml) was added to the organic layer at 25-30°C. Aqueous hydrochloric acid was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid. Combined the aqueous layers and washed with toluene. Layers were separated.
- Isopropyl acetate (100.0 ml) was added to aqueous layer at 20- 25°C. Cooled the mixture to 20-25°C. Sodium hydroxide solution was slowly added to the mixture at 20-25°C. Layers were separated and extracted aqueous layer with isopropyl acetate. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 45°C and co-distilled with diisopropyl ether. Diisopropyl ether (35.0 ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 2.5 gm.
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Abstract
The present invention relates to solid state forms of (S)-quinuclidin-3-yl 2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-ylcarbamate represented by the following structural formula.
Description
Solid state forms of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenvBthiazol-4-yl)propan-2-vB carbamate or salts and process for its preparation thereof Related Application:
This application claims the benefit of priority of our Indian patent application numbers 202141015993 filed on 05 April 2021 and 202141018048 filed on 19 April 2021 which is incorporated herein by reference.
Field of the Invention:
The present invention relates to solid state forms of (S)-quinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or salts and process for its preparation thereof.
The present invention also relates to crystalline form of (S)-quinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate oxalate and process for its preparation thereof.
Background of the Invention:
Venglustat is chemically known as (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4- yl)propan-2-yl)carbamate represented by the following structural formula.
Formula- 1
Venglustat oxalate is chemically known as (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl) thiazol-4-yl)propan-2-yl)carbamate oxalate represented by the following structural formula.
Formula- la
Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide -based glycosphingolipids. Because of its effect on
glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism.
(S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or a pharmaceutically acceptable salt was disclosed in US9126993 B2 (herein after described as US ‘993).
US ‘993 discloses process for the preparation of (S)-quinuclidin-3-yl (2-(2-(4-fluoro phenyl)thiazol-4-yl)propan-2-yl)carbamate.
Crystalline forms of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl) carbamate salts and its process was disclosed in US9518049 B2.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.
Brief description of the Invention:
The present invention relates to solid state forms of Venglustat or its salts and process for preparation thereof.
The present invention also relates to novel intermediate compounds useful in the preparation of Venglustat or its salts.
The present invention also relates to Venglustat oxalate of formula- la and crystalline form of Venglustat oxalate of formula- la and process for preparation thereof.
Brief description of Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form-M of Venglustat.
Figure-2: Illustrates the PXRD pattern of amorphous Form of Venglustat.
Figure-3: Illustrates the PXRD pattern of amorphous Form of Venglustat L-malate.
Figure 4: Illustrates the PXRD pattern of crystalline Form-M of Venglustat oxalate.
Detailed description of the Invention:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyro nitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2- methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t- pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The “suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide
and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, 1,8-diaza bicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5- ene (DBN), lithiumdiiso propylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methyl imidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
In the first embodiment, the present invention provides crystalline Form-M of Venglustat of formula- 1 characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 5.7, 11.4 and 13.9 ± 0.2 degrees of 2-theta.
The crystalline Form-M of Venglustat of formula- 1 is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure- 1.
In the second embodiment, the present invention provides a process for the preparation of crystalline Form-M of Venglustat, which comprises: a) contacting Venglustat with diisopropyl ether; and b) isolating the crystalline Form-M of Venglustat.
In the process of the second embodiment, isolation of crystalline Form-M of Venglustat can be carried out by any methods known in the art or crystalline Form-M of Venglustat can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In the process of the second embodiment, drying the crystalline Form-M of Venglustat by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven,
fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In the third embodiment, the present invention provides an amorphous form of Venglustat of formula- 1.
In the fourth embodiment, the present invention provides a process for the preparation of amorphous form of Venglustat of formula- 1, which comprises: a) providing a solution of Venglustat of formula- 1 in a suitable solvent or a mixture of solvents; and b) isolating the amorphous form of Venglustat of formula- 1.
In the process of fourth embodiment, the suitable solvent used in step-a) is selected from alcohol solvents.
In the process of the fourth embodiment, providing a solution of Venglustat comprises dissolving Venglustat in a suitable solvent at a suitable temperature of about 30°C and above. Optionally, the solution may be filtered to make it particle free.
In the process of the fourth embodiment, isolation of amorphous form of Venglustat can be carried out by any methods known in the art or amorphous form of Venglustat can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In the process of the fourth embodiment, drying the amorphous form of Venglustat by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be
carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In the fifth embodiment, the present invention provides an amorphous form of Venglustat L-malate of formula- lb.
In the sixth embodiment, the present invention provides a process for the preparation of amorphous form of Venglustat L-malate of formula-lb, which comprises: a) providing a solution of Venglustat, b) adding a solution of L-malic acid to the solution obtained in step-a), c) isolating the amorphous form of Venglustat L-malate of formula- lb.
In the process of the sixth embodiment, providing a solution of Venglustat, comprises dissolving Venglustat in a suitable solvent or a mixture of solvents at a suitable temperature of about 30°C and above. Optionally, the solution can be filtered to make it particle free.
In the process of sixth embodiment, the suitable solvent used in step-a) and b) is selected from alcohol solvents.
In the process of the sixth embodiment, isolation of amorphous form of Venglustat L- malate of formula- lb can be carried out by any methods known in the art or amorphous form of Venglustat L-malate of formula- lb can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In the process of the sixth embodiment, drying the amorphous form of Venglustat L- malate of formula- lb by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In the seventh embodiment, the present invention provides a process for the preparation
of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula-4 with methyl iodide in the presence of suitable base in a suitable solvent to provide compound of formula-3 ;
Formula-4 Formula-3 b) reacting compound of formula-3 with hydrazine hydrate to provide compound of formula-
In the process of the seventh embodiment, the suitable base used in step-a) is selected from inorganic base or organic base; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
In the eighth embodiment, the present invention provides a process for the preparation of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula- 11 with methyl iodide in the presence of alkali metal amides in a suitable solvent to provide compound of formula- 10; and
b) converting compound of formula- 10 to Venglustat of formula- 1 or its salts.
In the process of the eighth embodiment, the suitable alkali metal amides used in step-a) is selected from sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium
bis(trimethysilyl)amide (LiHMDS) and the like; and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
In the ninth embodiment, the present invention provides a process for the preparation of Venglustat of formula- 1 or its salts, which comprises: a) reacting compound of formula- 12 with compound of formula-7 to provide compound of formula- 10; and
Formula- 12 Form -7 Formula- 10 b) converting compound of formula- 10 to Venglustat of formula- 1 or its salts.
In the process of the ninth embodiment, the suitable solvent used in step-a) is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
In the tenth embodiment, the present invention provides novel intermediate compound of formula-3 represented by the following structural formula.
The above mentioned novel intermediate compound of formula-3 is useful in the preparation of Venglustat of formula- 1 or its salts.
Venglustat or its salts obtained according to the present invention can be purified using a suitable solvent selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.
The process of the present invention can be represented schematically as follows:
Formula- 13 Formula-7 Formula- 11
Formula- 12 Formula-7 Formula-10
Hydrolysis
In the eleventh embodiment, the present invention provides Venglustat oxalate of formula- la.
In the twelfth embodiment, the present invention provides crystalline form of Venglustat oxalate of formula- la.
In first aspect of twelfth embodiment provides crystalline form of Venglustat oxalate of formula- la characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.9, 13.7 and 18.2 ± 0.2 degrees of 2-theta herein after designated as Form-M.
In second aspect of twelfth embodiment, the crystalline Form-M of Venglustat oxalate of formula- la is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure-4.
In the thirteenth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Venglustat oxalate of formula- la, which comprises: c) providing a solution of Venglustat of formula- 1 in acetone; d) adding oxalic acid to solution obtained in step-a); and e) isolating the crystalline Form-M of Venglustat oxalate of formula- la.
In the process of the thirteenth embodiment, Venglustat dissolved in a suitable solvent at a suitable temperature of about 30°C and above. Optionally, the solution may be filtered to make it particle free.
In the process of the thirteenth embodiment, isolation of crystalline Form-M of Venglustat oxalate of formula- la can be carried out by any methods known in the art or crystalline Form-M of Venglustat oxalate of formula- la can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In the process of the thirteenth embodiment, drying of the crystalline Form-M of Venglustat oxalate of formula- la by suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable
temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
Venglustat of formula- 1 obtained according to the present invention is having R-isomer of Venglustat impurity less than 0.05% as measured by HPLC.
R-isomer of Venglustat
The Venglustat used in the present invention can be obtained by any of the processes known in the art.
Venglustat oxalate of formula- la is useful in the preparation of Venglustat free base or Venglustat malate.
Venglustat prepared according to the present invention is micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that are used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization is performed before drying, or after the completion of drying of the product.
The invention also encompasses pharmaceutical compositions comprising crystalline form of Venglustat oxalate of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The present invention also encompasses pharmaceutical composition comprising Amorphous Venglustat and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.
The present invention also encompasses pharmaceutical composition comprising Venglustat oxalate and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.
The present invention also encompasses pharmaceutical composition comprising Amorphous Venglustat L-malate and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients.
As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
P-XRD Method of Analysis: PXRD analyses of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A°.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of crystalline Form-M of Venglustat.
Tetrahydrofuran (621 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methyl propanoic acid of formula-9 (25.0 gms) at 25-30°C under nitrogen atmosphere and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethylamine (26.1 ml) and isobutyl chloroformate (18.65 ml) were slowly added to the mixture at 0-5°C and stirred for 15 minutes. Sodium azide (12.5 gms) and water (125 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours. Water was added to mixture at 25-30°C and stirred for 10 minutes. Ethyl acetate was added to mixture at 25-30°C and stirred for 10 minutes. Layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers, washed with sodium bicarbonate solution. Layers were separated and organic layer was washed with sodium chloride solution. Layers were separated and organic layer was washed with water. Distilled off the organic layer at 50°C and co-distilled with toluene. To the obtained compound, toluene (625 ml) was added at 25-30°C. Heated the mixture to 115-120°C
and stirred for 2 hours. (S)-Quinuclidin-3-ol (24.18 gms) was added to the mixture at 115-120°C and stirred for 17 hours. Cooled the mixture to 25-30°C. Water (250 ml) was added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer was washed with water. Water was added to organic layer at 25-30°C and stirred for 10 minutes. Aqueous hydrochloric acid solution was slowly added to the mixture at 25-30°C and stirred for 1 hour. Layers were separated and organic layer was washed with aqueous hydrochloric acid solution. Layers were separated. Combined the total aqueous layers and washed with toluene at 25-30°C. Layers were separated. Isopropyl acetate (625 ml) was added to aqueous layers at 25-30°C. Cooled the mixture to 20°C. Sodium hydroxide solution was slowly added to the mixture at 20°C and stirred for 15 minutes. Layers were separated and extracted aqueous layer with isopropyl acetate at 25-30°C. Combined the organic layers and washed with water at 25-30°C. Distilled off the organic layer below 50°C and co-distilled with diisopropyl ether. To the obtained compound, diisopropyl ether (625 ml) was added at 25-30°C and stirred for 2 hours. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 22.0 gms.
The PXRD pattern of the obtained compound is illustrated in Figure- 1.
Example-2: Preparation of crystalline Form-M of Venglustat.
Tetrahydrofuran (4000 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methyl propanoic acid of formula-9 (160 gms) at 25-30°C under nitrogen atmosphere and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethylamine (122 gms) and isobutyl chloroformate (125.20 gms) were slowly added to the mixture at 0-5°C and stirred for 80 minutes. Sodium azide (78.40 gms) and water (800 ml) were slowly added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 15 hours. Water (4000 ml) and ethyl acetate (2.0 lit) were added to mixture at 25-30°C and stirred for 1 hour. Layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers, washed with sodium bicarbonate solution at 25-30°C. Layers were separated and organic washed with sodium chloride solution at 25-30°C. Layers were separated and organic layer washed with water at 25-30°C. Distilled off the organic layer under vacuum and co-distilled with toluene. To the obtained compound, toluene (4000 ml) was added at 25-30°C. Heated the mixture to 120°C and stirred for 2 hours. (S)-Quinuclidin-3-ol (154.75 gms) was added to the mixture at 120°C and stirred for 15 hours. Cooled the mixture to 25-30°C. Water (1600 ml) was added to the mixture at
25-30°C and stirred for 20 minutes. Layers were separated and organic layer washed with water at 25-30°C. Water (4000 ml) was added to organic layer at 25-30°C. Aqueous hydrochloric acid solution was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid solution at 25-30°C. Layers were separated. Combined the total aqueous layers and washed with toluene at 25-30°C. Layers were separated. Isopropyl acetate (4000 ml) was added to aqueous layers at 25-30°C. Cooled the mixture to 20°C. Sodium hydroxide solution was slowly added to the mixture at 20°C and stirred for 10 minutes. Layers were separated and extracted aqueous layer with isopropyl acetate at 25- 30°C. Combined the organic layers and washed with water at 25-30°C. Distilled off the organic layer below 50°C and co-distilled with diisopropyl ether. To the obtained compound, diisopropyl ether (800 ml) as added at 25-30°C and stirred for 20 minutes. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 90 gms.
The PXRD pattern of the obtained compound is illustrated in Figure- 1.
Example-3: Preparation of amorphous form of Venglustat.
Methanol (25 ml) was added to Venglustat (1.0 gm) at 25-30°C and stirred for 30 minutes. Filtered the mixture through filter paper and washed with methanol. Distilled off the mixture under vacuum to get the title compound. Yield: 970 mg.
The PXRD pattern of the obtained compound is illustrated in Figure-2.
Example-4: Preparation of amorphous form of Venglustat L-malate.
Isopropanol (14 ml) was added to Venglustat (2.0 gms) at 25-30°C and stirred for 30 minutes. Filtered the mixture through filter paper. A solution of L-malic acid (0.689 gms) in isopropanol (13 ml) was slowly added to the filtrate at 25-30°C and stirred for 23-24 hours. Distilled off the solvent completely from the mixture below 50°C. To the obtained compound, methanol (50 ml) was added at 25-30°C and stirred for 30 minutes. Filtered the mixture through filter paper and washed with methanol. Distilled off the mixture under vacuum to get the title compound. Yield: 2.45 gms.
The PXRD pattern of the obtained compound is illustrated in Figure-3.
Example-5: Preparation of crystalline Form-M of Venglustat oxalate.
Acetone (5.0 ml) was added to Venglustat (200 mg) at 25-30°C and stirred for 20 minutes. Oxalic acid (71.2 mg) was added to the mixture at 25-30°C and stirred for 2 hours. Filtered the
solid, washed with acetone and dried to get the title compound. Yield: 180 mg.
The PXRD pattern of the obtained compound is illustrated in Figure-4.
Example-6: Preparation of crystalline Form-M of Venglustat oxalate.
Acetone (10 ml) was added to Venglustat (500 mg) at 25-30°C and stirred for 20 minutes. Filtered the mixture to make it particle free. Oxalic acid solution (oxalic acid (169.8 mg) dissolved in acetone (5.0 ml)) was added to mixture at 25-30°C. N-heptane (15 ml) was added to mixture at 25-30°C and stirred for 90 minutes. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 500 mg; Oxalic acid content: 18.51%.
The PXRD pattern of the obtained compound is illustrated in Figure-4.
Example-7: Preparation of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate of Formula-11.
Ethanol (40.0 ml) was added to 4-fhiorobenzothioamide of formula-7 (10.0 gm) at 25- 30°C and stirred for 10 minutes. Raised the temperature of the mixture to 50-55°C. Ethyl-4- chloro acetoacetate of formula- 13 (10.0 ml) was slowly added to the mixture at 50-55°C. Raised the temperature of the mixture to 75-80°C and stirred for 6 hours. Distilled off the mixture under vacuum at 75-80°C. Water (10.0 ml) and methyl tert-butyl ether (30.0 ml) were added to the obtained compound at 25-30°C and stirred for 30 minutes. Layers were separated and extracted aqueous layer with methyl tert-butyl ether. Combined the organic layers and washed with sodium bicarbonate solution at 25-30°C. Layers were separated and organic layer washed with water. Distilled off the organic layer below 55°C and co-distilled with n-heptane. n-Heptane (40.0 ml) was added to the obtained compound at 25-30°C and stirred for 3 hours. Filtered the solid, washed with n-heptane and stirred to get the title compound. Yield: 11.1 gm.
Example-8: Preparation of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate of Formula-10.
Tetrahydrofuran (70.0 ml) was added to potassium tert-butoxide (8.59 gm) at 25-30°C and stirred for 3 hours. Cooled the mixture to 0-5°C. Ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate (5.0 gm) and tetrahydrofuran (10.0 ml) were slowly added to the mixture at 0-5°C and stirred for 90 minutes. Methyl iodide (10.69 gm) and tetrahydrofuran (12.0 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour. Sodium chloride solution was slowly added to the mixture at 0-5°C and stirred for 15 minutes. Aqueous hydrochloric acid was slowly added to the mixture at 0-5°C and stirred for 15 minutes. Layers were separated and extracted aqueous layer
with tetrahydrofuran. Combined the organic layers. Distilled off the organic layer under vacuum at below 45°C to get the title compound. Yield: 6.2 gm.
Example-9: Preparation of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid of Formula-9.
Tetrahydrofuran (75.0 ml) was added to ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoate of formula- 10 (5.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 15-20°C. Lithium hydroxide (1.75 gm) and water (24.0 ml) were slowly added to the mixture at 15-20°C and stirred for 15 minutes. Raised the temperature of the mixture to 65-70°C and stirred for 12 hours. Cooled the mixture to 25-30°C. Methyl tert-butyl ether (40.0 ml) was added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated and aqueous layer washed with methyl tert-butyl ether. Cooled the aqueous layer to 0-5°C. Methyl tert-butyl ether (50.0 ml) was added to the aqueous layer at 0-5°C. Aqueous hydrochloric acid was slowly added to the mixture at 0-5°C and stirred for 10 minutes. Layers were separated and extracted aqueous layer with methyl tert-butyl ether. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 50°C. n-Heptane (35.0 ml) was added to the obtained compound 25-30°C and stirred for 2 hours. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 3.50 gm.
Example-10: Preparation of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid of Formula-9.
Tetrahydrofuran (700.0 ml) was added to potassium tert-butoxide (84.5 gm) at 25-30°C and stirred for 20 minutes. Cooled the mixture to 0-5°C. Ethyl 2-(2-(4-fluorophenyl)thiazol-4- yl)acetate (50.0 gm) and tetrahydrofuran (100.0 ml) were slowly added to the mixture at 0-5°C and stirred for 1 hour. Methyl iodide (106.9 gm) and tetrahydrofuran (120.0 ml) were slowly added to the mixture at 0-5°C and stirred for 10 minutes. Sodium chloride solution was slowly added to the mixture at 0-5°C and stirred for 10 minutes. Aqueous hydrochloric acid was slowly added to the mixture at 0-5°C and stirred for 10 minutes. Layers were separated and extracted aqueous layer with tetrahydrofuran. Combined the organic layers. Distilled off the organic layer under vacuum at below 65°C. Lithium hydroxide (20.0 gm) and water (500.0 ml) were slowly added to the mixture at 15-20°C. Raised the temperature of the mixture to 70-75°C and stirred for 16 hours. Cooled the mixture to 25-30°C. Methyl tert-butyl ether (100.0 ml) was added to the
mixture at 25-30°C and stirred for 15 minutes. Layers were separated and extracted aqueous layer with methyl tert-butyl ether. Methyl tert-butyl ether (100.0 ml) was added to the aqueous layer at 25-30°C. Cooled the mixture to 0-5°C. Aqueous hydrochloric acid was slowly added to the mixture at 0-5°C and stirred for 10 minutes. Layers were separated and extracted aqueous layer with methyl tert-butyl ether. Combined the organic layers. Distilled off the organic layer under vacuum at below 50°C. n-Heptane (270.0 ml) was added to the obtained compound 25-30°C and stirred for 2 hours. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 38.0 gm.
Example-11: Preparation of Venglustat.
Tetrahydrofuran (100.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (4.0 gm) at 25-30°C. Cooled the mixture to 0-5°C. Triethyl amine (3.05 gm) and isobutyl chloroformate (3.13 gm) were added to the mixture at 0-5°C and stirred for 15 minutes. Sodium azide (1.96) and water (20.0 ml) were added to the mixture at 0- 5°C and stirred for 10 minutes. Raised the temperature of the mixture to 25-30°C and stirred for 18 hours. Ethyl acetate (60.0 ml) and water (100.0 ml) were added to the mixture at 25-30°C. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Distilled off the organic layer under vacuum at below 50°C. Toluene (100.0 ml) was added to the obtained compound at 40-45°C and stirred for 30 minutes. (S)-Quinuclidin-3-ol (3.83 gm) was added to the mixture at 40-45°C. Raised the temperature of the mixture to 60-65°C and stirred for 12 hours. Distilled off the mixture under vacuum at below 50°C. Isopropyl acetate (100.0 ml), sodium bicarbonate and water were added to the obtained compound at 25-30°C and stirred for 10 minutes. Layers were separated and organic layer washed with sodium sulphate solution. Distilled off the organic layer under vacuum at below 50°C to get the title compound. Yield: 2.5 gm.
Example-12: Preparation of Venglustat.
Tetrahydrofuran (621.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (25.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (26.1 ml) and isobutyl chloroformate (18.65 ml) were added to the mixture at 0-5°C and stirred for 1 hour. Sodium azide (12.5) and water (125 ml) were added
to the mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours. Water (625.0 ml) was added to the mixture at 25-30°C and stirred for 10 minutes. Ethyl acetate (375.0 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Distilled off the organic layer under vacuum at below 50°C and co-distilled with toluene. Toluene (625.0 ml) was added to the obtained compound at 25-30°C. Raised the temperature of the mixture to 110-115°C and stirred for 90 minutes. (S)-Quinuclidin-3-ol (24.18 gm) was added to the mixture at 115-120°C and stirred for 16 hours. Cooled the mixture to 25-30°C. Water (250.0 ml) was added to the mixture at 25-30°C and stirred for 1 hour. Layers were separated and organic layer washed with water. Water (— ) was added to the organic layer at 25-30°C. Aqueous hydrochloric acid was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid. Combined the aqueous layers and washed with toluene. Layers were separated. Toluene (625.0 ml) was added to aqueous layer at 25-30°C. Cooled the mixture to 20-25°C. Sodium hydroxide solution was slowly added to the mixture at 20-25°C. Layers were separated and extracted aqueous layer with isopropyl acetate. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 45°C and co-distilled with diisopropyl ether. Diisopropyl ether (625.0 ml) was added to the obtained compound at 25-30°C and stirred for 2 hours. Liltered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 22.0 gm.
Example-13: Preparation of Venglustat.
Tetrahydrofuran (4000.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (160.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (122.0 gm) and isobutyl chloroformate (125.20 gm) were added to the mixture at 0-5°C and stirred for 90 minutes. Sodium azide (78.40 gm) and water (800.0 ml) were added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 15 hours. Water (4000.0 ml) and ethyl acetate (2000.0 ml) were added to the mixture at 25-30°C. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Distilled off the organic layer under vacuum at below 50°C and co-distilled with
toluene. Toluene (4000.0 ml) was added to the obtained compound 25-30°C. Raised the temperature of the mixture to 110-115°C and stirred for 40 minutes. (S)-Quinuclidin-3-ol (154.75 gm) was added to the mixture at 115-120°C and stirred for 16 hours. Cooled the mixture to 25- 30°C. Water (1600.0 ml) was added to the mixture at 25-30°C and stirred for 10 minutes. Layers were separated and organic layer washed with water. Water (4000.0 ml) was added to the organic layer at 25-30°C. Aqueous hydrochloric acid was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid. Combined the aqueous layers and washed with toluene. Layers were separated. Isopropyl acetate (4000.0 ml) was added to aqueous layer at 20-25°C. Cooled the mixture to 15-20°C. Sodium hydroxide solution was slowly added to the mixture at 15-20°C. Layers were separated and extracted aqueous layer with isopropyl acetate. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 45°C and co-distilled with diisopropyl ether. Diisopropyl ether (800.0 ml) was added to the obtained compound at 25-30°C and stirred for 10 minutes. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 90.0 gm.
Example-14: Preparation of R-isomer of Venglustat.
Tetrahydrofuran (125.0 ml) was added to 2-(2-(4-fluorophenyl)thiazol-4-yl)-2- methylpropanoic acid of formula-9 (5.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C. Triethyl amine (3.81 gm) and isobutyl chloroformate (3.91 gm) were added to the mixture at 0-5°C and stirred for 90 minutes. Sodium azide (2.45 gm) and water (25.0 ml) were added to the mixture at 0-5°C and stirred for 2 hours. Raised the temperature of the mixture to 25-30°C and stirred for 20 hours. Water (100.0 ml) and ethyl acetate (60.0 ml) were added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated and extracted aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium bicarbonate solution and sodium chloride solution. Organic layer washed with water. Distilled off the organic layer under vacuum at below 50°C and co-distilled with toluene. Toluene (25.0 ml) was added to the obtained compound 25-30°C. Raised the temperature of the mixture to 115-120°C and stirred for 1 hour. (R)-Quinuclidin-3-ol (4.5 gm) was added to the mixture at 115-120°C and stirred for 16 hours. Cooled the mixture to 25-30°C. Water (50.0 ml) was added to the mixture at 25-30°C and stirred for 10 minutes. Layers were separated and organic layer washed with water. Water
(50.0 ml) was added to the organic layer at 25-30°C. Aqueous hydrochloric acid was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and organic layer washed with aqueous hydrochloric acid. Combined the aqueous layers and washed with toluene. Layers were separated. Isopropyl acetate (100.0 ml) was added to aqueous layer at 20- 25°C. Cooled the mixture to 20-25°C. Sodium hydroxide solution was slowly added to the mixture at 20-25°C. Layers were separated and extracted aqueous layer with isopropyl acetate. Combined the organic layers and washed with water. Distilled off the organic layer under vacuum at below 45°C and co-distilled with diisopropyl ether. Diisopropyl ether (35.0 ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 2.5 gm.
Claims
1. Crystalline Form-M of Venglustat of formula- 1 characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 5.7, 11.4 and 13.9 ± 0.2 degrees of 2-theta.
2. Crystalline Form-M of Venglustat of formula- 1 as claimed in claim 1 is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure- 1.
3. A process for the preparation of crystalline Form-M of Venglustat, which comprises: a) contacting Venglustat with diisopropyl ether; and b) isolating the crystalline Form-M of Venglustat.
4. Amorphous Venglustat.
5. A process for the preparation of amorphous form of Venglustat of formula- 1, which comprises: a) providing a solution of Venglustat of formula- 1 in a solvent or a mixture of solvents; and b) isolating the amorphous form of Venglustat of formula- 1.
6. The process as claimed in claim 5 wherein, the solvent used in step-a) is alcohol solvent.
7. The process as claimed in claim 5 wherein, providing a solution of Venglustat comprises dissolving Venglustat in alcohol solvent at a temperature of about 30°C and above.
8. Amorphous Venglustat L-malate.
9. A process for the preparation of amorphous form of Venglustat L-malate of formula- lb, which comprises: a) providing a solution of Venglustat, b) adding a solution of L-malic acid to the solution obtained in step-a),
c) isolating the amorphous form of Venglustat L-malate of formula- lb.
10. The process as claimed in claim 9 wherein, providing a solution of Venglustat, comprises dissolving Venglustat in a solvent or a mixture of solvents
11. The process as claimed in claim 9 wherein, the solvent used in step-a) and b) is alcohol solvent.
12. The process as claimed in claim 9 wherein, dissolving Venglustat in a solvent comprises heating the solution to a temperature of about 30°C and above.
13. Venglustat oxalate.
14. Crystalline form of Venglustat oxalate.
15. Crystalline form of Venglustat oxalate of formula- la characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.9, 13.7 and 18.2 ± 0.2 degrees of 2-theta.
16. Crystalline form of Venglustat oxalate of formula- la as claimed in claim 15 is further characterized by the X-ray powder diffraction (XRD) pattern as illustrated in figure-4.
17. A process for the preparation of crystalline form of Venglustat oxalate of formula- la, which comprises: a) providing a solution of Venglustat of formula- 1 in acetone; b) adding oxalic acid to solution obtained in step-a); and c) isolating the crystalline form of Venglustat oxalate of formula- la.
18. The process as claimed in claim 17 wherein, dissolving Venglustat in acetone at a temperature of about 30°C and above.
19. Amorphous Venglustat L-malate obtained according to the preceding claims is useful for the preparation of pharmaceutical composition.
20. Amorphous Venglustat obtained according to the preceding claims is useful for the preparation of pharmaceutical composition.
21. A pharmaceutical composition comprising Amorphous Venglustat according to the preceding claims and a pharmaceutically acceptable carrier or diluent.
22. A pharmaceutical composition comprising Amorphous Venglustat L-malate according to the preceding claims and a pharmaceutically acceptable carrier or diluent.
23. Venglustat oxalate obtained according to the preceding claims is useful for the preparation of pharmaceutical composition.
24. A pharmaceutical composition comprising Venglustat oxalate according to the preceding claims and a pharmaceutically acceptable carrier or diluent.
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Non-Patent Citations (2)
Title |
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BASTIN R. J. ET AL.: "Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 4, no. 5, 2000, pages 427 - 435, XP008154792, DOI: 10.1021/OP000018U * |
CAIRA M R: "Crystalline polymorphism of organic compounds", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, DOI: 10.1007/3-540-69178-2_5 * |
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