NZ723880B2 - Process for preparing quinoline derivatives - Google Patents
Process for preparing quinoline derivatives Download PDFInfo
- Publication number
- NZ723880B2 NZ723880B2 NZ723880A NZ72388012A NZ723880B2 NZ 723880 B2 NZ723880 B2 NZ 723880B2 NZ 723880 A NZ723880 A NZ 723880A NZ 72388012 A NZ72388012 A NZ 72388012A NZ 723880 B2 NZ723880 B2 NZ 723880B2
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- NZ
- New Zealand
- Prior art keywords
- compound
- mixture
- approximately
- acid
- aprotic solvent
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
- 229940093918 Quinoline gynecological antiinfectives Drugs 0.000 title description 2
- 229940027991 antiseptics and disinfectants Quinoline derivatives Drugs 0.000 title description 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 103
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 64
- 239000003880 polar aprotic solvent Substances 0.000 claims abstract description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 40
- LVHBHZANLOWSRM-UHFFFAOYSA-N Itaconic acid Chemical compound OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229940086542 triethylamine Drugs 0.000 claims abstract description 20
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 136
- 238000000034 method Methods 0.000 claims description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 37
- 229940011051 isopropyl acetate Drugs 0.000 claims description 32
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 10
- BJEPYKJPYRNKOW-REOHCLBHSA-L (S)-malate(2-) Chemical class [O-]C(=O)[C@@H](O)CC([O-])=O BJEPYKJPYRNKOW-REOHCLBHSA-L 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 229940116298 L- MALIC ACID Drugs 0.000 claims description 7
- 235000011090 malic acid Nutrition 0.000 claims description 7
- 230000000171 quenching Effects 0.000 claims description 7
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N N-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- PFCUZDIEKKTHCH-UHFFFAOYSA-N acetonitrile oxide Chemical compound CC#N=O PFCUZDIEKKTHCH-UHFFFAOYSA-N 0.000 claims description 3
- LRDFRRGEGBBSRN-UHFFFAOYSA-N 2-methylpropanenitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 28
- ONIQOQHATWINJY-UHFFFAOYSA-N Cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 abstract description 11
- PFMAFXYUHZDKPY-UHFFFAOYSA-N 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid Chemical compound C=1C=C(F)C=CC=1NC(=O)C1(C(=O)O)CC1 PFMAFXYUHZDKPY-UHFFFAOYSA-N 0.000 abstract description 9
- JQWTVIFNRAALHM-UHFFFAOYSA-N 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carbonyl chloride Chemical compound C1=CC(F)=CC=C1NC(=O)C1(C(Cl)=O)CC1 JQWTVIFNRAALHM-UHFFFAOYSA-N 0.000 abstract description 7
- VXEQRXJATQUJSN-UHFFFAOYSA-N 4-(6,7-dimethoxyquinolin-4-yl)oxyaniline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC1=CC=C(N)C=C1 VXEQRXJATQUJSN-UHFFFAOYSA-N 0.000 abstract description 5
- WRVHQEYBCDPZEU-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinoline Chemical compound C1=CC(Cl)=C2C=C(OC)C(OC)=CC2=N1 WRVHQEYBCDPZEU-UHFFFAOYSA-N 0.000 abstract description 4
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-Aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 abstract description 2
- 229960001292 cabozantinib Drugs 0.000 abstract description 2
- QIOVYJNRTYWDAQ-UHFFFAOYSA-N FN(C(=O)C1(CC1)C(=O)Cl)C1=CC=CC=C1 Chemical compound FN(C(=O)C1(CC1)C(=O)Cl)C1=CC=CC=C1 QIOVYJNRTYWDAQ-UHFFFAOYSA-N 0.000 abstract 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 41
- 238000002360 preparation method Methods 0.000 description 27
- UZMWMNNHLOWIKU-UHFFFAOYSA-N FC1=CC=C(C=C1)NC(=O)C1(CC1)C(=O)NC1=CC=C(C=C1)OC1=NC2=CC(=C(C=C2C=C1)OC)OC Chemical compound FC1=CC=C(C=C1)NC(=O)C1(CC1)C(=O)NC1=CC=C(C=C1)OC1=NC2=CC(=C(C=C2C=C1)OC)OC UZMWMNNHLOWIKU-UHFFFAOYSA-N 0.000 description 26
- -1 N-[3-fluoro({6-(methyloxy)[(3- morpholinylpropyl)oxy]quinolinyl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide Chemical compound 0.000 description 25
- 239000000047 product Substances 0.000 description 23
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 21
- 201000010099 disease Diseases 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 150000003512 tertiary amines Chemical class 0.000 description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 9
- 125000004429 atoms Chemical group 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 230000002829 reduced Effects 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000001184 potassium carbonate Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 201000010874 syndrome Diseases 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 230000000051 modifying Effects 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000001808 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 238000005292 vacuum distillation Methods 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- 150000001448 anilines Chemical class 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002194 synthesizing Effects 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- NWNVXBNGKWBZGF-UHFFFAOYSA-N 4-(6,7-dimethoxyquinolin-2-yl)oxyaniline Chemical compound N1=C2C=C(OC)C(OC)=CC2=CC=C1OC1=CC=C(N)C=C1 NWNVXBNGKWBZGF-UHFFFAOYSA-N 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 102000030951 Phosphotransferases Human genes 0.000 description 3
- 108091000081 Phosphotransferases Proteins 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 235000012970 cakes Nutrition 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 210000004027 cells Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000000670 limiting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrugs Drugs 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Chemical group OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000001028 anti-proliferant Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000005340 bisphosphate group Chemical group 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000004701 malic acid derivatives Chemical class 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 102000027656 receptor tyrosine kinases Human genes 0.000 description 2
- 108091007921 receptor tyrosine kinases Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- KWMLJOLKUYYJFJ-AIECOIEWSA-N (2R,3R,4R,5S,6R)-2,3,4,5,6,7-hexahydroxyheptanoic acid Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-AIECOIEWSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-Bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/59—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
Abstract
Disclosed herein is a process for preparing Cabozantinib, where the precursor 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid is prepared by (e) contacting 1,1 -cyclopropane dicarboxylic acid with thionyl chloride in a polar aprotic solvent; (b) adding 4-fluoroaniline and triethyl amine in a polar aprotic solvent to the mixture of step (e). subsequently this is converted to 1-(-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride. The intermediate 4-Chloro-6,7-dimethoxy-quinoline is prepared from 6,7-dhnethoxy-quinoline-4-ol, followed by reaction with 4-Aminophenol to give 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine, which is then reacted with 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride to give N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in a polar aprotic solvent to the mixture of step (e). subsequently this is converted to 1-(-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride. The intermediate 4-Chloro-6,7-dimethoxy-quinoline is prepared from 6,7-dhnethoxy-quinoline-4-ol, followed by reaction with 4-Aminophenol to give 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine, which is then reacted with 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride to give N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
Description
PROCESS FOR PREPARING QUINOLINE DERIVATIVES
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of N.Z. Application No. 624328, which is the
national phase entry of P.C.T. International Application No. , filed
October 22, 2012, and claims the benefit of priority of U.S. Provisional Application No.
61/549,312, filed October 20, 2011, the entire contents of which are incorporated herein by
reference.
FIELD OF THE INVENTION
This disclosure relates to process of preparing compounds useful for modulating
protein kinase enzymatic activity. More specifically, this disclosure relates to a process for
preparing compounds useful for modulating cellular activities such as proliferation,
differentiation, programmed cell death, migration, and chemoinvasion.
BACKGROUND OF THE INVENTION
Modulation (particularly inhibition) of cell proliferation and angiogenesis, two
key cellular processes needed for tumor growth and survival (Matter A. Drug Disc Technol
2001 6, 1005-1024) is an attractive goal for development of small-molecule drugs. Anti-
angiogenic therapy represents a potentially important approach for the treatment of solid
tumors and other diseases associated with dysregulated vascularization, including ischemic
coronary artery disease, diabetic retinopathy, psoriasis, and rheumatoid arthritis. As well, cell
antiproliferative agents are desirable to slow or stop the growth of tumors.
One such target for small-molecule modulation of antiangiogenic and
antiproliferative activity is c-Met. The kinase c-Met, is the prototypic member of a subfamily
of heterodimeric receptor tyrosine kinases (RTKs) which include Met, Ron and Sea.
Expression of c-Met occurs in a wide variety of cell types including epithelial, endothelial,
and mesenchymal cells where activation of the receptor induces cell migration, invasion,
proliferation and other biological activities associated with “invasive cell growth.” As such,
signal transduction through c-Met receptor activation is responsible for many of the
characteristics of tumor cells.
N-(4-{[6,7-bis(methyloxy)quinolinyl]oxy}phenyl)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide and N-[3-fluoro({6-(methyloxy)[(3-
morpholinylpropyl)oxy]quinolinyl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide are two small molecule inhibitors of c-Met that are currently undergoing
clinical investigation as treatments for a range of cancers. There is accordingly an ongoing
need for new and efficient processes for making these two promising cancer therapies. It is an
object of the present invention to go some way towards meeting this need, and/or to at least
provide the public with a useful choice.
SUMMARY OF THE INVENTION
[0005a] A first aspect of the present invention provides a process for preparing Compound
Compound 1;
comprising:
(a) converting to ;
(b) reacting with to provide ;
(c) converting to ;
(d) reacting with to form
Compound 1;
wherein is prepared by:
(e) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar
aprotic solvent at room temperature; and
(f) adding a mixture comprising 4-fluoroaniline and triethyl amine in a polar
aprotic solvent to the mixture of step (e).
[0005b] A further aspect of the present invention provides a process for preparing
Compound 1:
Compound 1;
comprising:
(a) converting to ;
(b) reacting with to provide ;
(c) converting to ;
(d) reacting with to form
Compound 1;
wherein is prepared by:
(e) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in
isopropyl acetate at room temperature, followed by adding 4-fluoroaniline and triethyl amine
to the mixture, quenching the mixture with concentrated aqueous sodium hydroxide;
extracting into dilute aqueous base, acidifying the mixture with HCl,
and isolating by filtration.
[0005c] Another aspect of the present invention provides a process for preparing
Compound 1, L-malate salt:
Compound 1, L-malate salt;
comprising:
(a) converting to ;
(b) reacting with to provide ;
(c) converting to ;
(d) reacting with to form
Compound 1;
(e) reacting compound 1 with L-malic acid to form Compound 1, L-malate salt;
and wherein is prepared by:
(f) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in
isopropyl acetate at room temperature; and
(g) adding a mixture comprising 4-fluoroaniline and a triethyl amine in isopropyl
acetate to the mixture of step (f).
Disclosed is a process for preparing a compound of Formula A:
wherein R is H, F, Cl, or Br;
comprising
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar
aprotic solvent; and
(b) adding and a tertiary amine base to the mixture of step (a).
The compound of Formula A is used to form a compound of Formula I:
wherein:
R is halo;
R is halo;
R is (C -C )alkyl or (C -C )alkyl optionally substituted with heterocycloalkyl;
1 6 1 6
R is (C -C )alkyl; and
Q is CH or N.
In one embodiment, the compound of Formula I is compound 1:
CH O
H C O N
Compound 1
or a pharmaceutically acceptable salt thereof. Compound 1 is known as N-(4-{[6,7-
bis(methyloxy)quinolinyl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide. describes the synthesis of N-(4-{[6,7-
bis(methyloxy)quinolinyl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide (Example 12, 37, 38, and 48) and also discloses the therapeutic activity of this
molecule to inhibit, regulate, and/or modulate the signal transduction of kinases, (Assays,
Table 4, entry 289). Example 48 is on paragraph [0353] in , the entire
contents of which is incorporated by reference.
In another embodiment, the compound of Formula I is compound 2:
Compound 2
or a pharmaceutically acceptable salt thereof. Compound 2 is known as is N-[3-fluoro({6-
(methyloxy)[(3-morpholinylpropyl)oxy]quinolinyl}oxy)phenyl]-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide. WO 2005-030140 describes the synthesis of
Compound (I) (Examples 25, 30, 36, 42, 43 and 44) and also discloses the therapeutic activity
of this molecule to inhibit, regulate, and/or modulate the signal transduction of kinases,
(Assays, Table 4, entry 312). Compound 2 has been measured to have a c-Met IC value of
approximately 0.6 nanomolar (nM). PCT/US09/064341, which claims priority to U.S.
provisional application 61/199,088, filed November 13, 2008, describes a scaled-up synthesis
of compound 2.
Disclosed is a process for preparing a compound of Formula I as defined above:
comprising the steps of:
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar
aprotic solvent;
(b) adding and a tertiary amine base to the mixture of step (a)
to form a compound of Formula A; and
(c) coupling a compound of Formula A with an amine of Formula B to form a
compound of Formula I
The Compound of Formula B can be prepared as described in ,
as mentioned previously, the entire contents of which is incorporated by reference.
Alternative approaches to the synthesis of the compound of Formula I, compound A,
compound B, and Compounds 1 and 2 are disclosed in additional applications
PCT/2009/643411 and , and the entire contents of each are disclosed
herein by reference.
The mono-amidation process disclosed herein presents several significant
processing advantages. Prior approaches to making Compound A required mixing 1,1-
cyclopropanedicarboxylic acid with triethyl amine, and then adding thionyl chloride followed
by the aniline. The reaction was typically and undesirably exothermic. The inventors found
that the exotherm was eliminated by reordering the sequence of reagent additions. Reaction
times were significantly reduced, and the resulting product does not require additional
purification. Moreover, the process as disclosed herein is highly selective for formation of
the mono-amidation product Compound A: over the bis-amide
H H (R )
(R )
. The bis-amide, if present, is readily removed using
the isolation conditions developed by the inventors.
The process disclosed herein is generalizable for the selective mono-amidation of
symmetric dicarboxylic acids using an array of primary or secondary amines. Thus,
disclosed is a process for making a mono-amide from the corresponding dicarboxylic acid,
comprising:
(a) contacting a dicarboxylic acid with thionyl chloride in a polar aprotic solvent;
(b) adding a primary amine and a tertiary amine base to the resulting mixture.
There are many different aspects and embodiments of the disclosure described
herein below, and each aspect and each embodiment is non-limiting in regard to the scope of
the disclosure. The terms “aspects” and “embodiments” are meant to be non-limiting
regardless of where the terms “aspect” or “embodiment” appears in this specification. The
transitional term "comprising" as used herein, which is synonymous with "including,"
"containing," or “characterized by,” is inclusive or open-ended and does not exclude
additional, unrecited elements.
[0014a] In the description in this specification reference may be made to subject matter
which is not within the scope of the appended claims. That subject matter should be readily
identifiable by a person skilled in the art and may assist in putting into practice the invention
as defined in the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
The following abbreviations and terms have the indicated meanings throughout:
Abbreviation Meaning
Ac Acetyl
br Broad
°C Degrees Celsius
c- Cyclo
CBZ CarboBenZoxy = benzyloxycarbonyl
d Doublet
dd Doublet of doublet
dt Doublet of triplet
DCM Dichloromethane
DMA N,N-dimethylacetamide
DME 1,2-dimethoxyethane
DMF N,N-Dimethylformamide
DMSO dimethyl sulfoxide
Dppf 1,1’-bis(diphenylphosphano)ferrocene
DSC Differential scanning calorimetry
EI Electron Impact ionization
Et Ethyl
g Gram(s)
GVS Gravimetric vapor sorption
h or hr Hour(s)
HPLC High pressure liquid chromatography
KF Karl Fisher water content determination
kg Kilogram
kV Kilovolt
L Liter(s)
LCMS Liquid chromatography - Mass spectrometry
mA Milliampere
Abbreviation Meaning
Me Methyl
M Molar or molarity
m Multiplet
Mm Millimeter
MEK Methyl ethyl ketone
mg Milligram(s)
MHz Megahertz (frequency)
Min Minute(s)
mL Milliliter(s)
µL Microliter(s)
μm Micrometer
µM Micromole(s) or micromolar
mM Millimolar
mmol Millimole(s)
Mol Mole(s)
MS Mass spectral analysis
MTBE Methyl t-butyl ether
N Normal or normality
nM Nanomolar
NMR Nuclear magnetic resonance spectroscopy
q Quartet
psi Pounds per square inch
rpm Revolutions per minute
RH Relative humidity
RT Room temperature
s Singlet
t or tr Triplet
TFA Trifluoroacetic acid
TGA Thermogravimetric analysis
THF Tetrahydrofuran
TLC Thin layer chromatography
Abbreviation Meaning
XRPD X-ray powder diffraction
Angle rotation in radians
The symbol “-” means a single bond; “=” means a double bond.
When chemical structures are depicted or described, unless explicitly stated
otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of
four. For example, in the structure on the left-hand side of the schematic below there are nine
hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a
particular atom in a structure is described in textual formula as having a hydrogen or
hydrogens as substitution (expressly defined hydrogen), for example, -CH CH -. It is
understood by one of ordinary skill in the art that the aforementioned descriptive techniques
are common in the chemical arts to provide brevity and simplicity to description of otherwise
complex structures.
H H H
Br Br
If a group “R” is depicted as “floating” on a ring system, as for example in the
formula:
then, unless otherwise defined, a substituent “R” may reside on any atom of the ring system,
assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the
ring atoms, so long as a stable structure is formed.
If a group “R” is depicted as floating on a fused ring system, as for example in the
formulae:
, or , or
then, unless otherwise defined, a substituent “R” may reside on any atom of the fused ring
system, assuming replacement of a depicted hydrogen (for example the -NH- in the formula
above), implied hydrogen (for example as in the formula above, where the hydrogens are not
shown but understood to be present), or expressly defined hydrogen (for example where in
the formula above, “Z” equals =CH-) from one of the ring atoms, so long as a stable structure
is formed. In the example depicted, the “R” group may reside on either the 5-membered or
the 6-membered ring of the fused ring system. When a group “R” is depicted as existing on a
ring system containing saturated carbons, as for example in the formula:
where, in this example, “y” can be more than one, assuming each replaces a currently
depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined,
where the resulting structure is stable, two “R’s” may reside on the same carbon. A simple
example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the
depicted ring (an “annular” carbon). In another example, two R’s on the same carbon,
including that carbon, may form a ring, thus creating a spirocyclic ring (a “spirocyclyl”
group) structure with the depicted ring as for example in the formula.
“(C -C )Alkyl” or “alkyl” means a linear or branched hydrocarbon group having
one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like. “C alkyl” refers to, for
example, n-hexyl, iso-hexyl, and the like.
“Heterocycloalkyl” means a saturated or partially unsaturated monovalent
monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated monovalent
fused bicyclic group of 5 to 12 ring atoms in which one or more, for example one, two, three,
or four ring heteroatoms independently selected from -O-, -S(O) - (n is 0, 1, or 2), -N=,
-N(R )- (where R is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining
ring atoms being carbon. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-,
or -C(=NH)- group. Fused bicyclic radical includes bridged ring systems. Unless otherwise
stated, the valency of the group may be located on any atom of any ring within the radical,
valency rules permitting. In particular, when the point of valency is located on a nitrogen
atom, R is absent. In another embodiment the term heterocycloalkyl includes, but is not
limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl,
4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-
oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl,
isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl,
octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and the
derivatives thereof, and N-oxide or a protected derivative thereof.
“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.
“Yield” for each of the reactions described herein is expressed as a percentage of
the theoretical yield.
“Patient” for the purposes of the present invention includes humans and other
animals, particularly mammals, and other organisms. Thus the processes are applicable to
both human therapy and veterinary applications. In another embodiment the patient is a
mammal, and in another embodiment the patient is human.
A “pharmaceutically acceptable salt” of a compound means a salt that is
pharmaceutically acceptable and that possesses the desired pharmacological activity of the
parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic.
Additional information on suitable pharmaceutically acceptable salts can be found in
Remington’s Pharmaceutical Sciences, 17 ed., Mack Publishing Company, Easton, PA,
1985, which is incorporated herein by reference or S. M. Berge, et al., “Pharmaceutical
Salts,” J. Pharm. Sci., 1977;66:1-19, both of which are incorporated herein by reference.
Examples of pharmaceutically acceptable acid addition salts include those formed
with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid,
propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, malic
acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic
acid, 4,4’-methylenebis-(3-hydroxyenecarboxylic acid), 3-phenylpropionic acid,
trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic
acid, and salicylic acid and the like.
“Prodrug” refers to compounds that are transformed (typically rapidly) in vivo to
yield the parent compound of the above formulae, for example, by hydrolysis in blood.
Common examples include, but are not limited to, ester and amide forms of a compound
having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically
acceptable esters of the compounds of this invention include, but are not limited to, alkyl
esters (for example with between approximately one and approximately six carbons) the alkyl
group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and
arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable
amides of the compounds of this invention include, but are not limited to, primary amides,
and secondary and tertiary alkyl amides (for example with between approximately one and
approximately six carbons). Amides and esters of the compounds of the present invention
may be prepared according to conventional processes. A thorough discussion of prodrugs is
provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the
A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B.
Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are
incorporated herein by reference for all purposes.
“Therapeutically effective amount” is an amount of a compound of the invention,
that when administered to a patient, ameliorates a symptom of the disease. A therapeutically
effective amount is intended to include an amount of a compound alone or in combination
with other active ingredients effective to modulate c-Met, and/or VEGFR2, or effective to
treat or prevent cancer. The amount of a compound of the invention which constitutes a
“therapeutically effective amount” will vary depending on the compound, the disease state
and its severity, the age of the patient to be treated, and the like. The therapeutically effective
amount can be determined by one of ordinary skill in the art having regard to their knowledge
and to this disclosure.
“Treating” or “treatment” of a disease, disorder, or syndrome, as used herein,
includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e.
causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an
animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does
not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting
the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the
disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
As is known in the art, adjustments for systemic versus localized delivery, age, body weight,
general health, sex, diet, time of administration, drug interaction and the severity of the
condition may be necessary, and will be ascertainable with routine experience.
Process
In one aspect, this disclosure relates to a process for preparing a compound of
Formula A:
wherein R is H, F, Cl, or Br;
comprising
(a) contacting 1,1-cyclopropanedicarboxylic acid with thionyl chloride in a polar
aprotic solvent; and
(b) adding and a tertiary amine base to the mixture of step (a).
In the process, 1,1-cyclopropanedicarboxylic acid is combined with a polar aprotic
solvent to form a mixture. In one embodiment, the polar aprotic solvent is selected from the
group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate,
acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide, or combinations thereof. In
another embodiment, the polar aprotic solvent is selected form the group consisting of
dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone,
dimethylformamide, and acetonitrile, or combinations thereof. In another embodiment, the
polar aprotic solvent is selected form the group consisting of dichloromethane,
tetrahydrofuran, ethyl acetate, and isopropyl acetate, or combinations thereof. In one
embodiment, the polar aprotic solvent is isopropyl acetate.
The volume of polar aprotic solvent used will vary depending on the reaction
scale. Typically, approximately 5-10 volumes of polar aprotic solvent are used relative to the
volume of 1,1-cyclopropanedicarboxylic acid that is used. More typically, 6-9 volumes of
polar aprotic solvent are used. More typically, 7.5-8.5 volumes of polar aprotic solvent are
used. Preferably, approximately 8 volumes of the polar aprotic solvent are used.
Next, thionyl chloride is added to the mixture comprising 1,1-
cyclopropanedicarboxylic acid and the polar aprotic solvent. A molar excess of thionyl
chloride is used relative to the number of moles of 1,1-ccyclopropanedicarboxylic acid that is
used. Typically, approximately 1.01 to 1.5 molar equivalents of thionyl chloride are used
relative to the number of moles of 1,1-cyclopropanedicarboxylic acid that are used. More
typically, approximately 1.01 to 1.2 molar equivalents of thionyl chloride are used. More
typically, approximately 1.01 to 1.1 molar equivalents of thionyl chloride are used. More
typically, approximately 1.05 molar equivalents of thionyl chloride are used.
The mixture comprising 1,1-cyclopropoanedicarboxylic acid, thionyl chloride, and
the polar aprotic solvent is stirred or otherwise agitated for 2 to 24 hours. “Ambient
temperature” generally means that no external heating device, such as a heating jacket,
heating mantle, or the like, is employed to increase the temperature of the mixture.
Typically, the temperature is approximately 23 to 27 °C. More typically, the temperature is
approximately 24 to 26 °C. Typically, the temperature is approximately 25 °C. The stirring
at room temperature typically continues for approximately 6 to 16 hours. More typically, the
stirring continues for approximately 13-15 hours at approximately 25 °C.
Next, a mixture of an optionally substituted aniline and a
tertiary amine base in a polar aprotic solvent is added to the mixture. Typically, the optionally
substituted aniline is 4-fluoroaniline.
A molar excess of aniline is used relative to the number of moles of 1,1-
cyclopropanedicarboxylic acid. Typically, approximately 1.01 to 1.5 molar equivalents of
aniline are used relative to the number of moles of 1,1-cyclopropanedicarboxylic acid that are
used. More typically, approximately 1.01 to 1.2 molar equivalents of aniline are used. More
typically, approximately 1.05 to 1.15 molar equivalents of aniline are used. More typically,
approximately 1.1 molar equivalents of aniline are used.
The tertiary amine base is typically a trialkyl amine, wherein the alkyl groups are
the same or different and may be linear or branched. The use of trialkyl amine bases is well-
known to the skilled artisan, and many are commercially available such as triethylamine, di-
isopropylethyl amine, or the like. Typically the tertiary amine base is triethyl amine. A
molar excess of tertiary amine base is used relative to the number of moles of 1,1-
cyclopropanedicarboxylic acid. Typically, approximately 1.01 to 1.5 molar equivalents of
tertiary amine base are used relative to the number of moles of 1,1-cyclopropanedicarboxylic
acid that are used. More typically, approximately 1.01 to 1.2 molar equivalents of tertiary
amine base are used. More typically, approximately 1.05 to 1.15 molar equivalents of aniline
are used. More typically, approximately 1.1 molar equivalents of tertiary amine base are
used.
The optionally substituted aniline and tertiary amine base are typically combined
in a polar aprotic solvent before they are added to the 1,1-cyclopropanedicarboxylic
acid/thionyl chloride/isopropyl acetate mixture. The polar aprotic solvent that is used is
typically the same as the solvent that is used to form the 1,1-cyclopropanedicarboxylic acid
mixture, and is selected form the group consisting of dichloromethane, tetrahydrofuran, ethyl
acetate, isopropyl acetate, acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide,
or combinations thereof. In another embodiment, the polar aprotic solvent is selected form
the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate,
acetone, dimethylformamide, and acetonitrile, or combinations thereof. In another
embodiment, the polar aprotic solvent is selected form the group consisting of
dichloromethane, tetrahydrofuran, ethyl acetate, and isopropyl acetate, or combinations
thereof. In one embodiment, the polar aprotic solvent is isopropyl acetate.
The volume of polar aprotic solvent used to form the aniline/tertiary amine base
mixture will vary depending on the reaction scale. Typically, approximately 1-5 volumes of
polar aprotic solvent are used relative to volume of optionally substituted aniline that are
used. More typically, 1.5-3 volumes of polar aprotic solvent are used. More typically,
approximately 2 volumes of polar aprotic solvent are used.
The resulting combined mixture is allowed to mix at ambient temperature for 0.5
to 5 hours, and more preferably from 1 to 3 hours. More typically the mixture is allowed to
mix for 2 hours.
The mixture, which at this point is typically a slurry comprising Compound A, is
then quenched, by treating with a concentrated aqueous base such as 5N aqueous NaOH,
KOH, or K PO , or the like. In one embodiment, the base is NaOH. The amount of aqueous
base employed to quench the reaction will vary depending the on the reaction scale. For the
scale described above, typically approximately 4-6 volumes of 5N NaOH are used. The
organic phase of the resulting biphasic mixture is then subsequently extracted with multiple
washes of 0.5N NaOH and the aqueous phases are combined. The combined basic extracts
are back extracted with an aprotic solvent such as heptane. The combined aqueous phases are
then subsequently acidified with an aqueous mineral acid such as HCl, H SO , or the like.
Typically the acid used is 30 percent HCl in water. The acid is added to the combined
aqueous phases to form a slurry. Compound A is then isolated by filtration.
In a further embodiment, a process for preparing a compound of Formula A is
provided:
wherein R is H, F, Cl, or Br;
comprising
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in
isopropyl acetate at room temperature; and
(b) adding a mixture comprising and triethyl amine in
isopropyl acetate to the resulting mixture.
In a further embodiment, a process for preparing a compound of Formula A is
provided:
wherein R is H, F, Cl, or Br;
comprising
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in
isopropyl acetate at room temperature;
(b) adding and triethyl amine to the mixture;
(c) quenching the mixture of step (b) with concentrated aqueous sodium
hydroxide;
(d) extracting compound A into dilute aqueous base
(e) acidifying the mixture with HCl; and
(f) isolating Compound A by filtration.
In a further embodiment, a process for preparing a compound of Formula A-1 is
provided:
comprising
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in
isopropyl acetate at room temperature; and
(b) adding a mixture comprising 4-fluoroaniline and triethyl amine in isopropyl
acetate to the resulting mixture.
In a further embodiment, a process for preparing a compound of Formula A-1 is
provided:
comprising
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in
isopropyl acetate at room temperature;
(b) adding a mixture comprising 4-fluoroaniline and triethyl amine in isopropyl
acetate to the resulting mixture;
(c) quenching the mixture with concentrated aqueous sodium hydroxide;
(d) extracting compound A-1 into dilute aqueous base;
(e) acidifying the mixture with HCl; and
(f) isolating Compound A by filtration.
Disclosed is a process for preparing Compound 1:
CH F
H C O N
Compound 1
comprising the steps of:
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar
aprotic solvent;
(b) adding 4-fluoraniline and triethyl amine to the mixture of step (a) to form a
compound of Formula A-1; and
(c) coupling a compound of Formula A-1 with an amine of Formula B-1 to form
Compound 1
Disclosed is a process for preparing Compound 1:
Compound 1
comprising the steps of:
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar
aprotic solvent;
(b) adding 4-fluoraniline and triethyl amine to the mixture of step (a) to form a
compound of Formula A-1;
(c) quenching the mixture of step (b) with concentrated aqueous sodium
hydroxide;
(d) extracting the compound of Formula A-1 into dilute aqueous base;
(e) acidifying the mixture of step (d) with HCl;
(f) isolating the compound of Formula A-1 by filtration; and
(g) coupling a compound of Formula A-1 with an amine of Formula B-1 to form
Compound 1
Disclosed is a process for preparing Compound 2:
Compound 2
comprising the steps of:
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar
aprotic solvent;
(b) adding 4-fluoraniline and triethyl amine to the mixture of step (a) to form a
compound of Formula A-1; and
(c) coupling a compound of Formula A-1 with an amine of Formula B-2 to form
Compound 2
Disclosed is a process for preparing Compound 2:
Compound 2
comprising the steps of:
(a) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar
aprotic solvent;
(b) adding 4-fluoraniline and triethyl amine to the mixture of step (a) to form a
compound of Formula A-1;
(c) quenching the mixture of step (b) with concentrated aqueous sodium
hydroxide;
(d) extracting the compound of Formula A-1 into dilute aqueous base;
(e) acidifying the mixture of step (d) with HCl;
(f) isolating the compound of Formula A-1 by filtration; and
(g) coupling a compound of Formula A-1 with an amine of Formula B-2 to form
Compound 2
As described herein, reaction of thionyl chloride with 1,1-
cyclopropanedicarboxylic acid in a polar aprotic solvent as described herein offers a
significant advantage over previous processes in that the reaction is not exothermic. A
previous reaction variant wherein SOCl was added to a mixture of 1,1-
cyclopropanedicarboxylic acid and Et N in tetrahydrofuran was very exothermic. The
process as described herein is noteworthy because carboxylic acids do not normally convert
to the corresponding acyl chlorides when treated with SOCl at ambient temperature.
The process as disclosed herein is highly selective for formation of the mono-
(R )
(R )
amidation product Compound A over the bis-amide:
or . Typically, less than 5 percent, or more typically
less than 1 percent, of the bis-amide is formed via the process disclosed herein as evidenced
by HPLC analysis of in process control samples. Moreover, the bis-amide, if present, is
normally completely removed using the isolation conditions.
Advantageously, the described process also considerably shortens the time taken
for the production of a batch of Compound A. Currently, the process for large scale
production of Compound A requires several days and subsequent purification by
recrystallization. Using the improved process, the typical production time is expected to take
one-two days and does not require additional recrystallization.
Experimental Procedures
The invention is illustrated further by the following examples in Scheme 1 and the
description thereof, which are not to be construed as limiting the invention in scope or spirit
to the specific procedures described in them. Those having skill in the art will recognize that
the starting materials may be varied and additional steps employed to produce compounds
encompassed by the invention, as demonstrated by the following examples. Those skilled in
the art will also recognize that it may be necessary to utilize different solvents or reagents to
achieve some of the above transformations.
Unless otherwise specified, all reagents and solvents are of standard commercial
grade and are used without further purification. The appropriate atmosphere to run the
reaction under, for example, air, nitrogen, argon, and the like, will be apparent to those
skilled in the art.
Preparation of 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (Compound
A-1)
The starting 1,1-cyclopropanedicarboxylic acid was treated with thionyl chloride
(1.05 equivalents) in approximately 8 volumes of isopropyl acetate at 25 ºC for 5 hours. The
resulting mixture was then treated with a solution of 4-fluoroaniline (1.1 equivalents) and
triethylamine (1.1 equivalents) in isopropyl acetate (2 volumes) over 1 hour. The product
slurry was quenched with 5N NaOH solution (5 volumes) and the aqueous phase is discarded.
The organic phase was extracted with 0.5N NaOH solution (10 volumes) and the basic
extract was washed with heptane (5 volumes) and subsequently acidified with 30% HCl
solution to give a slurry. Compound A-1 was isolated by filtration.
Compound A-1 was prepared on a 1.00 kg scale using 1,1-
cyclopropanedicarboxylic acid as the limiting reagent to furnish 1.32 kg of Compound A-1
(77% isolated yield; 84% mass balance) with 99.92% purity (HPLC) and 100.3% assay.
Preparation of N-(4-{[6,7-bis(methyloxy)quinolinyl]oxy}phenyl)-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) and the (L)-malate salt
thereof.
A synthetic route that can be used for the preparation of N-(4-{[6,7-
bis(methyloxy)quinolinyl]oxy}phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide and the (L)-malate salt thereof is depicted in Scheme 1.
Scheme 1
Another synthetic route that can be used for the preparation of N-(4-{[6,7-
bis(methyloxy)quinolinyl]oxy}phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide and the (L)-malate salt thereof is depicted in Scheme 2.
Scheme 2
Preparation of 4–Chloro–6,7–dimethoxy–quinoline
A reactor was charged sequentially with 6,7–dimethoxy–quinoline–4–ol (47.0 kg)
and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and
phosphorus oxychloride (POCl , 130.6 kg) was added. After the addition of POCl , the
temperature of the reaction mixture was raised to approximately 77°C. The reaction was
deemed complete (approximately 13 hours) when less than 3% of the starting material
remained (in-process high-performance liquid chromatography [HPLC] analysis). The
reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled
solution of dichloromethane (DCM, 482.8 kg), 26 % NH OH (251.3 kg), and water (900 L).
The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated.
The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and
the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed
with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the
organic phase was concentrated by vacuum distillation with the removal of solvent
(approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor
containing organic phase and concentrated by vacuum distillation with the removal of solvent
(approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then
charged and the temperature of the mixture was adjusted to – 20 to – 25 C and held for 2.5
hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0
kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound
(35.6 kg).
Preparation of 4–(6, 7 –Dimethoxy–quinoline–4–yloxy)–phenylamine
4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg)
was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t-
butoxide (21.4 kg), and DMA (167.2 kg) at 20 – 25 C. This mixture was then heated to 100
– 105 C for approximately 13 hours. After the reaction was deemed complete as determined
using in-process HPLC analysis (less than 2% starting material remaining), the reactor
contents were cooled at 15 to 20 C and water (pre-cooled, 2 to 7 C, 587 L) charged at a rate
to maintain 15 to 30 C temperature . The resulting solid precipitate was filtered, washed with
a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake
was then dried at approximately 25 C on filter to yield crude 4–(6, 7 –dimethoxy–quinoline–
4–yloxy)–phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4–(6, 7 –
dimethoxy–quinoline–4–yloxy)–phenylamine was refluxed (approximately 75 C) in a
mixture of tetrahydrofuran (THF, 211.4 kg) and DMA (108.8 kg) for approximately 1 hour
and then cooled to 0 to 5 C and aged for approximately 1 hour after which time the solid was
filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25
C to yield 4–(6, 7 –dimethoxy–quinoline–4–yloxy)–phenylamine (34.0 kg).
Alternative Preparation of 4–(6, 7 –Dimethoxy–quinoline–4–yloxy)–phenylamine
4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-Aminophenol (30.8 kg) and
sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF) were charged to a
reactor, followed by N,N-dimethylacetamide (DMA, 293.3 kg). This mixture was then
heated to 105 to 115 C for approximately 9 hours. After the reaction was deemed complete as
determined using in-process HPLC analysis (less than 2% starting material remaining), the
reactor contents were cooled at 15 to 25 C and water (315 kg) was added over a two hour
period while maintaining the temperature between 20 and 30 C. The reaction mixture was
then agitated for an additional hour at 20 to 25 C. The crude product was collected by
filtration and washed with a mixture of 88 kg water and 82.1 kg DMA, followed by 175 kg
water. The product was dried on a filter drier for 53 hours. The LOD showed less than 1%
w/w.
In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used
and the reaction temperature was increased from 110 to 120 C. In addition, the cool down
temperature was increased to 35 to 40 C and the starting temperature of the water addition
was adjusted to 35 to 40 C, with an allowed exotherm to 45 C.
Preparation of 1–(4–Fluoro–phenylcarbamoyl)–cyclopropanecarbonyl chloride
Oxalyl chloride (12.6 kg) was added to a solution of 1–(4–fluoro–
phenylcarbamoyl)–cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and
N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not
exceed 25 C. This solution was used in the next step without further processing.
Alternative Preparation of 1–(4–Fluoro–phenylcarbamoyl)–cyclopropanecarbonyl
chloride
A reactor was charged with 1–(4–fluoro–phenylcarbamoyl)–
cyclopropanecarboxylic acid (35 kg), 344 g DMF, and 175kg THF. The reaction mixture
was adjusted to 12 to 17 °C and then to the reaction mixture was charged 19.9 kg of oxalyl
chloride over a period of 1 hour. The reaction mixture was left stirring at 12 to 17 °C for 3 to
8 hours. This solution was used in the next step without further processing.
Preparation of cyclopropane–1,1–dicarboxylic acid [4–(6,7–dimethoxy– quinoline–4–
yloxy)–phenyl]–amide (4–fluoro–phenyl)–amide
The solution from the previous step containing 1–(4–fluoro–phenylcarbamoyl)–
cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy-
quinolineyloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7
kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 °C. When
the reaction was complete (in approximately 20 minutes), water (653 L) was added. The
mixture was stirred at 20 to 25 C for approximately 10 hours, which resulted in the
precipitation of the product. The product was recovered by filtration, washed with a pre-made
solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at
approximately 25 C and then at approximately 45 C under vacuum to afford the title
compound (41.0 kg, 38.1 kg, calculated based on LOD).
Alternative Preparation of cyclopropane–1,1–dicarboxylic acid [4–(6,7–dimethoxy–
quinoline–4–yloxy)–phenyl]–amide (4–fluoro–phenyl)–amide
A reactor was charged with 4-(6,7-dimethoxy-quinolineyloxy)-phenylamine
(35.7 kg, 1 equivalent), followed by 412.9 kg THF. To the reaction mixture was charged a
solution of 48.3 K CO in 169 kg water. The acid chloride solution of described in the
Alternative Preparation of 1–(4–Fluoro–phenylcarbamoyl)–cyclopropanecarbonyl chloride
above was transferred to the reactor containing 4-(6,7-dimethoxy-quinolineyloxy)-
phenylamine while maintaining the temperature between 20 to 30 °C over a minimum of two
hours. The reaction mixture was stirred at 20 to 25 °C for a minimum of three hours. The
reaction temperature was then adjusted to 30 to 25 °C, and the mixture was agitated. The
agitation was stopped and the phases of the mixture were allowed to separate. The lower
aqueous phase was removed and discarded. To the remaining upper organic phase was added
804 kg water. The reaction was left stirring at 15 to 25 °C for a minimum of 16 hours.
The product precipitated. The product was filtered and washed with a mixture of
179 kg water and 157.9 THF in two portions. The crude product was dried under a vacuum
for at least two hours. The dried product was then taken up in 285.1 kg THF. The resulting
suspension was transferred to reaction vessel and agitated until the suspension became a clear
(dissolved) solution, which required heating to 30 to 35 °C for approximately 30 minutes.
456 kg water was then added to the solution, as well as 20 kg SDAG-1 ethanol (ethanol
denatured with methanol over two hours). The mixture was agitated at 15 to 25 °C for at
least 16 hours. The product was filtered and washed with a mixture of 143 kg water and
126.7 THF in two portions. The product was dried at a maximum temperature set point of 40
In an alternative procedure, the reaction temperature during acid chloride
formation was adjusted to 10 to 15 °C. The recrystallization temperature was changed from
to 25 °C to 45 to50 °C for 1 hour and then cooled to 15 to 25 °C over 2 hours.
Preparation of cyclopropane–1,1–dicarboxylic acid [4–(6,7–dimethoxy– quinoline–4–
yloxy)–phenyl]–amide (4–fluoro–phenyl)–amide, XL184 (L) malate salt
Cyclopropane–1,1–dicarboxylic acid [4–(6,7–dimethoxy– quinoline–4–yloxy)–
phenyl]–amide (4–fluoro–phenyl)–amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl
ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was
heated to reflux (approximately 74 C) for approximately 2 h. The reactor temperature was
reduced to 50 to 55 C, and the reactor contents were filtered. These sequential steps described
above were repeated two more times starting with similar amounts of 1-5 (13.3 kg), L-Malic
acid (4.96 kg), MEK (198.6 kg), and water (37.2 kg). The combined filtrate was
azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual
volume 711 L; KF < 0.5 % w/w) at approximately 74 C. The temperature of the reactor
contents was reduced to 20 to 25 C and held for approximately 4 hours, resulting in solid
precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 C
to afford the title compound (45.5 kg).
Alternative Preparation of cyclopropane–1,1–dicarboxylic acid [4–(6,7–dimethoxy–
quinoline–4–yloxy)–phenyl]–amide (4–fluoro–phenyl)–amide, (L) malate salt
Cyclopropane–1,1–dicarboxylic acid [4–(6,7–dimethoxy– quinoline–4–yloxy)–
phenyl]–amide (4–fluoro–phenyl)–amide (47.9 kg), L-malic acid (17.2), 658.2 kg methyl
ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor and the mixture was
heated 50 to 55 °C for approximately 1 to 3 hours, and then at 55 to 60 °C for an additional 4
to 5 hours. The mixture was clarified by filtration through a 1 μm cartridge. The reactor
temperature was adjusted to 20 to 25 C and vacuum distilled with a vacuum at 150 to 200
mm Hg with a maximum jacket temperature of 55 °C to the volume range of 558 to 731 L.
The vacuum distillation was performed two more times with the charge of 380 kg
and 380.2 kg methyl ethyl ketone, respectively. After the third distillation, the volume of the
batch was adjusted to 18 v/w of Cyclopropane–1,1–dicarboxylic acid [4–(6,7–dimethoxy–
quinoline–4–yloxy)–phenyl]–amide (4–fluoro–phenyl)–amide by charging 159.9 kg methyl
ethyl ketone to give a total volume of 880L. An additional vacuum distillation was carried
out by adjusting 245.7 methyl ethyl ketone. The reaction mixture was left with moderate
agitation at 20 to 25 C for at least 24 hours. The product was filtered and washed with 415.1
kg methyl ethyl ketone in three portions. The product was dried under a vacuum with the
jacket temperature set point at 45 C.
In an alternative procedure, the order of addition was changes so that a solution of
17.7 kg L-malic acid dissolved in 129.9 kg water was added to Cyclopropane–1,1–
dicarboxylic acid [4–(6,7–dimethoxy– quinoline–4–yloxy)–phenyl]–amide (4–fluoro–
phenyl)–amide (48.7 kg) in methyl ethyl ketone (673.3 kg).
Preparation of Compound 2
Compound 2 was prepared as provided in Scheme 3 and the accompanying
experimental examples.
Scheme 3
H CO
H CO
HNO ,H SO
3 2 4
CH Cl ,H O
2 2 2
K CO ,Bu NBr
Xb 2 3 4
Tol uene
Pd - C
H CO
3 H CO
HCO H
NaOEt
HCO K
HCO Et
E tOH
E tOH
OH NO
H CO
H CO
POCl HO
CH CN
2lutidine
H CO
3 Cl
H ,Pd-C
2 O H
H CO
E tOH, H O, HCl
K CO ,H O, T H F
2 3 2
F NH N
H CO
In Scheme 3, Xb is Br or Cl. For the names of the intermediates described within
the description of Scheme 3 below, Xb is referred to as halo, wherein this halo group for
these intermediates is meant to mean either Br or Cl.
Preparation of 1-[5 methoxy-4 (3-halo propoxy)- 2 nitro-phenyl]- ethanone
Water (70 L) was charged to the solution of 1-[4-(3-halo propoxy)- 3-methoxy
phenyl] ethanone (both the bromo and the chloro compound are commercially available). The
solution was cooled to approximately 4 °C. Concentrated sulfuric acid (129.5 kg) was added
at a rate such that the batch temperature did not exceed approximately 18 °C. The resulting
solution was cooled to approximately 5 °C and 70 percent nitric acid (75.8 kg) was added at a
rate such that the batch temperature did not exceed approximately 10 °C. Methylene chloride,
water, and ice were charged to a separate reactor. The acidic reaction mixture was then added
into this mixture. The methylene chloride layer was separated, and the aqueous layer was
back extracted with methylene chloride. The combined methylene chloride layers were
washed with aqueous potassium bicarbonate solution and concentrated by vacuum
distillation. 1-Butanol was added and the mixture was again concentrated by vacuum
distillation. The resulting solution was stirred at approximately 20 °C, during which time the
product crystallized. The solids were collected by filtration, washed with 1-butanol to afford
compound the title compound, which was isolated as a solvent wet cake, and used directly in
the next step. H NMR (400MHz, DMSO-d6): δ 7.69 (s, 1H), 7.24 (s, 1H); 4.23 (m, 2H),
3.94 (s, 3H), 3.78 (t)-3.65 (t) (2H), 2.51 (s, 3H), 2.30-2.08 (m, 2H) LC/MS Calcd for
[M(Cl)+H] 288.1, found 288.0; Calcd for [M(Br)+H] 332.0, 334.0, found 331.9, 334.0.
Preparation of 1-[5-methoxy(3-morpholinyl-propoxy)nitro-phenyl]-ethanone
The solvent wet cake isolated in the previous step was dissolved in toluene. A
solution of sodium iodide (67.9 kg) and potassium carbonate (83.4 kg) was added to this
solution, followed by tetrabutylammonium bromide (9.92 kg) and morpholine (83.4 kg). The
resulting 2 phase mixture was heated to approximately 85 °C for approximately 9 hours. The
mixture was then cooled to ambient temperature. The organic layer was removed. The
aqueous layer was back extracted with toluene. The combined toluene layers were washed
sequentially with two portions of saturated aqueous sodium thiosulfate followed by two
portions of water. The resulting solution of the title compound was used in the next step
without further processing. H NMR (400MHz, DMSO-d6): δ 7.64 (s, 1H), 7.22 (s, 1H),
4.15 (t, 2H), 3.93 (s, 3H), 3.57 (t, 4H), 2.52 (s, 3H), 2.44-2.30 (m, 6H), 1.90 (quin, 2H);
LC/MS Calcd for [M+H] 339.2, found 339.2.
Preparation of 1-[2-aminomethoxy(3-morpholinyl- propoxy)-phenyl]-ethanone
The solution from the previous step was concentrated under reduced pressure to
approximately half of the original volume. Ethanol and 10 percent Pd/C (50 percent water
wet, 5.02 kg) were added; the resulting slurry was heated to approximately 48 °C, and an
aqueous solution of formic acid (22.0 kg) and potassium formate (37.0 kg) was added. When
the addition was complete and the reaction deemed complete by thin layer chromatography
(TLC), water was added to dissolve the by-product salts. The mixture was filtered to remove
the insoluble catalyst. The filtrate was concentrated under reduced pressure and toluene was
added. The mixture was made basic (pH of approximately 10) by the addition of aqueous
potassium carbonate. The toluene layer was separated and the aqueous layer was back
extracted with toluene. The combined toluene phases were dried over anhydrous sodium
sulfate. The drying agent was removed by filtration and the resulting solution was used in the
next step without further processing. H NMR (400MHz, DMSO-d6): δ 7.11 (s, 1H),, 7.01
(br s, 2H), 6.31 (s, 1H), 3.97 (t, 2H), 3.69 (s, 3H), 3.57 (t, 4H), 2.42 (s, 3H), 2.44-2.30 (m,
6H), 1.91 (quin, 2H LC/MS Calcd for [M+H] 309.2, found 309.1.
Preparation of 6-methoxy(3-morpholinyl-propoxy)-quinolin- 4-ol, sodium salt
A solution of sodium ethoxide (85.0 kg) in ethanol and ethyl formate (70.0 kg)
was added to the solution from the previous step. The mixture was warmed to approximately
44 °C for approximately 3 hours. The reaction mixture was cooled to approximately 25°C.
Methyl t-butyl ether (MTBE) was added which caused the product to precipitate. The product
was collected by filtration and the cake was washed with MTBE and dried under reduced
pressure at ambient temperature. The dried product was milled through a mesh screen to
afford 60.2 kg of the title compound. H NMR (400MHz, DMSO-d6): δ 11.22 (br s, 1H),
8.61 (d, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.17 (d, 1H), 4.29 (t, 2 H), 3.99 (m, 2H), 3.96 (s, 3H),
3.84 (t, 2H), 3.50 (d, 2H), 3.30 (m, 2H), 3.11 (m, 2H), 2.35 (m, 2H), LC/MS Calcd for
[M+H] 319.2, found 319.1.
Preparation of 4-chloromethoxy(3 morpholinyl)-quinoline
Phosphorous oxychloride (26.32 kg) was added to a solution of 6-methoxy(3-
morpholinyl-propoxy)-quinolinol (5.00 kg) in acetonitrile that was heated to 50 to 55
°C. When the addition was complete, the mixture was heated to reflux (approximately 82 °C)
and held at that temperature, with stirring for approximately 18 hours, at which time it was
sampled for in process HPLC analysis. The reaction was considered complete when no more
than 5 percent starting material remained. The reaction mixture was then cooled to 20 to 25
°C and filtered to remove solids. The filtrate was then concentrated to a residue. Acetronitrile
was added and the resulting solution was concentrated to a residue. Methylene chloride was
added to the residue and the resulting solution was quenched with a mixture of methylene
chloride and aqueous ammonium hydroxide. The resulting two phase mixture was separated,
and the aqueous layer was back extracted with methylene chloride. The combined methylene
chloride solutions were dried over anhydrous magnesium sulfate, filtered, and concentrated to
a solid. The solids were dried at 30 to 40 °C under reduced pressure to afford the title
compound (1.480 kg). H NMR (400MHz, DMSO-d6): δ 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s,
1H), 7.38 (s, 1H), 4.21 (t, 2 H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97 (quin, 2H)
LC/MS Calcd for [M+H] 458.2, found 458.0.
Preparation of 4-(2-fluoronitro-phenoxy)methoxy(3-morpholinyl
propoxy)quinoline
A solution of 4-chloromethoxy(3 morpholinyl)-quinoline (2.005 kg, 5.95
mol) and 2 fluoronitrophenol (1.169 kg, 7.44 mol) in 2,6-lutidine was heated to 140 to 145
°C, with stirring, for approximately 2 hours, at which time it was sampled for in process
HPLC analysis. The reaction was considered complete when less than 5 percent starting
material remained. The reaction mixture was then cooled to approximately 75 °C, and water
was added. Potassium carbonate was added to the mixture, which was then stirred at ambient
temperature overnight. The solids that precipitated were collected by filtration, washed with
aqueous potassium carbonate, and dried at 55 to 60 °C under reduced pressure to afford the
title compound (1.7 kg). H NMR (400MHz, DMSO-d6): δ 8.54 (d, 1H), 8.44 (dd, 1H), 8.18
(m, 1H), 7.60 (m, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 6.75 (d, 1H), 4.19 (t, 2H), 3.90 (s, 3H), 3.56
(t, 4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H). LC/MS Calcd for [M+H] 337.1, 339.1,
found 337.0, 339.0.
Preparation of 3-fluoro[6-methoxy(3-morpholinyl-propoxy)-quinolinyloxy]-
phenylamine
A reactor containing 4-(2-fluoronitro-phenoxy)methoxy(3-morpholin
yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250
g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was
pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient
temperature. When the reaction was complete (typically 2 hours), as evidenced by in process
HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction
mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate
was added to the filtrate until the pH of the solution was approximately 10. The resulting
suspension was stirred at 20 to 25 °C for approximately 1 hour. The solids were collected by
filtration, washed with water, and dried at 50 to 60 °C under reduced pressure to afford the
title compound (1.164 kg). H NMR (400MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H),
7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t,
2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for
[M+H] 428.2, found 428.1.
Preparation of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride
Oxalyl chloride (291 mL) was added slowly to a cooled (approximately 5 °C)
solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid in THF at a rate such
that the batch temperature did not exceed 10°C. When the addition was complete, the batch
was allowed to warm to ambient temperature and held with stirring for approximately 2
hours, at which time in process HPLC analysis indicated the reaction was complete. The
solution was used in the next step without further processing.
Preparation of cyclopropane-1,1-dicarboxylic acid {3-fluoro[6-methoxy(3-
morpholinyl-propoxy)-quinolinylamino]phenyl}-amide-(4 fluorophenyl)-amide
The solution from the previous step was added to a mixture of 3-fluoro[6-
methoxy(3-morpholinyl-propoxy)-quinolinyloxy]-phenylamine (1160 kg) and
potassium carbonate (412.25 g) in THF and water at a rate such that the batch temperature
was maintained at approximately 15 to 21 °C. When the addition was complete, the batch
was warmed to ambient temperature and held with stirring for approximately 1 hour, at which
time in process HPLC analysis indicated the reaction was complete. Aqueous potassium
carbonate solution and isopropyl acetate were added to the batch. The resulting two phase
mixture was stirred, and then the phases were allowed to separate. The aqueous phase was
back extracted with isopropyl acetate. The combined isopropyl acetate layers were washed
with water followed by aqueous sodium chloride and then slurried with a mixture of
magnesium sulfate and activated carbon. The slurry was filtered over Celite®, and the filtrate
was concentrated to an oil at approximately 30 °C under vacuum to afford the title
compound, which was carried into the next step without further processing. H NMR
(400MHz, DMSO-d6): δ 10.41 (s, 1H), 10.03 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m,
2H), 7.53 (m, 2H), 7.42 (m, 2H), 7.16 (t, 2H), 6.41 (d, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.59 (t,
4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]
633.2, found 633.1.
Preparation of the bisphosphate salt of cyclopropane-1,1-dicarboxylic acid {3-fluoro
[6-methoxy(3-morpholinyl-propoxy)-quinolinylamino]phenyl}-amide (4-fluoro-
phenyl)-amide
Cyclopropane-1,1-dicarboxylic acid {3-fluoro[6-methoxy(3-morpholinyl-
propoxy)-quinolinylamino]phenyl}-amide-(4 fluoro phenyl)-amide from the previous step
was dissolved in acetone and water. Phosphoric acid (85%, 372.48 g) was added at a rate
such that the batch temperature did not exceed 30 °C. The batch was maintained at
approximately 15 to 30 °C with stirring for 1 hour, during which time the product
precipitated. The solids were collected by filtration, washed with acetone, and dried at
approximately 60 °C under vacuum to afford the title compound (1.533 kg). The title
compound has a c-Met IC value of less than 50 nM. The bisphosphate salt is not shown in
scheme 3. H NMR (400 MHz, DMSO-d6): (diphosphate) δ 10.41 (s, 1H), 10.02 (s, 1H),
8.48 (d, 1H), 7.93 (dd, 1H), 7.65 (m, 2H), 7.53 (d, 2H), 7.42 (m, 2H), 7.17 (m, 2H), 6.48 (d,
1H), 5.6 (br s, 6H), 4.24 (t, 2H), 3.95 (s, 3H), 3.69 (bs, 4H), 2.73 (bs, 6H), 2.09 (t, 2H), 1.48
(d, 4H).
Procedure for direct coupling
F NH
Cl OH O
O F O
NaOt Bu
N O N
N O N
O NH O
Solid sodium tert-butoxide (1.20 g; 12.5 mmol) was added to a suspension of the
chloroquinoline (3.37 g; 10 mmol) in dimethylacetamide (35 mL), followed by solid 2-
fluorohydroxyaniline. The dark green reaction mixture was heated at 95 to 100 °C for 18
hours. HPLC analysis showed approximately 18 percent starting material remaining and
approximately 79 percent product. The reaction mixture was cooled to below 50 °C,
additional sodium tert-butoxide (300 mg; 3.125 mmol) and aniline (300 mg; 2.36 mmol)
were added, and heating at 95 to 100 °C was resumed. HPLC analysis after 18 hours revealed
less than 3 percent starting material remaining. The reaction was cooled to below 30 °C, and
ice water (50 mL) was added while maintaining the temperature below 30 °C. After stirring
for 1 hour at room temperature, the product was collected by filtration, washed with water (2
x 10 mL) and dried under vacuum on the filter funnel, to yield 4.11 g of the coupled product
as a tan solid (96% yield; 89%, corrected for water content). H NMR and MS: consistent
with product; 97.8% LCAP; approximately 7 weight percent water by KF.
Preparation of Compound 2 Hydrate Form
The hydrate of Compound 2 was prepared by adding 4.9614 g of Compound 1 and
50 mL of n-propanol to a 250 mL beaker. The suspension was heated to 90 °C with stirring
via a magnetic stir bar at 200 rpm. After 2 hours, the solids were fully dissolved in an amber
solution. At the 1 hour and 2 hour timepoints, 10 mL of n-propanol was added to account
for evaporative effects and return the volume of the solution to 50 mL. The solution was
then hot-filtered through a 1.6 μm glass fiber filter. The solution was then allowed to dry
overnight in the beaker to a powder, which was then redissolved in 150 mL of a 1:1 mixture
of acetone and water, and slurried overnight (16 hours) with a foil lid to prevent evaporation.
The slurried solids were then collected by vacuum filtration. The final weight recovered was
3.7324 g (75% yield). This batch was stored at ambient conditions for several days prior to
analysis.
Karl Fisher water content determinations were performed using a standard
procedure. Water content was measured with a Brinkmann KF1V4 Metrohm 756
Coulometer equipped with a 703 Ti stirrer and using Hydranal Coulomat AG reagent.
Samples were introduced into the vessel as solids. Approx 30-35 mg of sample was used per
titration. A sample of crystalline Compound (I) prepared in Example 1.1.2 was measured in
duplicate and was found to have an average water content be 2.5% w/w, with each replicate
agreeing to within 0.1%.
A gravimetric vapor sorption (GVS) study was run using a standard procedure.
Samples were run on a dynamic vapor sorption analyzer (Surface Measurement Systems)
running DVSCFR software. Sample sizes were typically 10 mg. A moisture adsorption
desorption isotherm was performed as outlined below. The standard isotherm experiment,
performed at 25 °C, is a two-cycle run, starting at 40% RH (relative humidity), increasing
humidity to 90% RH, decreasing humidity to 0% RH, increasing humidity again to 90% RH,
and finally decreasing humidity to 0% RH in 10% RH intervals. The crystalline Compound 1
prepared in Example 1.1.1 showed a 2.5% weight gain at 25 °C and 90% humidity. The GVS
sorption and desorption curves showed evidence that the hydrate behaves as an isomorphic
desolvate (Stephenson, G. A.; Groleau, E. G.; Kleeman, R. L.; Xu, W.; Rigsbee, D. R. J.
Pharm. Sci. 1998, 87, 536-42).
The X-ray powder diffraction pattern of Compound 1 crystalline hydrate prepared
above was acquired using a PANalytical X’Pert Pro diffractometer. The sample was gently
flattened onto a zero-background silicon insert sample holder. A continuous 2 θ scan range of
2° to 50° was used with a CuK α radiation source and a generator power of 40 kV and 45 mA.
A 2 θ step size of 0.017 degrees/step with a step time of 40.7 seconds was used. Samples
were rotated at 30 rpm. Experiments were performed at room temperature and at ambient
humidity. , the entire contents of which are incorporated herein by
reference, shows the XRPD pattern for N-[3-fluoro({6-(methyloxy)[(3-morpholin
ylpropyl)oxy]quinolinyl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide crystalline hydrate. The following peaks at an experimental º2θ + 0.1 °2 θ
were identified in the XRPD pattern: 6.6, 9.0, 10.2, 12.0, 12.2, 13.1, 13.3, 14.6, 15.6, 16.2,
17.0, 17.1, 17.4, 18.2, 18.4, 18.7, 20.0, 20.3, 20.8, 21.7, 22.1, 23.1, 23.4, 23.8, 24.2, 24.5,
.0. Only peaks below 25 °2 θ are given as these are generally preferred for the
identification of crystalline pharmaceutical forms. The entire list of peaks, or a subset
thereof, may be sufficient to characterize the hydrate of Compound 1.
DSC thermograms were acquired using a TA Instruments Q2000 differential
scanning calorimeter. A sample mass of 2.1500 mg of Compound 1 crystalline hydrate was
weighed out directly into an aluminum DSC pan. The pan was sealed by applying pressure
by hand and pushing each part the pan together (also known as a loose lid configuration).
The temperature was ramped from 25 ºC to 225 ºC at 10 ºC/minute. A peak melting
temperature of 137.4 ºC and a heat flow of 44.2 J/g was measured for the melting endotherm.
After the melting event, recrystallization occurs to an anhydrous form, which then melts at
194.1 ºC.
TGA thermograms were acquired using a TA Instruments Q500
Thermogravimetric Analyzer. The sample pan was tared, and 9.9760 milligrams of
Compound (I) crystalline hydrate was placed in the pan. The temperature was ramped from
ºC to 300 ºC at 10 ºC/minute. A weight loss of 2.97% was observed up to 160 ºC, with an
additional weight loss beyond 200 ºC from decomposition.
Preparation of Compound 2 Crystalline Hydrate with Different Hydration States.
Five 150 mg aliquots were taken from the crystalline hydrate batch prepared
above and were placed in 10 mL screw-top vials. With the vial tops removed, these aliquots
were each stored in chambers with desiccant (Dri-Rite®, tricalcium silicate, RH 2-3%),
saturated lithium bromide (6% RH), saturated lithium chloride (11% RH), saturated
magnesium chloride (33% RH), and saturated sodium chloride (75% RH). The samples were
removed after 2 weeks and immediately sealed with a cap for analysis and characterized.
The foregoing disclosure has been described in some detail by way of illustration
and example, for purposes of clarity and understanding. The invention has been described
with reference to various specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications can be made while remaining
within the spirit and scope of the invention. It will be obvious to one of skill in the art that
changes and modifications can be practiced within the scope of the appended claims.
Therefore, it is to be understood that the above description is intended to be illustrative and
not restrictive. The scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be determined with reference to the
following appended claims, along with the full scope of equivalents to which such claims are
entitled.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that
such documents, or such sources of information, in any jurisdiction, are prior art, or form part
of the common general knowledge in the art.
Claims (23)
1. A process for preparing Compound 1: Compound 1; comprising: (a) converting to ; (b) reacting with to provide ; (c) converting to ; (d) reacting with to form Compound 1; wherein is prepared by: (e) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in a polar aprotic solvent at room temperature; and (f) adding a mixture comprising 4-fluoroaniline and triethyl amine in a polar aprotic solvent to the mixture of step (e).
2. The process of claim 1, wherein is contaminated with approximately 5 percent or less of the bisamide .
3. The process of claim 1 or 2, wherein the polar aprotic solvent in step (e) is selected from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethyl formamide, acetonitrile, and dimethyl sulfoxide, or combinations thereof.
4. The process of any one of claims 1-3, wherein the polar aprotic solvent in step (e) is isopropyl acetate, and wherein approximately 5 to 10 volumes of polar aprotic solvent are used relative to volume of 1,1-cyclopropanedicarboxylic acid that is used.
5. The process of any one of claims 1-4, wherein approximately 8 volumes of polar aprotic solvent are used in step (e) relative to volume of 1,1-cyclopropanedicarboxylic acid that is used.
6. The process of any one of claims 1-5, wherein approximately 1.01 to 1.2 molar equivalents of thionyl chloride are used in step (e).
7. The process of any one of claims 1-6, wherein approximately 1.05 molar equivalents of thionyl chloride are used in step (e).
8. The process of any one of claims 1-7, wherein the mixture of step (e) is stirred at ambient temperature for 2 to 24 hours.
9. The process of any one of claims 1-8, wherein the mixture of step (e) is stirred at approximately 24-26 °C for 6 to 16 hours.
10. The process of any one of claims 1-9, wherein approximately 1.01 to 1.5 molar equivalents of 4-fluoroaniline are used relative to the number of moles of 1,1- cyclopropanedicarboxylic acid that are used and approximately 1.01 to 1.5 molar equivalents of triethyl amine are used relative to the number of moles of 1,1-cyclopropanedicarboxylic acid that are used.
11. The process of any one of claims 1-10, wherein the polar aprotic solvent in step (f) is selected from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide, or combinations thereof.
12. The process of claim 11, wherein the polar aprotic solvent in step (f) is isopropyl acetate.
13. The process of claim 12, wherein approximately 2 volumes of isopropyl acetate are used.
14. The process of any one of claims 1-13, wherein the resulting mixture of step (f) is allowed to stir for approximately 0.75 to 4 hours at ambient temperature.
15. The process of any one of claims 1-14, further comprising quenching the mixture of step (f) with a concentrated aqueous base.
16. The process of claim 15, wherein the aqueous base is selected from the group consisting of NaOH, KOH, and K PO .
17. The process of any one of claims 1-16, further comprising (g) a step of converting Compound 1 to Compound 1, L-malate salt, by reacting Compound 1 with L-malic acid.
18. A process for preparing Compound 1: Compound 1; comprising: (a) converting to ; (b) reacting with to provide ; (c) converting to ; (d) reacting with to form Compound 1; wherein is prepared by: (e) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature, followed by adding 4-fluoroaniline and triethyl amine to the mixture, quenching the mixture with concentrated aqueous sodium hydroxide; extracting into dilute aqueous base, acidifying the mixture with HCl, and isolating by filtration.
19. A process for preparing Compound 1, L-malate salt: Compound 1, L-malate salt; comprising: (a) converting to ; (b) reacting with to provide ; (c) converting to ; (d) reacting with to form Compound 1; (e) reacting compound 1 with L-malic acid to form Compound 1, L-malate salt; and wherein is prepared by: (f) contacting 1,1-cyclopropane dicarboxylic acid with thionyl chloride in isopropyl acetate at room temperature; and (g) adding a mixture comprising 4-fluoroaniline and a triethyl amine in isopropyl acetate to the mixture of step (f).
20. A process of any one of claims 1-18 substantially as herein described with reference to any example thereof.
21. Compound 1, as defined in claim 1, when prepared by a process of any one of claims 1-18.
22. A process of claim 19 substantially as herein described with reference to any example thereof.
23. Compound 1, L-malate salt, as defined in claim 19, when prepared by a process of claim 19.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161549312P | 2011-10-20 | 2011-10-20 | |
US61/549,312 | 2011-10-20 | ||
NZ624328A NZ624328B2 (en) | 2011-10-20 | 2012-10-22 | Process for preparing quinoline derivatives |
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Publication Number | Publication Date |
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NZ723880A NZ723880A (en) | 2018-03-23 |
NZ723880B2 true NZ723880B2 (en) | 2018-06-26 |
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