NZ721592B2 - Method for producing substituted 5-fluoro-1h-pyrazolopyridines - Google Patents
Method for producing substituted 5-fluoro-1h-pyrazolopyridinesInfo
- Publication number
- NZ721592B2 NZ721592B2 NZ721592A NZ72159212A NZ721592B2 NZ 721592 B2 NZ721592 B2 NZ 721592B2 NZ 721592 A NZ721592 A NZ 721592A NZ 72159212 A NZ72159212 A NZ 72159212A NZ 721592 B2 NZ721592 B2 NZ 721592B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- formula
- give
- salts
- mixture
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 26
- LTYNYHHABUSSHS-UHFFFAOYSA-N 5-fluoro-1H-pyrazolo[4,3-b]pyridine Chemical class FC1=CC=C2NN=CC2=N1 LTYNYHHABUSSHS-UHFFFAOYSA-N 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 224
- 239000012453 solvate Substances 0.000 claims description 74
- 239000000203 mixture Substances 0.000 claims description 68
- 239000011780 sodium chloride Substances 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 239000002585 base Substances 0.000 claims description 26
- -1 alkali metal salt Chemical class 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 20
- 239000012442 inert solvent Substances 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000002329 infrared spectrum Methods 0.000 claims description 16
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 14
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 13
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- 150000007513 acids Chemical class 0.000 claims description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- UAVOCTDYPKOULU-UHFFFAOYSA-N methylchloranuidyl formate Chemical compound C[Cl-]OC=O UAVOCTDYPKOULU-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 230000001603 reducing Effects 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- GZDFHIJNHHMENY-UHFFFAOYSA-N DMPC Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 5
- 239000004316 dimethyl dicarbonate Substances 0.000 claims description 5
- 235000010300 dimethyl dicarbonate Nutrition 0.000 claims description 5
- 239000003638 reducing agent Substances 0.000 claims description 5
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1H-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 claims description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 12
- 208000008787 Cardiovascular Disease Diseases 0.000 abstract description 6
- 230000000069 prophylaxis Effects 0.000 abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 29
- 238000002360 preparation method Methods 0.000 description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- 229960004592 isopropanol Drugs 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000001291 vacuum drying Methods 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 229940113083 morpholine Drugs 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 230000002194 synthesizing Effects 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 150000001204 N-oxides Chemical class 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- MBABOKRGFJTBAE-UHFFFAOYSA-N Methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- GMVPRGQOIOIIMI-DODZYUBVSA-N Alprostadil Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DODZYUBVSA-N 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000001184 potassium carbonate Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- NBUKAOOFKZFCGD-UHFFFAOYSA-N 2,2,3,3-tetrafluoropropan-1-ol Chemical compound OCC(F)(F)C(F)F NBUKAOOFKZFCGD-UHFFFAOYSA-N 0.000 description 5
- 229960000583 Acetic Acid Drugs 0.000 description 5
- GUVUOGQBMYCBQP-UHFFFAOYSA-N DMPU Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 5
- SBZXBUIDTXKZTM-UHFFFAOYSA-N Diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 5
- 150000004682 monohydrates Chemical class 0.000 description 5
- 150000002829 nitrogen Chemical group 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 5
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 4
- XGINAUQXFXVBND-UHFFFAOYSA-N 1,2,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidine Chemical compound N1CC=CN2CCCC21 XGINAUQXFXVBND-UHFFFAOYSA-N 0.000 description 4
- OSWSZHMBICDPQH-UHFFFAOYSA-N 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate Chemical compound FC(F)C(F)(F)COS(=O)(=O)C(F)(F)F OSWSZHMBICDPQH-UHFFFAOYSA-N 0.000 description 4
- FHNCCAGEZMNIHZ-UHFFFAOYSA-N 3,4,5,5a,6,7,8,9-octahydro-2H-1,2-benzodiazepine Chemical compound N1CCCC2CCCCC2=N1 FHNCCAGEZMNIHZ-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M Sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N Trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 150000004683 dihydrates Chemical class 0.000 description 4
- 239000008079 hexane Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N Potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 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
- 201000010099 disease Diseases 0.000 description 3
- DVWGQBBJLJWPKJ-UHFFFAOYSA-N ethyl 5-amino-1-[(2-fluorophenyl)methyl]pyrazole-3-carboxylate Chemical compound N1=C(C(=O)OCC)C=C(N)N1CC1=CC=CC=C1F DVWGQBBJLJWPKJ-UHFFFAOYSA-N 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000001187 sodium carbonate Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 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
- HNOJSDJMLDYOIK-UHFFFAOYSA-N 5-fluoro-1H-pyrazolo[3,4-b]pyridine Chemical group FC1=CN=C2NN=CC2=C1 HNOJSDJMLDYOIK-UHFFFAOYSA-N 0.000 description 2
- JLFVIEQMRKMAIT-UHFFFAOYSA-N AC1L9MNZ Chemical compound O.O.O JLFVIEQMRKMAIT-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
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N Potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000000451 chemical ionisation Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 230000002093 peripheral Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000005229 pyrazolopyridines Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- C07D471/04—Ortho-condensed systems
Abstract
The disclosure relates to a method for producing novel substituted 5-fluoro-1H-pyrazolopyridines of the formula (VI) which are suitable as an intermediate for producing medicaments and for producing medicaments for the treatment and/or prophylaxis of cardiovascular disorders. In particular, the 5-fluoro-1H-pyrazolopyridines of the formula (VI) are suitable for producing compounds which serves for producing medicaments, for producing medicaments for the treatment and/or prophylaxis of cardiovascular disorders. uoro-1H-pyrazolopyridines of the formula (VI) are suitable for producing compounds which serves for producing medicaments, for producing medicaments for the treatment and/or prophylaxis of cardiovascular disorders.
Description
Method for producing substituted 5-fluoro-1H-pyrazolopyridines
This is a divisional application divided out from New Zealand Application No. 624593 , which is
the national phase entry in New Zealand of PCT international application
(published as ). This application claims the benefit of European Provisional
Patent Application Nos. 11190789.5, filed on 25 November 2011, and 11192301.7, filed on 7
er 2011, the contents of the ing ations are incorporated herein by reference in
their entirety.
The present application relates to a novel and efficient s for preparing novel substituted 5-
fluoro-1H-pyrazolopyridines of the a (VI)
N N
CN (VI)
which serve as an intermediate for production of medicaments and for production of medicaments
for treatment and/or prophylaxis of cardiovascular disorders.
More particularly, the 5-fluoro-1H-pyrazolopyridines of the formula (VI) are suitable for
preparation of compound of the formula (I)
N N
2 NH
3 (I),
which serves for tion of medicaments and for production of medicaments for treatment
and/or prophylaxis of cardiovascular disorders.
The compound of the a (I) acts as a stimulator of soluble guanylate cyclase and can be used
as an agent for prophylaxis and/or treatment of cardiovascular ers, for example for treatment of
hypertension and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular
disorders, of thmias, for treatment of thromboembolic ers and ischaemias such as
myocardial infarction, stroke, transitory and ischaemic attacks, peripheral perfusion disorders,
prevention of restenoses such as after thrombosis therapy, percutaneous uminal angioplasty
(PTA), percutaneous uminal ry angioplasty (PTCA), bypass, and for treatment of
arteriosclerosis, asthmatic disorders and diseases of the urogenital system, for example prostate
hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, glaucoma, pulmonary
hypertension, gastroparesis, scleroderma and incontinence.
The nd of the a (I) may be present in various crystal forms and solvates. The
compound of the formula (I) exists in five polymorphs with melting points 257°C (polymorph I),
253°C (polymorph II), 247°C (polymorph III), 246°C (polymorph IV), 234°C orph V), a
dimethylformamide/water solvate (DMF content 13.6%, water content 0.9%), a di-dimethyl
sulphoxide solvate (stoichiometric value: 26.8% DMSO), a triacetic acid solvate (29.7% acetate), a
monohydrate (4.1% water) and a dihydrate (7.8% water). The prior art, ,
bes the compound of the formula (I) in Example 1 as a substance.
The crystal polymorph of the compound of the formula (I) in polymorph (I) is notable for ity
and particularly for the fact that it is stable even in the micronization process and thus no
conversion and recrystallization takes place.
The di-dimethyl sulphoxide solvate of the compound of the formula (I) has the advantage of much
better filterability than the substance in the prior art. Furthermore, the preparation process via the
di-dimethyl sulphoxide solvate of the nd of the formula (I) leads to a very high purity of the
compound of the formula (I).
WO 03/095451, and disclose the synthesis of lopyridines
unsubstituted on the pyridine ring. In these disclosures, the bicyclic ring system is built up by reaction
of phenylbenzyl hydrazine with ethyl cyanopyruvate. This synthesis method is unsuitable for the
formation of 5-fluoro-1H-pyrazolopyridines.
describes the synthesis of 5-fluoro-1H-pyrazolo[3,4-b]pyridineamine E.
Selective dechlorination of the nicotinic acid A to give the compound B, uent sion to
the amide C, the reduction thereof to the nitrile and the final cyclization with hydrazine hydrate
form the 5-fluoro-1H-pyrazolo[3,4-b]pyridine core. Scheme 1 below illustrates the synthesis.
Scheme 1:
O O O
F F F
OH i) OH ii) NH
Cl N Cl N Cl N Cl
A B C
N H
F CN N
iii) iv)
N Cl
D E
[i) Pd(OAc)2, PPh3, NEt3, HCO2H; ii) 1) (COCl)2, CH2Cl2, cat. DMF, 2) NH3 (g), dioxane, iii)
TFAA, NEt3; iv) H2NNH2x H2O, n-BuOH].
A disadvantage of this process is that, proceeding from 5-fluoro-1H-pyrazolo[3,4-b]pyridine E,
further steps such as the diazotization reaction and conversion to the iodo compound, followed by
an alkylation with a benzyl derivative and subsequent functionalization for introduction of the
cyano group are required in order to obtain the desired 5-fluoro-1H-pyrazolopyridines of the
a (VI). This is illustrated by way of example in Scheme 2.
Scheme 2:
A further disadvantage is that the diazotization is conducted under anhydrous conditions and the
diazonium salt has to be isolated, which necessitates considerable safety precautions on conversion
to the industrial scale and thus causes high production costs.
A further disadvantage is that the tion with a benzyl derivative proceeds unselectively and the
t is obtained in only a low yield after complex purification and tion of the isomers.
A r antage is that, in the course of cyanation, toxic copper cyanide has to be handled,
which necessitates additional safety precautions in the preparation and in the disposal of mother
liquors and aqueous phases, and thus causes high production costs.
A further disadvantage is that the preparation of 5-fluoro-1H-pyrazolopyridines of the formula
(VI), ing to the process described in Scheme 1, entails the preparation and purification of
seven intermediates and affords only a small overall yield.
It is an object of the present invention to provide an efficient s with high yield for
preparation of 5-fluoro-1H-pyrazolopyridines of the formula (VI)
N N
CN (VI)
as a key component for an efficient process with high yield for preparation of compound of the
formula (I)
N N
2 NH
3 (I)
and the N-oxides, salts, solvates, salts of N-oxides and solvates of the N-oxides and salts
thereof;and/or at least to provide the public with a useful choice.
This object is achieved in accordance with the present invention, as follows. Scheme 3 below
illustrates the individual reaction steps by way of example.
Scheme 3:
2 N
R1 F a) N N
N + N
N H
R2 F
O O
O O
CH O
3 CH
(II) (III) (IV)
N N
N N
b) N
F c)
O 2 CN
(V) (VI)
N N N
N N
d) e) N
NH F
F 2 NH
N 2
x HCl
H N N N
2 Ph
(VII) (VIII)
N N N
N N
f) N g)
F NH N
N 2 F NH
N 2
H N NH
2 H N N
2 H O
(IX) (I)
[a): LiCl, , EtOH; b) formamide, NaOMe/MeOH, EtOH; c) POCl3, CH3CN, sulpholane;
d) 1. NaOMe/MeOH, 2. NH4Cl/EtOH; e) DMF, NEt3, phenylazomalononitrile; f) Pd/C, H2, DMF;
g) iPrOH, methyl chloroformate, NEt3].
Step a) is y known for the unsubstituted pyrazolopyridines through (WO 03/004503
(Example IIIb) and WO 03/095451 (Example 2A)):
2 N
aa)a) N N
N + N
N H
O O
O O
CH O
3 CH
(II) H J
[aa): CF3SO3H, reflux for 3 days, chromatography, 49.9% yield].
Compared to the prior art (WO 03/004503, Example IIIb and WO 03/095451, Example 2A), the
preparation of IV proceeds with a much higher yield.
A further advantage is that, rather than the corrosive trifluoroacetic acid, ethanol, which is much
less expensive, is used as the solvent.
A further advantage is that the on time is considerably shorter compared to the prior art.
A further advantage is that the ation of IV proceeds with high selectivity and the product is
formed in high purity without icant by-product formation, and no complex purification
procedures are required.
A further advantage is that IV is obtained by crystallization in high yield and purity.
Steps d) – g) are already known for the unsubstituted pyrazolopyridines through WO 03/095451,
and and can be used analogously.
In this specification where reference has been made to patent specifications, other external
nts, 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
al 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.
Summary of the invention
In a first aspect, the invention es a process for preparing the compound of the formula (VI)
N N
F (VI),
CN
wherein the compound of the formula (V)
N N
O 2
is prepared by reaction of an ester of the formula (IVa)
N N
O (IVa)
in which
T1 is )-alkyl
with formamide
and the compound of formula (V) is dehydrated to give the compound of formula (VI).
In a second aspect, the invention provides a process for preparing the compound of formula (I)
N N
2 NH
3 (I),
wherein the compound of formula (VI)
N N
F (VI)
CN
is used,
n the compound of formula (VI) is ed by the process from the first aspect by
converting the compound of the formula (VI) to the compound of the formula (VII)
N N
x HCl (VII),
subsequently reacting the latter in an inert solvent in the presence of a suitable base with
the compound of the a (VIIIa)
NC CN
(VIIIa)
to give the compound of the formula (VIII)
N N
2 N
(VIII),
and then reducing the latter in an inert solvent in the presence of a suitable reducing agent
to give the compound (IX)
N N
2 NH
2 (IX),
and thereafter reacting the latter with methyl chloroformate or with dimethyl dicarbonate in
the presence of a suitable base with or without solvent to give the compound of the formula
(I), and optionally converting the ing compound of the formula (I) with the
appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the
salts f.
In a further aspect, the invention provides a crystalline substance compound of the formula (I) in
the form of the di-dimethyl sulphoxide e,
N N O
N S
Me Me
H N O
2 NH
O S
Me Me
characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the
2 theta angle at 18.8, 20.3, 21.7.
In a r aspect, the invention provides a crystalline substance compound of the formula (I) in
the form of the di-dimethyl sulphoxide solvate,
N N O
N S
Me Me
H N O
2 NH
O S
Me Me
characterized in that the IR um of the compound exhibits band maxima at 1720,
1628, 1481 cm-1.
In a r aspect the invention provides a process for preparing the compound of the formula (I)
as the di-dimethyl sulphoxide solvate in crystalline form, terized in that the compound of the
formula (I), present in one or more polymorphs or as a solvate in dimethyl sulphoxide or a mixture
of yl sulphoxide and an inert solvent, is stirred at a temperature of 20 - 120°C and the didimethyl
sulphoxide solvate is isolated.
In a further aspect the invention provides a compound of formula (VI) when prepared by a process
according to the first aspect.
In a r aspect the invention provides a compound of formula (I) when prepared by a process
according to the second aspect.
The invention is defined in the claims. r, the disclosure which follows may refer to
additional s and other subject matter outside the scope of the present claims. This disclosure
is retained for technical purposes.
Detailed description
Specifically, the process according to the invention for preparing a compound of the formula (VI)
N N
F (VI)
comprises the cyclization of the 5-aminopyrazole derivative (IIa)
2 N
O T1
(IIa)
in which
T1 is (C1-C4)-alkyl,
in the presence of a suitable acid with the aldehyde (III)
F R2
H N
O (III)
in which R1 and R2 are each independently methyl, ethyl, pyl, phenyl or, together
with the nitrogen atom to which they are bonded, are
N N N N N O
, , or ,
to give the ester of the formula (IVa)
N N
O (IVa)
in which T1 is as defined above,
the subsequent reaction thereof with ammonia or formamide to give the amide of the formula (V)
N N
NH (V)
O 2
and the subsequent dehydration to give the nitrile (VI).
Described herein is use of the compound of the formula (VI)
N N
CN (VI)
for ation of the compound of the formula (I)
N N
2 NH
3 (I)
and the N-oxides, salts, solvates, salts of es and solvates of the N-oxides and salts thereof.
Described herein is use of the compound of the formula (III)
R1 F
N H
O (III)
in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, together
with the nitrogen atom to which they are bonded, are
N N N N N O
, , or ,
for preparation of the compound of the formula (I)
N N
2 NH
3 (I)
and the N-oxides, salts, solvates, salts of N-oxides and solvates of the N-oxides and salts thereof.
Described herein is use of the compound of the formula (VI) for preparation of the compound of
the formula (I) as specified above, wherein the compound of the formula (VI) is ted to the
compound of the formula (VII)
N N
x HCl (VII),
the latter is subsequently reacted in an inert solvent in the presence of a suitable base with
the nd of the formula (VIIIa)
NC CN
(VIIIa)
to give the compound of the formula (VIII)
N N
2 N
(VIII),
and then the latter is reduced in an inert solvent in the presence of a suitable reducing agent
to give the nd (IX)
N N
2 NH
2 (IX),
then the latter is reacted in the presence of a suitable base in the ce or absence of a
solvent with methyl chloroformate or with dimethyl dicarbonate to give the compound of
the formula (I)
N N
2 NH
3 (I),
and the resulting nd of the formula (I) is optionally converted with the appropriate (i)
solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
The conversion (VI) → (VII) is ed by s known to those skilled in the art in a age
process, first to form the imino ester with sodium methoxide in methanol at 0°C to +40°C and then
nucleophilic addition of one ammonia lent, for example ammonia or ammonium chloride, in
acetic acid or an alcohol to form the amidine (VII) at +50 to +150°C.
Suitable alcohols for the conversion (VI) → (VII) are alcohols such as methanol, ethanol, n-
propanol, isopropanol, n-butanol or tert-butanol.
Inert solvents for the s step (VII) + (VIIIa) → (VIII) are alcohols such as methanol, ethanol,
n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane,
tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as
e, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as
dimethylformamide (DMF), dimethyl sulphoxide (DMSO), sulpholane, N,N'-
dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water.
It is likewise le to use mixtures of the solvents ned. Preference is given to DMF and
sulpholane.
Suitable bases for the process step (VII) + (VIIIa) → (VIII) are alkali metal hydroxides, for
example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates
such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali
metal hydrogencarbonates such as sodium hydrogencarbonate or potassium hydrogencarbonate,
alkali metal des such as sodium methoxide or potassium methoxide, sodium ethoxide or
potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine,
ropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undecene (DBU) or 1,5-
diazabicyclo[4.3.0]nonene (DBN). Preference is given to triethylamine.
The reaction (VII) + (VIIIa) → (VIII) is generally conducted within a temperature range of +20°C
to +150°C, preferably at +80°C to +120°C, optionally in a microwave. The conversion can be
effected at standard, elevated or reduced pressure (for example from 0.5 to 5 bar). In l,
standard re is employed.
The compound of the formula (VIIIa) can be prepared analogously to the literature L. F. eri,
J. F. Tanker, A. Bendich, J. Am. Chem. Soc., 1949, 71, 533.
The reductions (VIII) → (IX) are effected in the presence of a suitable catalyst in an inert solvent
within a temperature range of +20°C to +100°C under hydrogen pressure (for example from 1 to
100 bar). Preference is given to a temperature range of 40°C to 80°C and a hydrogen pressure
range of 5 to 70 bar.
Inert ts for the reduction (VIII) → (IX) are, for example, alcohols such as methanol, ethanol,
n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane,
tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other ts such as
dimethylformamide (DMF), dimethyl sulphoxide , imethylpropyleneurea (DMPU),
N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It is likewise possible to use
mixtures of the solvents mentioned. Preference is given to DMF and ne.
Suitable catalysts for the conversion (VIII) → (IX) are, for example, palladium on activated carbon,
platinum on carbon, palladium hydroxide or Raney nickel.
The reduction (VIII) → (IX) can alternatively be effected with a metal or metal salt, for example
iron, zinc or ) chloride in a suitable acid, for example hydrogen chloride/hydrochloric acid,
sulphuric acid, phosphoric acid or acetic acid, within a temperature range of +20°C to +140°C.
Inert solvents for process step (IX) → (I) are, for example, alcohols such as methanol, ethanol, npropanol
, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, ropyl ether,
dioxane, tetrahydrofuran, glycol dimethyl ether or lene glycol dimethyl ether, halogenated
hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, oroethylene or
chlorobenzene, arbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil
ons, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO),
N,N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), acetonitrile, ethyl acetate or
else water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to
isopropanol and tetrahydrofuran, and to a mixture of panol and tetrahydrofuran.
Suitable bases for the s step (IX) → (I) are alkali metal hydrides such as sodium hydride,
alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide,
alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or
caesium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate or
potassium hydrogencarbonate, alkali metal alkoxides such as sodium methoxide or ium
methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines
such as triethylamine, diisopropylethylamine, pyridine, thylaminopyridine, 1,8-
diazabicyclo[5.4.0]undecene (DBU) or 1,5-diazabicyclo[4.3.0]nonene (DBN). Preference is
given to triethylamine.
The reaction (IX) → (I) is generally conducted within a temperature range of -10°C to +70°C,
preferably at 0°C to +50°C. The conversion can be effected at standard, elevated or reduced
pressure (for example from 0.5 to 5 bar). In general, rd pressure is employed.
nds of the formula (IIa) are known from the ture and can be prepared in analogy to
Example 20A in WO 00/06569.
Compounds of the formula (III) are known from the literature H. Yamanaka, S. Yamashita and T.
Ishihara, Synlett 353-354 (1993). The synthesis disclosed therein is illustrated in Scheme 4.
Scheme 4:
O O F
F O O
S j) S
Cl + O F
HO F
NO F F
2 NO
K (XII) L
F O O F
k) Bn l)
N F + O + N F
N I -
F F Bn F F
(XVIb) M N
F F O F
m) n)
+ N H
N F + N H
F O O
O (IIIb) (IIIa)
[k) 3 eq dimethylbenzylamine, 130 – 140°C; l) 10 eq CH3I, reflux, m) 1M NaOH, 20°C; n) DMSO-
H2O (1:1), morpholine, 40°C, 3h].
A disadvantage of this process is that, in the preparation of (XVIb), according to H. Yamanaka, M.
Kuwabara, M. Okudo, K. Fukunishi and M. Nomura, Nippon Kagaku Kaishi (10) 1988-1994
(1985), only a yield of 66% is ed and, in this process, very large amounts (2.79 kg per kg of
(XVIb)) of by-product hyldibenzyl nitrobenzenesulphonate) are obtained, which have to be
removed and disposed of.
A further disadvantage of this process is that, according to H. Yamanaka, H. ashi, M.
Kuwabara, K. Fukunishi and M. Nomura, Nippon Kagaku Kaishi (7) 1036-1043 (1988),
proceeding from (XVIb), the alkylation requires 10 equivalents of the carcinogenic alkylating agent
methyl .
A further disadvantage of this process is that, ing to H. Yamanaka, S. Yamashita and T.
Ishihara, t 353-354 (1993), the reaction of O with morpholine forms not only the desired
product (IIIb) but also 11% of the by-product (IIIa), which necessitates a complex purification, the
result being that the overall synthesis for preparation of (IIIb) gives only a low overall yield and
causes high production costs.
The synthesis described therein, however, is unsuitable for the preparation of the aldehydes of the
formula (III) on the rial scale, and so a new and efficient sis has been developed,
which is illustrated by way of example in Scheme 5.
Scheme 5:
O O O O F F
F S S F + o) F S
O HO F O F
F F
F F F F F F F F
(X) (XI) (XII)
F F
p) q)
N F N F
O F F O F F
(XIII) (XIV)
O F
r) +
N F s) N H
O F
CH3SO3- O
(XV) (IIIa)
[o) without solvent; p) dichloromethane or without solvent, morpholine; q) without solvent, methyl
methanesulphonate; r) NaOH, water; s) line/triethylamine.]
The compound of the formula (XIII) is known according to the literature Markovskii, L. N.;
Kolesnik, N. P.; Shermolovich, Yu. G Zhurnal Obshchei Khimii (1980), 50(4), 826-829. The
synthesis disclosed therein is illustrated in Scheme 6.
Scheme 6:
O O O F
O F + N F
F F N 21% F F
H O
(XIII)
The sis described therein, r, for reasons including the low yield, is unsuitable for the
preparation of the aldehydes of the formula (III) on the industrial scale.
Described herein is a s for preparing compounds of the formula (III)
R1 F
N H
O (III)
in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, together
with the nitrogen atom to which they are bonded, are
N N N N N O
, , or ,
wherein trifluoromethanesulphonic anhydride of the formula (X) is reacted with 2,2,3,3-tetrafluoro-
1-propanol of the a (XI) without solvent and the resulting 2,2,3,3-tetrafluoropropyl
trifluoromethanesulphonate of the formula (XII) is reacted with a compound of the formula (XIIa)
R2 (XIIa)
in which R1 and R2 are each as defined above
to give a compound of the formula (XIIIa)
N F
R2 F F (XIIIa)
in which R1 and R2 are each as d above
and with methyl methanesulphonate to give a compound of the formula (XIVa)
R2 +
N F
R1 F F
CH3SO3-
(XIVa)
in which R1 and R2 are each as d above
and with sodium hydroxide to give a compound of the a (XVa)
R2 +
N F
R1 F
CH3SO3-
(XVa)
in which R1 and R2 are each as defined above
and finally converted under basic conditions to give the compound of the formula (III).
Described herein is a process for preparing the compound of the formula (IIIa)
O F
N H
O (IIIa)
wherein trifluoromethanesulphonic anhydride of the formula (X) is d with 2,2,3,3-tetrafluoro-
1-propanol of the formula (XI) without solvent and the resulting 2,2,3,3-tetrafluoropropyl
trifluoromethanesulphonate of the formula (XII) is reacted with morpholine to give a compound of
the formula (XIII)
N F
O F F
(XIII)
and with methyl methanesulphonate to give a compound of the formula (XIV)
N F
O F F
CH3SO3-
(XIV)
and with sodium hydroxide to give a compound of the a (XV)
N F
O F
CH3SO3-
(XV)
and finally with on of morpholine to give the compound of the formula (III).
The new synthesis has the advantage over the prior art that the intermediate (XII) and the
intermediates (XIV) and (XV) unknown to date need not be isolated, which greatly reduces the
industrial complexity of the synthesis.
The yields of the ing aldehydes of the formula (III) are much higher with the new synthesis
s than in the prior art.
"Basic conditions" in the context of the invention and/or other processes described herein for the
process step (XIVa) to (XVa) means that the acid formed in the on is ged by auxiliary
bases, for example sodium hydroxide, potassium hydroxide, potassium carbonate, sodium
carbonate, or triethylamine to form the corresponding salts.
Compared to the prior art, the preparation of (XIII) proceeds with a much higher yield. It is
advantageous that no solvent is required for preparation of (XII), and that the intermediate XII is
used without further purification in the subsequent stage to give (XIII).
A further advantage of this process is that no significant wastes are formed in the preparation of
(XIII). It is also advantageous that the trifluoromethanesulphonic acid and morpholine can be
recovered from the morpholinium trifluoromethanesulphonate formed.
Compared to the prior art, the preparation of (XIV) requires only one equivalent of the alkylating
agent. The reaction is conducted without solvent and proceeds virtually quantitatively, which
es a high space-time yield.
A further advantage of this process is that the t (XIV) is not isolated, (XIV) is ved in
water and this solution is reacted with sodium hydroxide solution to give (XV).
A further advantage of this process is that the product (XV) is also not isolated; reaction of the
s solution with line affords (IIIa) as the sole t in high yield.
A r advantage of this s is that (IIIa) is obtained in high overall yield and purity by
crystallization.
The cyclization of the 5-aminopyrazole derivative of the compound (IIa) with the aldehyde of the
compound (III) to give the compound of the formula (IV) is effected in an inert solvent, optionally
in the presence of an acid and optionally of an alkali metal salt, within a temperature range of
+10°C to +200°C, ably at +20°C to +100°C, at standard pressure, within, for e 2 to 50
hours, preferably within 2 to 20 hours.
Acids are, for example, hydrochloric acid, trifluoroacetic acid and methanesulphonic acid.
Preference is given to methanesulphonic acid and hloric acid.
Alkali metal salts are sodium chloride or lithium chloride. A preferred alkali metal salt is lithium
chloride.
Inert solvents are, for example, alcohols such as methanol, l, n-propanol or iso-propanol, n-
butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene
glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or
mineral oil fractions or other solvents, acetonitrile or methylformamide, or mixtures of
solvents. Preference is given to ethanol, diethylene glycol dimethyl ether or dioxane.
The preferred ion of the amide (IVa) → (V) is effected by reaction in an inert solvent with
formamide in the presence of a base within a temperature range of 0°C to + 150°C, preferably of
+20°C to +130°C, at standard pressure or elevated pressure, within 2 to 24 hours.
Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or opanol.
Preference is given to ethanol.
Suitable bases for the preferred process step (IVa) → (V) are alkali metal carbonates such as
lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal
hydrogencarbonates such as sodium hydrogencarbonate or potassium hydrogencarbonate, alkali
metal alkoxides such as sodium ide or potassium methoxide, sodium ethoxide or potassium
ethoxide or potassium tert-butoxide, or organic amines such as triethylamine,
diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undecene (DBU) or 1,5-
diazabicyclo[4.3.0]nonene (DBN). Preference is given to sodium methoxide and sodium
ethoxide.
The formation of the amide (IVa) → (V) is alternatively ed by reaction with ammonia within
a temperature range of 0°C to + 50°C, preferably of +20°C to +30°C, at standard pressure or
elevated pressure, within 24 to 72 hours.
Inert ts are, for example, alcohols such as methanol, ethanol, n-propanol or iso-propanol.
Preference is given to using a solution of ammonia in methanol in a concentration of 5N to 7N.
The dehydration of the amide (V) to the nitrile (VI) is effected in an inert t, optionally in the
presence of a suitable base, with a suitable dehydrating agent, for example phosphorus oxychloride,
trifluoroacetic anhydride, acetic anhydride or trifluoromethanesulphonic anhydride, within a
temperature range of 0°C to +150°C, preferably at +50°C to +110°C, within 1 to 12 hours.
ence is given to phosphorus oxychloride.
Inert solvents are ethers such as diethyl ether, e, tetrahydrofuran (THF), glycol dimethyl
ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane,
cyclohexane or mineral oil fractions or other solvents, pyridine, sulpholane, acetonitrile or N,N-
dimethylformamide, or mixtures of solvents. Preference is given to sulpholane and acetonitrile.
Suitable bases are, for example, organic amines such as triethylamine, diisopropylethylamine,
pyridine, 1,8-diazabicyclo[5.4.0]undecene (DBU) or 1,5-diazabicyclo[4.3.0]nonene (DBN).
Preference is given to pyridine.
The nds described herein may also be in the form of the salts, solvates or solvates of the
salts thereof.
The compounds bed herein may, depending on the structure, also be in the form of the
tautomers thereof.
Preferred salts described herein are physiologically acceptable salts of the compounds used and
prepared in the process described herein.
Physiologically acceptable salts of the compounds used and ed in the process described
herein e acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for
example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, oric acid,
methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,
naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric
acid, fumaric acid, maleic acid and benzoic acid.
Physiologically acceptable salts of the nds used and prepared in the process bed
herein also include salts of customary bases, by way of example and with preference alkali metal
salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium
salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms,
by way of e and with preference ethylamine, diethylamine, triethylamine,
ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine,
arginine, lysine, ethylenediamine and methylpiperidine.
In the context of the ion and/or other processes described herein, solvates refer to those
forms of the compounds used and prepared in the process according to the invention and/or
described herein which, in the solid or liquid state, form a complex by coordination with solvent
molecules. Hydrates are a specific form of the solvates in which the coordination is with water.
In the context of the present invention and/or other compounds described herein, the substituents,
unless specified otherwise, are each d as s:
Alkyl in the context of the invention and/or other nds described herein is a linear or
branched alkyl radical having 1 to 4 carbon atoms. Preferred examples include: , ethyl, n-
propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
The t invention is illustrated in detail below by miting preferred examples and
comparative examples. Unless stated otherwise, all amounts given refer to percentages by weight.
The present invention provides a process for ing the nd of the formula (VI)
N N
F (VI),
wherein the compound of the formula (V)
N N
O 2
is prepared by reaction of an ester of the formula (IVa)
N N
O (IVa)
in which
T1 is (C1-C4)-alkyl
with formamide, and the compound of formula (V) is dehydrated to give the compound of formula
(VI).
The present invention further provides a process as described above, wherein an ester of the
formula (IVa) is ed by cyclization of the 5-aminopyrazole derivative (IIa)
2 N
O T1
(IIa)
in which
T1 is (C1-C4)-alkyl
in the ce of an acid and an alkali metal salt with an aldehyde of the formula (III)
F R1
H N
O (III)
in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, together with the
nitrogen atom to which they are , are
N N N N N O
, , or
to give the ester of formula (IVa).
The present invention further provides a process as described above, wherein the aldehyde used in
the cyclization reaction is the compound of the formula (IIIa)
F O
H N
O (IIIa).
Described herein is a process for preparing aldehydes of the formula (III)
F R1
H N
O (III)
in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, er with the
nitrogen atom to which they are bonded, are
N N N N N O
, , or ,
characterized in that trifluoromethanesulphonic ide is reacted with 2,2,3,3-tetrafluoro
ol without solvent and the resulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate is
reacted with a compound of the formula (XIIa)
R2 (XIIa)
in which R1 and R2 are each as defined above, to give a compound of the formula (XIIIa)
N F
R2 F F (XIIIa)
in which R1 and R2 are each as defined above
and with methyl methanesulphonate to give a compound of the formula (XIVa)
R2 +
N F
R1 F F
CH3SO3-
(XIVa)
in which R1 and R2 are each as defined above
and with sodium hydroxide to give a compound of the formula (XVa)
R2 +
N F
R1 F
CH3SO3-
(XVa)
in which R1 and R2 are each as defined above
and finally converted under basic conditions to give the compound of the formula (III).
Described herein is a process for preparing the compound of the formula (IIIa)
O F
N H
O (IIIa),
n trifluoromethanesulphonic anhydride of the a (X) is reacted with 2,2,3,3-tetrafluoro-
1-propanol of the formula (XI) without solvent and the resulting 2,2,3,3-tetrafluoropropyl
trifluoromethanesulphonate of the formula (XII) is d with morpholine to give a compound of
the formula (XIII)
N F
O F F
(XIII)
and with methyl methanesulphonate to give a compound of the formula (XIV)
N F
O F F
CH3SO3-
(XIV)
and with sodium hydroxide to give a compound of the formula (XV)
N F
O F
(XV)
and finally with addition of morpholine to give the compound of the formula (IIIa).
bed herein is a process for preparing the compound of the formula (I)
N N
2 NH
3 (I),
wherein the compound of the formula (VI)
N N
F (VI)
is used,
wherein the compound of formula (VI) is prepared by the process specified above and the resulting
compound of the formula (I) is optionally converted with the riate (i) solvents and/or (ii)
acids or bases to the solvates, salts and/or solvates of the salts thereof.
Described herein is a process for preparing the compound of the a (I), characterized in that
the compound of the formula (VI)
N N
F (VI)
are used,
these being characterized in that they are prepared by the processes specified above and the
resulting nd of the formula (I) are optionally converted with the appropriate (i) solvents
and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
Described herein is a process for preparing the nd of the formula (I), terized in that
the compound of the formula (VI)
N N
F (VI)
CN
are used,
these being characterized in that they are prepared by the processes specified above and the
resulting compound of the formula (I) are optionally converted with the appropriate (i) solvents
and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
Described herein is a s for preparing compound (I), characterized in that the compound of
the formula (VI) is used, this being prepared by the processes specified above, by converting the
compound of the formula (VI) to the compound of the formula (VII)
N N
x HCl (VII),
subsequently reacting the latter in an inert solvent in the presence of a suitable base with the
compound of the formula (VIIIa)
NC CN
(VIIIa)
to give the compound of the formula (VIII)
N N
2 N
(VIII),
and then reducing the latter in an inert solvent in the ce of a suitable reducing agent to give
the compound (IX)
N N
2 (IX),
and thereafter reacting the latter with methyl chloroformate or with dimethyl dicarbonate in the
presence of a le base with or without solvent to give the compound of the formula (I), and
optionally converting the resulting nd of the formula (I) with the appropriate (i) solvents
and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
Described herein is the compound of the formula (I) in crystalline form of polymorph I
N N
2 NH
3 (I),
characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta
angle at 5.9, 6.9, 22.7.
Described herein is the nd of the formula (I) in polymorph (I) as described above,
characterized in that the x-ray diffractogram of the nd exhibits peak maxima of the 2 theta
angle at 5.9, 6.9, 16.2, 16.5, 24.1, 22.7, 24.7.
Described herein is the compound of the formula (I) in crystalline form of polymorph I
N N
2 NH
3 (I),
characterized in that the IR spectrum of the compound exhibits band maxima at 1707, 1633, 1475
cm-1.
bed herein is the nd of the formula (I) in polymorph (I) as described above,
characterized in that the IR spectrum of the compound exhibits band maxima at 1707, 1633, 1566,
1475, 1255, 1223 cm-1.
Described herein is a process for preparing the compound of the formula (I) in crystalline form of
polymorph I, characterized in that the compound of the formula (I), present in one or more
polymorphs or as a solvate in an inert solvent, is stirred at a temperature of 20°C - 120°C and the
compound of the formula (I) is isolated in crystalline polymorph I.
Preferred solvents for the process for preparing the compound of the formula (I) in crystalline form
of polymorph I are a mixture of ethyl e/ethanol/water, isopropanol, a mixture of
isopropanol/water, methanol, a mixture of ol/water, acetonitrile, acetone, tetrahydrofuran
and methyl tert-butyl ether.
A preferred temperature range for the process for preparing the compound of the formula (I) in
crystalline form of polymorph I is from 20°C to 90°C.
Described herein is a compound of the formula (I) in rph (I) as described above for ent
of ers.
Described herein is a medicament sing a compound of the formula (I) in polymorph (I) as
described above and no greater proportions of any other form of the compound of the formula (I) in
polymorph (I) as described above. Further described is a medicament comprising a compound of the
formula (I) in polymorph (I) as described above in more than 90 per cent by weight based on the total
amount of the compound of the formula (I) present in polymorph (I) as described above.
Described herein is use of the compound of the formula (I) in polymorph (I) as described above for
tion of a ment for treatment of cardiovascular disorders.
Described herein is a method for treatment of vascular disorders by administering an effective
amount of a compound of the formula (I) in polymorph (I) as described above.
The present invention further provides the lline substance compound of the formula (I) as the
di-dimethyl sulphoxide solvate
N N O
N S
Me Me
H N O
2 NH
O S
Me Me
3 (I),
characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta
angle at 18.8, 20.3, 21.7.
The present invention further provides the crystalline substance compound above of the formula (I)
as the di-dimethyl xide solvate, characterized in that the x-ray diffractogram of the
compound exhibits peak maxima of the 2 theta angle at 12.0, 16.6, 17.8, 18.8, 20.3, 21.7.
The present invention further provides the crystalline substance compound of the formula (I) as the
di-dimethyl sulphoxide solvate
N N O
N S
Me Me
H N O
2 NH
O S
Me Me
3 (I),
characterized in that the IR spectrum of the nd exhibits band maxima at 1720, 1628, 1481
cm-1.
The present invention r provides the crystalline nce compound above of the formula (I)
as the di-dimethyl sulphoxide solvate, characterized in that the IR spectrum of the compound
exhibits band maxima at 1720, 1628, 1481, 1234, 1041, 1017 cm-1.
The present invention further provides a process for preparing the compound of the formula (I) as
the di-dimethyl xide solvate in crystalline form, characterized in that the compound of the
formula (I), present in one or more polymorphs or as a solvate in dimethyl sulphoxide or a mixture
of dimethyl sulphoxide and an inert t, for example ethyl acetate, is stirred at a temperature of
- 120°C and the di-dimethyl sulphoxide solvate is isolated. Preference is given to a temperature
range of 20 to 90°C.
Described herein is the compound of the a (XIV)
N F
O F F
CH3SO3-
(XIV)
and the salts, solvates and solvates of the salts thereof.
Described herein is the compound of the formula (XV)
N F
O F
(XV)
and the salts, solvates and solvates of the salts thereof.
A. Examples
Abbreviations:
Ac acetyl
CI chemical ionization (in MS)
DCI direct chemical ionization (in MS)
DMF dimethylformamide
DMSO dimethyl sulphoxide
eq. equivalent(s)
ESI electrospray ionization (in MS)
Et ethyl
GC/MS gas chromatography-coupled mass spectrometry
sat. ted
h )
HPLC high-pressure high-performance liquid chromatography
HV high vacuum
conc. concentrated
LC/MS liquid chromatography-coupled mass spectrometry
Me methyl
min minute(s)
MS mass spectrometry
NMR nuclear magnetic resonance spectroscopy
rac racemic / racemate
Rf retention factor (in thin layer chromatography on silica gel)
RT room temperature
Rt retention time (in HPLC)
SFC supercritical fluid chromatography
THF tetrahydrofuran
UV iolet ometry
v/v volume to volume ratio (of a solution)
All x-ray diffractometry data were obtained with the following acquisition parameters:
ctometer system PANalytical XPERT-PRO
Scan axis Gonio
Anode material Cu
K-Alpha1 [Å] 1.54060
K-Alpha2 [Å] 1.54443
K-A2 / K-A1 ratio 0
Scan Mode: Transmission
Scan type: 2theta:omega
2theta figure: ± 0.2°
All infrared spectroscopy data were obtained with the following acquisition parameters:
Spectrometer: Perkin Elmer Spectrum One with diamond ATR unit
Parameter: 32 scans
Resolution: 2 cm-1
Example 1
3-Tetrafluoropropyl trifluoromethanesulphonate
O O F
F S
O F
F F F
Method A:
252.5 g (0.895 mol) of trifluoromethanesulphonic anhydride were heated to 40°C and, at this
temperature, 130.0 g (0.984 mol) of 2,2,3,3-tetrafluoropropanol were metered in while cooling.
After the metered addition had ended, the reaction mixture was heated to °C and d for 2
h. The mixture was cooled to 20°C and the reaction solution was used without further purification
in the reaction for Example 2.
Method B:
50.0 g (0.379 mol) of 2,2,3,3-tetrafluoropropanol were cooled to 0°C and 106.8 g (0.379 mol) of
oromethanesulphonic anhydride were added se at 0° - 4°C. Subsequently, the reaction
mixture was stirred at 25°C for 2 h, heated to 70°-75°C and stirred for 2 h. The mixture was cooled
to 20°C and the reaction solution was distilled at 116° - 118°C. This gave 85.1 g (85.1 % of theory)
of the title compound.
1H NMR (400 MHz, CDCl
3): δ = 4.69 (t, J=11.86 Hz, 2 H) 5.54 - 6.23 (m, 1 H) ppm.
Example 2
4-(2,2,3,3-Tetrafluoropropyl)morpholine
N F
O F F
Method A:
311.9 g (3.58 mol) of morpholine were dissolved in 290 ml of dichloromethane and cooled to
-15°C. At -15° - 0°C, 371.4 g (max. 0.895 mol) of the reaction solution from Example 1 were
added dropwise while cooling and then the mixture was stirred at 0° - 5°C for 30 min. The reaction
mixture was heated to 40°C and stirred for 4.5 h. After cooling to 20°C, 320 ml of water were
added and the phases were separated. The organic phase was washed three times with 190 ml each
time of water and concentrated on a rotary evaporator at 30°C/30 mbar. The residue (160.7 g) was
distilled at 67° - 68°C/18 mbar. This gave 151.7 g (84.3 % of theory) of the title compound.
1H NMR (400 MHz, CDCl
3): δ = 2.53 - 2.70 (m, 4 H) 2.89 (tt, J=14.03, 1.74 Hz, 2 H) 3.61 - 3.78
(m, 4 H) 5.83 - 6.22 (m, 1 H) ppm.
Method B:
158.5 g (1.82 mol) of line were cooled to 5°C. At 5° - 10°C, 189.5 g (max. 0.455 mol) of
the reaction solution from Example 1 were added dropwise while cooling and then the mixture was
stirred at 5° - 10°C for 30 min. The reaction mixture was heated to 40°C and d for 1 h. After
g to 20°C, 160 ml of water and 160 ml of toluene were added and the phases were separated.
The organic phase was washed with 160 ml of water and concentrated on a rotary evaporator at
50°C/50 mbar. The residue (81.0 g) was distilled at 67° - 68°C/18 mbar. This gave 77.0 g (84.1 %
of theory) of the title compound.
Example 3
4-Methyl(2,2,3,3-tetrafluoropropyl)morpholinium methanesulphonate
N F
O F F
CH3SO3-
Method A:
143.7 g (1.31 mol) of methyl methanesulphonate were heated to 135°C and, at this temperature,
250.0 g (1.243 mol) of the compound from Example 2 were added dropwise. Subsequently, the
mixture was stirred at 100°C for 22 h. The reaction mixture was cooled to 85°C and 375 ml of
panol were added. After cooling to 0° - 5°C, the mixture was stirred for a further 30 min and
the product was filtered off with suction. The product was washed three times with 125 ml each
time of isopropanol and dried in a vacuum drying cabinet at 45°C under a gentle nitrogen stream.
This gave 336.8 g (87.1% of ) of the title compound.
1H NMR (400 MHz, D
2O): δ = 2.81 (s, 3 H) 3.55 (s, 3 H) 3.68 - 3.93 (m, 4 H) 4.01 - 4.24 (m, 4 H)
4.33 - 4.51 (m, 2 H) 6.13 - 6.48 (m, 1 H) ppm.
Method B:
.0 g (181.3 mmol) of methyl methanesulphonate were heated to 135°C and, at this temperature,
.1g (172.7 mmol) of the compound from Example 2 were added dropwise. The mixture was
stirred at 135°C for 3 h and then 40 ml of water were added. After g to 50°C, the aqueous
solution of the title nd was used in the subsequent stage (see e 4).
Example 4
4-Methyl[2,3,3-trifluoropropenyl]morpholinium methanesulphonate
N F
O F
CH3SO3-
16.9 g (189.9 mmol) of 45% sodium hydroxide solution were metered into the aqueous solution of
the compound from Example 3, Method B (max. 172.7 mmol) at 50° - 55°C, and the mixture was
stirred at 50°C for 1 h. The reaction mixture was cooled to 20°C and the precipitated salts were
filtered off with suction and washed with 5 ml of water. The aqueous product solution (102.1 g;
max. 172.7 mmol) was used in the subsequent stage (see Example 5).
For ical purposes, a sample was concentrated and dried.
1H NMR (400 MHz, D
2O): δ = 2.81 (s, 3 H) 3.59 (s, 3 H) 3.76 - 3.85 (m, 2 H) 3.97 - 4.09 (m, 4 H)
4.12 - 4.20 (m, 2 H) 6.39 - 6.69 (m, 1 H) 6.74 - 6.83 (m, 1 H) ppm.
Example 5
2-Fluoro(morpholinyl)acrylaldehyde
O F
N H
Method A:
An aqueous on of the compound from Example 4 (max. 251.5 mmol) was heated to 75°C.
Subsequently, 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine were
added dropwise. The mixture was stirred at 75°C for 2 h and cooled to 23°C, and 290 ml of
dichloromethane and 100 ml of triethylamine were added. The phases were separated, the aqueous
phase was washed with a e of 290 ml of dichloromethane and 100 ml of triethylamine, and
the combined organic phases were filtered, washed with 250 ml of sat. aqueous potassium
carbonate solution and concentrated on a rotary evaporator at 40°C. 50 ml of toluene were added
and the mixture was concentrated further. This gave 34.2 g (81.9% of theory) of the title
compound.
Method B:
A mixture of 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine was heated
to 75°C and an aqueous solution of the compound from Example 4 (max. 251.5 mmol) was added
dropwise within 25 min. Subsequently, the mixture was stirred at 75°C for 2 h and cooled to 23°C,
and 290 ml of dichloromethane and 100 ml of triethylamine were added. The mixture was filtered,
the phases were separated, the aqueous phase was washed with a mixture of 290 ml of
dichloromethane and 100 ml of triethylamine, and the combined organic phases were washed with
250 ml of sat. aqueous potassium carbonate solution and concentrated on a rotary evaporator at
40°C. 50 ml of toluene were added and the mixture was trated r. This gave 35.3 g
(83.4% of ) of the title compound.
1H NMR (500 MHz, CDCl
3): δ = 3.51 - 3.60 (m, 4 H) 3.72 - 3.83 (m, 4 H) 6.16 (d, J=27.1 Hz, 1 H)
8.59 (d, J=18.9 Hz, 1 H) ppm.
Method C:
A mixture of 30.2 g (345.3 mmol) of morpholine and 52.5 g (518.0 mmol) of triethylamine was
heated to 75°C and the aqueous solution of the compound from Example 4, Method B (max. 172.7
mmol) was added dropwise at 75° - 80°C. The mixture was stirred under reflux for 2 h, cooled to
23°C and washed with 100 ml of dichloromethane. The aqueous phase was washed twice with a
mixture of 100 ml of romethane and 15 ml of ylamine, and the combined c
phases were washed with 85 ml of sat. aqueous potassium carbonate solution and concentrated
under reduced re at 45° - 50°C. 120 ml of toluene and 60 ml of toluene were distilled off.
The suspension was stirred at room temperature overnight, and the product was filtered off with
suction and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen . This gave
19.2 g (68.3% of theory) of the title compound.
Example 6
Ethyl 5-fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinecarboxylate
N N
Method A:
22.3 g (84.8 mmol) of ethyl 5-amino(2-fluorobenzyl)-1H-pyrazolecarboxylate (preparation
described for Example 20A in WO 00/06569) were initially charged in 59.5 ml of ethanol, and 11.0
ml (169.6 mmol) of methanesulphonic acid, 9.0 g (212.1 mmol) of lithium chloride and 15.0 g
(84.8 mmol) of the compound from Example 5 were added at RT. The mixture was stirred at reflux
temperature for 4.5 h. After cooling to room ature, the product was filtered off with n,
washed twice with 4.5 ml of ethanol and stirred with 325 ml of water for 1 h. The solids were
filtered off with suction, washed twice with 11.5 ml of water and dried in a vacuum drying t
at 50°C under a gentle nitrogen stream. This gave 21.8 g (81.0% of theory) of the title compound.
MS (ESIpos): m/z = 318 (M+H)+
1H NMR (400 MHz, DMSO-d
6): δ = 1.37 (t, 3H), 4.40 (q, 2H), 5.86 (s, 2H), 7.15 - 7.27 (m, 3H),
7.36 - 7.41 (m, 1H), 8.25 (d, 1H), 8.78 (s br., 1H) ppm.
Method B:
27.0 g (635.2 mmol) of m chloride and 42.2 g (254.1 mmol) of the compound from e
were initially charged in 75 ml of ethanol and heated to reflux temperature. At this temperature, a
solution of 66.9 g (254.1 mmol) of ethyl 5-amino(2-fluorobenzyl)-1H-pyrazolecarboxylate
(preparation described for Example 20A in WO 00/06569) and 33.0 ml (508.2 mmol) of
methanesulphonic acid in 180 ml of ethanol were added within 10 min. The mixture was stirred at
reflux temperature for 2 h, then 120 ml of isopropanol were added, the mixture was cooled to 62°C,
0.6 g of the title compound were used for seeding and the mixture was cooled to 5°C within 4 h.
The product was filtered off with suction, stirred with 120 ml of isopropanol, filtered off with
n, washed with 180 ml of water, stirred with 300 ml of water for 0.5 h, filtered off with
suction, washed with 300 ml of water and dried in a vacuum drying t at 50°C under a gentle
nitrogen stream. This gave 65.1 g (80.7% of theory) of the title compound.
Method C:
.42 g (20.6 mmol) of ethyl 5-amino(2-fluorobenzyl)-1H-pyrazolecarboxylate (preparation
described for Example 20A in WO 69) were initially d in 20 ml of ethanol, and 1.5 g
(41.1 mmol) of hydrogen chloride were introduced. This solution was metered into 3.42 g (20.6
mmol) of the compound from e 5 in 50 ml of l at reflux temperature within 10 min.
The mixture was d at reflux temperature for 2 h, then 10 ml of isopropanol were added and the
mixture was cooled to 5°C. The product was filtered off with suction, washed with 10 ml of
isopropanol and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This
gave 4.84 g (74.2% of theory) of the title compound.
Example 7
5-Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinecarboxamide
N N
O 2
ml of ethanol, 14.9 ml (441.2 mmol) of formamide and 3.6 g (66.2 mmol) of sodium methoxide
solution in methanol (30%) were added to 7.0 g (22,1 mmol) of the compound obtained in Example
6. The reaction mixture was heated to 95° - 100°C and the low boilers were distilled off. The
mixture was stirred at 125°C for 1.5 h, 30 ml of water were added, and the mixture was cooled to
room temperature and stirred for 1 h. The precipitated solids were filtered off with suction, washed
three times with 8.5 ml each time of water and dried in a vacuum drying cabinet at 45°C under a
gentle en stream. This gave 6.2 g (97.5% of theory) of the title compound.
MS (ESIpos): m/z = 289 (M+H)+
1H NMR (400 MHz, DMSO-d
6): δ = 5.87 (s, 2H), 7.12 - 7.26 (m, 3H), 7.34 - 7.40 (m, 1H), 7.60 (s
br., 1H), 7.87 (s br., 1H), 8.28 (dd, 1H), 8.72 (dd, 1H) ppm.
Example 8
-Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinecarbonitrile
N N
17.3 g (60.0 mmol) of the nd obtained in Example 7 were heated to 103° - 107°C in 40.5
ml of sulpholane and 5.4 ml of acetonitrile. Thereafter, 6.9 g (45.0 mmol) of phosphorus
oxychloride were slowly added dropwise while stirring, the dropping funnel was rinsed with 2.8 ml
of acetonitrile, then the mixture was stirred at 107°C for 1.5 h until conversion was complete
(HPLC). Thereafter, the mixture was cooled to room temperature, and 2.8 ml of
sulpholane/acetonitrile (5:1 vol/vol) and then 17.8 ml of water were added dropwise. The e
was stirred for 0.5 h, a solution of 9.4 g of aqueous ammonia (28%) in 22.7 ml of water was added
dropwise and the e was stirred for a further 2 h. The precipitated solids were filtered off with
suction, washed three times with 20.5 ml each time of water and dried in a vacuum drying t
at 50°C under a gentle nitrogen stream. This gave 14.7 g (91.9% of theory) of the title nd.
MS (ESIpos): m/z = 271 (M+H)+
1H NMR (400 MHz, DMSO-d
6): δ = 5.87 (s, 2H), 7.17 - 7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H)
ppm.
Example 9
-Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinecarboximidamide hydrochloride
N N
NH x HCl
HN 2
406.0 g (1.50 mol) of the compound from Example 8 were suspended in 2.08 l of ethanol.
Subsequently, 54.1 g (0.30 mol) of sodium methoxide in methanol (30%) were added and the
mixture was stirred at room temperature overnight. 88.4 g (1.65 mol) of ammonium chloride were
added, and the mixture was heated to 65°C and stirred at 65°C for 3.5 h. The solvents were distilled
off and the residue was stirred with 1.6 l of ethyl acetate overnight. The precipitated solids were
filtered off with suction, washed twice with 140 ml each time of ethyl acetate and dried in a
vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 441.4 g (90.7% of theory)
of the title compound.
MS (ESIpos): m/z = 288 (M+H)+
1H NMR (400 MHz, DMSO-d
6): δ = 5.90 (s, 2H), 7.15 - 7.20 (m, 1H), 7.22 - 7.28 (m, 1H), 7.29 -
7.35 (m, 1H), 7.36 - 7.43 (m, 1H), 8.48 (dd, 1H), 8.86 (dd, 1H), 9.35 (br. s, 3H) ppm.
Example 10
[(E)-phenyldiazenyl]malononitrile
Method A:
262 g of conc. hydrochloric acid (2.59 mol) and 117.5 ml of water were added dropwise at 0° - 5°C
to 1525 ml of water and 117.5 g (1.26 mol) of aniline. Subsequently, a on of 87.1 g (1.26
mol) of sodium nitrite in 222.5 ml of water was added se within 1 h and rinsed in with 60 ml
of water, and the mixture was stirred at 0° - 5°C for 15 min. Thereafter, at this temperature, a
solution of 131.4 g (1.60 mol) of sodium acetate in 665 ml of water (19 ml) was added se
within 45 min and rinsed in with 60 ml of water, and a solution of 83.4 g (1.26 mol) of
nitrile in 233 ml of ethanol was added dropwise within 1 h. 68.5 ml of ethanol were used to
rinse it in, and the mixture was stirred at 0° - 5°C for 2 h. The yellow solids were filtered off with
suction and washed three times with 625 ml each time of water and with 488 ml of cold toluene.
The still-moist residue was dissolved in 872 g of DMF. This gave 1117.0 g of DMF solution of the
title compound.
Method B:
87.4 g of conc. hydrochloric acid (0.86 mol) and 39.5 ml of water were added dropwise at 0° - 5°C
to 508.5 ml of water and 39.2 g (0.42 mol) of aniline. Subsequently, a solution of 29.0 g (0.42 mol)
of sodium nitrite in 74.5 ml of water was added dropwise within 1 h and rinsed in with 20 ml of
water, and the mixture was stirred at 0° - 5°C for 15 min. Thereafter, at this temperature, a solution
of 43.8 g (0.54 mol) of sodium acetate in 221.5 ml of water was added dropwise within 45 min and
rinsed in with 20 ml of water, and a solution of 27.8 g (0.42 mol) of malononitrile in 77.5 ml of
ethanol was added dropwise within 1 h. 23 ml of ethanol were used to rinse it in, and the mixture
was stirred at 0° - 5°C for 2 h. The yellow solids were filtered off with suction and washed three
times with 208.5 ml each time of water and with 162.5 ml of cold toluene. 103.1 g of moist product
were obtained. 13.8 g of the moist product were dissolved in 13.9 g of sulpholane. This gave 27.7 g
of sulpholane on of the title compound.
Example 11
2-[5-Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinyl][(E)-
phenyldiazenyl]pyrimidine-4,6-diamine
N N
2 N
Method A:
448.2 g (1.38 mol) of the nd from Example 9 were suspended in 1059 ml of DMF. The
mixture was heated to 85°C and 212 ml (1.52 mol) of ylamine were added dropwise at this
temperature. uently, 1751 g of the DMF solution from Example 10 were added dropwise
within 20 min and rinsed in with 490 ml of DMF, and the mixture was stirred at 100°C overnight.
The reaction e was cooled to RT, 656 ml of water were added dropwise and the mixture was
stirred at RT for 0.5 h, then cooled to 0° - 5°C and stirred for a further 1 h. The solids were filtered
off with suction, washed twice, each time with a solution of 1443 g of water and 236 g of methanol,
and then washed with 586 ml of ol, suction-dried and dried in a vacuum drying t at
50°C under a gentle nitrogen stream. This gave 522.2 g (82.5% of theory) of the title compound.
1H NMR (400 MHz, DMSO-d
6): δ = 5.84 (s, 2 H) 7.14 - 7.28 (m, 3 H) 7.34 - 7.41 (m, 2 H) 7.46 -
7.52 (m, 2 H) 7.95 (br. s, 2 H) 8.02 (dd, 2 H) 8.50 (br. s, 2 H) 8.70 - 8.73 (m, 1 H) 9.02 - 9.06 (m, 1
H) ppm.
Method B:
.0 g (92.7 mmol) of the compound from e 9 were suspended in 72 ml of DMF. The
mixture was heated to 100°C and a mixture of 14.2 ml (101.9 mmol) of triethylamine and 150 g of
the DMF solution from Example 10 was added dropwise at this temperature within 30 min. 30 ml
of DMF were used to rinse it in and the mixture was stirred at 100°C for 20 h. The reaction mixture
was cooled to 95° - 90°C, 24 ml of water were added dropwise within 10 min, then the mixture was
cooled to 0° - 5°C within 1.5 h and stirred for 1 h. The solids were filtered off with suction, washed
with a solution of 60 g of water and 60 g of dimethylformamide, washed twice, each time with a
solution of 50 g of water and 50 g of ol, and then with 40 ml of methanol, suction-dried and
dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 35.5 g (83.7%
of theory) of the title compound.
Method C:
11.7 g (36.0 mmol) of the compound from Example 9 were suspended in 15.6 ml of sulpholane.
The mixture was heated to 100°C and a mixture of 5.5 ml (39.6 mmol) of triethylamine and 27.7 g
of the sulpholane on from Example 10 Method B was added dropwise at this temperature
within 35 min. 2 ml of sulpholane were used to rinse it in and the mixture was stirred at 100°C for
2.5 h. The reaction mixture was cooled to 60°C, 90 ml of isopropanol were added dropwise, then
the mixture was cooled to 0° - 5°C within 15 min and stirred for 2.5 h. The solids were filtered off
with suction, washed three times, each time with 50 g of water and 24 ml of isopropanol, suctiondried
and dried in a vacuum drying t at 50°C under a gentle nitrogen stream. This gave 14.2
g (85.9% of theory) of the title compound.
Example 12
2-[5-Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinyl]pyrimidine-4,5,6-triamine
N N
2 NH
Method A:
182.0 g (0.39 mol) of the compound from e 11 were initially charged in 1.82 l of DMF and
then 4.2 g of palladium (5% on carbon, 50% water-moist) were added. Hydrogenation was effected
at 60°C and hydrogen pressure 60 bar while stirring overnight. The mixture was filtered through
guhr and washed through with 150 ml of DMF and then with 150 ml of methanol, and
concentrated at 60° - 70°C down to a weight of 425 g of distillation residue. The residue was
heated to 75° - 80°C, 300 ml of methanol were added dropwise at this temperature and the mixture
was stirred for 15 min. The mixture was cooled to RT within 1 h, then 1290 ml of water were
added dropwise and the mixture was stirred overnight. The solids were filtered off with n,
washed twice with 500 ml each time of water, suction-dried and dried in a vacuum drying t
at 50°C under a gentle nitrogen stream. This gave 159.7 g of the title compound. The product has a
content of 73.7% by weight and 12.4% by weight of DMF (80.3% of theory) and was used thus in
the uent stage. According to the intensity of the water wash, the DMF content was in the
range of 10 – 17% by weight.
Method B:
.0 g of the DMF-containing solids from Method A were suspended in 220 ml of water and
filtered with suction through a suction . The solids were washed four times on the suction filter
with 100 ml each time of water at 95°C, suction-dried and dried in a vacuum drying cabinet at
50°C under a gentle nitrogen stream. This gave 21.2 g of the DMF-free title compound.
MS (ESIpos): m/z = 369 (M+H)+
For analytical purposes, a sample was purified by means of silica gel filtration:
1H NMR (400 MHz, DMSO-d
6): δ = 4.04 (br. s, 2 H) 5.75 (s, 2 H) 5.86 (br. s, 4 H) 7.10 - 7.26 (m,
3 H) 7.32 - 7.39 (m, 1 H) 8.61 - 8.64 (m, 1 H) 8.85 (dd, 1 H) ppm.
e 13
Methyl {4,6-diamino[5-fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinyl]pyrimidin
bamate
N N
H N O
2 N
O CH
Method A:
4.0 g (77.0% by weight, 8.36 mmol) of the compound from Example 12 in 37.9 ml of isopropanol
were heated to 35°C and then 0.84 ml (10.87 mmol) of methyl chloroformate was added dropwise.
The mixture was stirred at 35° - 40°C for 20 h and heated to 50°C, and 9.5 ml of methanol were
added. Subsequently, 1.9 ml of triethylamine were added dropwise within 0.5 h and rinsed in with
1.3 ml of ol, and the mixture was stirred at 50°C for 1 h. Thereafter, the reaction mixture
was cooled to RT and d at RT for 1 h, and the solids were filtered off with suction, washed
three times with 8 ml each time of ethanol, suction-dried and dried in a vacuum drying t at
50°C under a gentle nitrogen stream. This gave 3.4 g of crude product. 3.0 g of the crude product
were stirred in 8 ml of DMSO for 5 min, 13.0 ml of ethyl acetate and 50 mg of activated carbon
were added, and the mixture was heated at reflux (84°C) for 15 min. The suspension was hotfiltered
and the filter residue was washed with 1.9 ml of ethyl acetate1). 60 ml of ethyl acetate and
16 ml of ethanol were heated to 60°C, and the combined filtrates were added dropwise and stirred
at 60°C for 1.5 h. The suspension was cooled to RT within 25 min, stirred for a further 1.5 h,
cooled further to 0° - 5°C and stirred for a further 1 h. The solids were ed off with suction,
washed twice with 6.4 ml each time of ethyl acetate, suction-dried and dried in a vacuum drying
cabinet at 50°C under a gentle nitrogen stream. This gave 2.2 g (70.0% of theory) of the title
compound.
MS (ESIpos): m/z = 427 (M+H)+
1H NMR (400 MHz, DMSO-d
6): δ = 3.62 (br s, 3H), 5.79 (s, 2H), 6.22 (br s, 4H), 7.10 - 7.19 (m,
2H), 7.19 - 7.26 (m, 1H), 7.32 - 7.40 (m, 1H), 7.67 and 7.99 (2 br s, 1H), 8.66 (m, 1H), 8.89 (dd,
1H) ppm.
1) ing to the preparation process bed, the di-dimethyl sulphoxide solvate is
obtained at this point, and this is characterized in Tables 2 and 4 by the reflections in the
x-ray diffractogram and bands in the IR spectrum.
The di-dimethyl xide solvate of the compound of the formula (I) has the advantage of much
better filterability than the nce in the prior art. Furthermore, the preparation process via the
di-dimethyl sulphoxide solvate of the compound of the formula (I) leads to a very high purity of the
compound of the formula (I).
Method B:
4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were
heated to 35°C and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The
mixture was stirred at 35° - 40°C for 16.5 h and cooled to RT, and 2.1 ml of aqueous ammonia
(28%) were added. Subsequently, 4.2 ml of water were added and the mixture was stirred for 2.5 h.
The solids were ed off with suction, washed twice with 5 ml each time of water, suction-dried
and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 4.4 g of
crude product.
Method C:
4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were
heated to 35°C and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The
mixture was stirred at 35° - 40°C for 16.5 h, and 9.5 ml of methanol were added at 50°C.
Subsequently, 2.42 ml of triethylamine were added dropwise within 20 min and rinsed in with 1.3
ml of methanol, and the e was stirred at 50°C for 1 h. Thereafter, the reaction mixture was
cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three
times with 8 ml each time of methanol, suction-dried and dried in a vacuum drying cabinet at 50°C
under a gentle nitrogen stream. This gave 4.3 g of crude product.
Method D:
6.9 g of the crude product were stirred in 18.4 ml of DMSO for 5 min, 30.0 ml of ethyl e and
115 mg of activated carbon were added, and the mixture was heated at reflux (84°C) for 15 min.
The suspension was hot-filtered and the filter e was washed with 4.4 ml of ethyl acetate. 138
ml of ethyl acetate were heated to 50°C, and the combined filtrates were added dropwise and
stirred at 45 - 50°C for 1 h. The suspension was cooled to 0° - 5°C within 1.5 h and stirred for a
further 1 h. The solids were filtered off with suction, washed twice with 14.8 ml each time of ethyl
acetate and suction-dried for 1 h. 6.4 g of the di-dimethyl sulphoxide solvate were obtained as a
moist product1).
Method E:
2.0 g of the di-dimethyl xide solvate were stirred at reflux temperature in 40 ml of ethyl
acetate and 11.1 ml of ethanol for 17 h, cooled to RT and stirred for a further 1 h. The solids were
filtered off with suction, washed four times with 1.4 ml each time of ethyl acetate and dried in a
vacuum drying cabinet at 50°C under a gentle en stream. This gave 1.4 g of the title
compound t in polymorph I.
Method F:
0.5 g of the di-dimethyl sulphoxide e were stirred at reflux temperature in 12.5 ml of t
for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction,
washed with 2 ml of solvent and suction-dried for 30 min. This gave 0.3 g of the title compound
present in polymorph I.
The ing solvents were used:
1.) 9 ml of ethyl acetate/3.5 ml of ethanol/0.3 ml of water
2.) 12.5 ml of isopropanol
3.) 12.5 ml of isopropanol/0.3 ml of water
4.) 12.5 ml of methanol
.) 12.5 ml of methanol/0.3 ml of water
6.) 12.5 ml of acetonitrile
7.) 12.5 ml of acetone
8.) 12.5 ml of tetrahydrofuran,
9.) 12.5 ml of methyl tert-butyl ether
Table 1 indicates the reflections of the x-ray diffractogram. Table 3 shows the bands of the IR
spectrum.
The compound (I) in crystalline polymorph I is notable for higher stability and more particularly
for the fact that it is stable in the micronization process and hence no conversion and
recrystallization takes place.
The compound of the formula (I) can be prepared by processes described above. This affords the
compound of the a (I) in a crystal polymorph referred to hereinafter as polymorph I.
Polymorph I has a melting point of 257°C and a characteristic x-ray diffractogram featuring the
reflections (2 theta) 5.9, 6.9, 16.2, 16.5, 24.1 and 24.7, and a characteristic IR spectrum ing
the band maxima (in cm-1) 1707, 1633, 1566, 1475, 1255 and 1223 (Tables 1 and 3, Figures 1 and
Surprisingly, four further polymorphs, a monohydrate, a dihydrate, a ter solvate and a didimethyl
sulphoxide solvate, and also a triacetic acid solvate of the compound of the formula (I) were
found. The compound of the formula (I) in polymorph II melts at approx. 253°C; the compound of the
formula (I) in polymorph III has a melting point of approx. 127°C. Polymorph IV of the compound of
the formula I melts at a temperature of 246°C, while polymorph V has a g point of 234°C. The
monohydrate contains approx. 4.1% water, the ate contains 7.8% water, the ter solvate
contains 13.6% dimethylformamide and 0.9 % water, the di-DMSO solvate contains 26.8% yl
sulphoxide and the tic acid solvate contains 29.7% acetate. Each of the crystalline forms
mentioned has a characteristic x-ray diffractogram and IR spectrum (Tables 2 and 3, Figures 1 - 4, 6
- 14).
Table 1: X-ray diffractometry for polymorphs I to V
Reflections
Polymorph I Polymorph II rph III Polymorph IV Polymorph V
[2 theta] [2 theta] [2 theta] [2 theta] [2 theta]
.9 4.9 6.2 6.2 3.2
6.9 7.3 6.8 8.7 5.1
8.3 9.7 8.7 12.4 5.4
.4 9.9 9.8 15.8 6.4
.5 10.8 12.4 18.1 6.6
11.3 14.3 15.8 18.6 10.2
11.6 14.9 17.5 19.2 10.7
11.9 15.6 18.1 19.6 11.8
12.2 16.5 18.6 20.2 12.8
14.5 18.1 19.1 20.9 13.2
14.7 18.3 19.6 21.8 15.2
.1 19.6 20.1 22.3 15.5
16.2 21.0 21.0 23.1 15.7
16.5 21.8 21.9 23.7 16.3
.0 22.4 22.8 24.2 17.0
21.9 23.1 23.7 26.0 17.7
22.7 23.7 24.5 26.5 17.9
23.5 27.1 25.3 29.2 19.6
24.1 28.1 25.7 31.3 22.1
24.7 26.8 33.8 22.8
.4 27.5 23.5
.7 28.2 24.4
26.6 29.6 26.3
28.0 30.9 27.9
.2 31.3 28.3
31.6 29.3
32.8 30.3
33.8
34.6
Table 2: X-ray diffractometry for polymorph hydrates and solvates
Reflections
Monohydrate Dihydrate DMF/water di-DMSO Acetic acid
[2 theta] [2 theta] solvate e solvate
[2 theta] [2 theta] [2 theta]
6.0 5.9 8.2 6.9 5.3
8.5 7.9 9.2 11.0 7.2
9.6 8.7 9.7 12.0 9.3
12.1 9.0 11.9 13.8 10.0
13.6 11.8 12.5 14.1 10.7
.5 13.7 12.7 15.7 11.0
17.3 14.7 13.3 16.1 11.6
18.2 15.8 14.1 16.2 11.9
19.3 16.4 15.6 16.6 12.5
19.7 18.1 16.0 17.1 14.1
.2 19.3 16.5 17.7 14.4
.9 19.8 16.8 17.8 14.8
21.5 20.6 17.6 18.8 16.6
22.2 21.7 18.3 19.9 18.0
23.5 21.7 19.3 20.3 18.8
24.1 22.5 19.4 20.7 19.2
.7 22.7 19.6 21.3 19.4
26.8 22.9 19.8 21.7 19.6
27.5 23.4 20.0 21.9 19.7
29.4 23.7 20.5 22.4 20.1
.8 24.9 20.6 22.8 20.4
32.2 25.5 20.7 23.6 21.0
26.0 21.0 24.1 21.6
26.8 21.8 24.4 22.9
27.1 22.2 25.2 23.5
27.8 22.4 25.5 24.1
28.9 22.8 25.9 24.4
.7 23.1 26.6 24.8
31.3 23.6 26.9 25.5
32.0 23.9 28.9 26.5
24.8 29.9 26.8
.2 30.9 27.7
.6 33.2 31.5
.8 33.4
26.1 33.9
26.7
26.8
27.2
27.6
28.1
28.4
28.6
29.4
29.7
.3
.6
31.4
31.5
31.7
32.1
32.4
32.6
32.7
34.1
34.3
34.7
.6
.9
36.6
Table 3: IR spectra of polymorphs I to V
Band maxima
rph I Polymorph II Polymorph III Polymorph IV Polymorph V
[cm-1] [cm-1] [cm-1] [cm-1] [cm-1]
690 691 697 698 691
744 752 744 752 745
761 771 753 773 759
774 779 773 809 773
810 810 808 833 809
845 848 835 873 847
872 871 873 911 873
899 903 913 936 896
960 933 935 955 912
1059 958 954 1058 933
1072 1031 1034 1077 961
1112 1067 1059 1104 1033
1157 1082 1075 1161 1057
1208 1111 1103 1207 1083
1223 1202 1161 1225 1112
1255 1223 1206 1237 1152
1305 1249 1256 1207
1319 1264 1237 1277 1224
1353 1305 1253 1317 1255
1370 1349 1278 1356 1305
1435 1368 1319 1370 1318
1475 1436 1355 1425 1351
1566 1456 1370 1457 1371
1620 1480 1424 1472 1436
1633 1566 1437 1490 1478
1707 1620 1458 1496 1567
2956 1704 1476 1573 1628
3130 2953 1489 1585 1707
3277 3132 1570 1618 2956
3332 3278 1587 1691 3143
3385 3361 1619 3208 3277
3490 3488 1695 3290 3319
3503 3203 3376 3452
3315 3482 3492
3379
3479
Table 4: IR spectra of the hydrates and solvates
Band maxima
Monohydrate Dihydrate DMF/water di-DMSO Acetic acid
[cm-1] [cm-1] e solvate solvate
[cm-1] [cm-1] [cm-1]
696 745 662 713 709
743 752 724 762 739
761 760 745 778 762
774 774 771 811 777
810 809 812 873 801
834 835 846 902 835
873 874 867 953 872
912 913 896 1017 918
953 937 932 1041 941
1066 955 965 1078 955
1079 1032 1054 1111 1059
1104 1061 1072 1164 1099
1160 1080 1096 1210 1113
1176 1105 1117 1234 1167
1205 1160 1160 1281 1236
1222 1174 1209 1321 1252
1236 1206 1243 1364 1357
1249 1224 1304 1432 1423
1278 1236 1356 1457 1456
1356 1259 1389 1481 1492
1370 1309 1434 1521 1577
1423 1356 1481 1569 1601
1456 1371 1561 1628 1643
1474 1422 1624 1720 1702
1491 1473 1654 3144 3342
1575 1497 1729 3288
1620 1575 3159 3423
1669 1622 3404
3294 1688 3498
3331 3195
3479 3304
3472
3676
Figure 1: IR spectrum of the compound of the formula (I) in polymorphs I, II and III
Figure 2: IR spectrum of the compound of the formula (I) in polymorphs IV, V and as the
triacetic acid solvate
Figure 3: IR spectrum of the compound of the formula (I) as the di-DMSO solvate,
DMF/water e and monohydrate
Figure 4: IR spectrum of the compound of the formula (I) as the dihydrate
Figure 5: X-ray diffractogram of the compound of the formula (I) in rph I
Figure 6: X-ray diffractogram of the compound of the formula (I) in polymorph II
Figure 7: X-ray diffractogram of the compound of the formula (I) in polymorph III
Figure 8: X-ray ctogram of the compound of the formula (I) in rph IV
Figure 9: X-ray diffractogram of the compound of the formula (I) in polymorph V
Figure 10: X-ray ctogram of the compound of the formula (I) as the triacetic acid
solvate
Figure 11: X-ray diffractogram of the compound of the a (I) as the di-DMSO solvate
Figure 12: X-ray diffractogram of the compound of the formula (I) as the DMF-water solvate
Figure 13: X-ray diffractogram of the compound of the formula (I) as the monohydrate
Figure 14: X-ray diffractogram of the compound of the formula (I) as the dihydrate
Claims (14)
1. A process for preparing the compound of the formula (VI) N N F (VI), wherein the compound of the formula (V) N N O 2 5 (V) is prepared by reaction of an ester of the formula (IVa) N N O (IVa) in which T1 is (C1-C4)-alkyl 10 with formamide and the nd of formula (V) is dehydrated to give the compound of formula (VI).
2. s according to Claim 1, wherein an ester of the formula (IVa) is prepared by cyclizing the 5-aminopyrazole derivative (IIa) O T1 (IIa) in which 5 T1 is (C1-C4)-alkyl in the presence of an alkali metal salt and an acid with an aldehyde of the a (III) F R1 H N O (III) in which R1 and R2 together with the nitrogen atom to which they are bonded, are N N N N N O , , or 10 to give the ester of formula (IVa).
3. Process according to Claims 1 and 2, wherein the aldehyde used in the cyclization reaction is the compound of the formula (IIIa) F O H N O (IIIa).
4. A process for preparing the compound of formula (I), N N 2 NH 3 (I), wherein the compound of a (VI) N N F (VI) 5 is used, wherein the compound of formula (VI) is prepared by the process from Claims 1 or 2, by converting the compound of the formula (VI) to the compound of the formula (VII) N N x HCl (VII), subsequently ng the latter in an inert solvent in the presence of a suitable base with the compound of the formula (VIIIa) NC CN (VIIIa) to give the compound of the formula (VIII) N N 2 N 5 (VIII), and then reducing the latter in an inert solvent in the presence of a suitable reducing agent to give the compound (IX) N N 2 NH 2 (IX), and thereafter reacting the latter with methyl chloroformate or with dimethyl dicarbonate in the presence of a suitable base with or without solvent to give the compound of the formula (I), and optionally converting the resulting compound of the formula (I) with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or es of the 5 salts thereof.
5. A process for preparing the compound of the a (I), wherein the compound of the formula (VI) N N F (VI) is used, this compound being prepared according to the process of any one of Claims 1 to 3, by 10 converting the compound of the a (VI) to the compound of the formula (VII) N N x HCl (VII), subsequently reacting the latter in an inert t in the presence of a suitable base with the compound of the formula (VIIIa) NC CN (VIIIa) to give the nd of the formula (VIII) N N 2 N (VIII), and then reducing the latter in an inert t in the presence of a suitable reducing agent to give the compound (IX) N N 2 NH 5 2 (IX), and thereafter reacting the latter with methyl chloroformate or with dimethyl dicarbonate in the presence of a suitable base with or without solvent to give the compound of the formula (I), and optionally converting the resulting compounds of the formula (I) with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the 10 salts thereof.
6. Crystalline nce compound of the formula (I) in the form of the di-dimethyl sulphoxide solvate, N N O N S Me Me H N O 2 NH O S Me Me characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 18.8, 20.3, 21.7.
7. Compound according to Claim 6, characterized in that the x-ray diffractogram of the compound ts peak maxima of the 2 theta angle at 12.0, 16.6, 17.8, 18.8, 20.3, 21.7.
8. lline substance compound of the formula (I) in the form of the di-dimethyl 10 sulphoxide solvate, N N O N S Me Me H N O 2 NH O S Me Me characterized in that the IR spectrum of the compound exhibits band maxima at 1720, 1628, 1481 cm-1.
9. Compound ing to Claim 8, characterized in that the IR spectrum of the compound exhibits band maxima at 1720, 1628, 1481, 1234, 1041, 1017 cm-1. 5
10. Process for preparing the compound of the formula (I) as the di-dimethyl sulphoxide solvate in crystalline form, characterized in that the compound of the formula (I), present in one or more polymorphs or as a solvate in dimethyl sulphoxide or a mixture of dimethyl sulphoxide and an inert solvent, is stirred at a ature of 20 - 120°C and the didimethyl sulphoxide solvate is isolated.
11. A compound of a (VI) when prepared by a process according to any one of claims 1 to 3.
12. A compound of a (I) when prepared by a process according to claim 4 or 5.
13. A process of any one of claims 1 to 5, or 10 substantially as herein described with reference to any example thereof.
14. A compound of any one of claims 6 to 9, 11, or 12 substantially as herein bed with reference to any example thereof.
Priority Applications (1)
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NZ724215A NZ724215B2 (en) | 2011-11-25 | 2012-11-21 | Method for producing substituted 5-fluoro-1h-pyrazolopyridines |
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EP11190789.5 | 2011-11-25 | ||
EP11190789 | 2011-11-25 | ||
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EP11192301.7 | 2011-12-07 | ||
NZ624593A NZ624593B2 (en) | 2011-11-25 | 2012-11-21 | Method for producing substituted 5-fluoro-1h-pyrazolopyridines |
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NZ721592B2 true NZ721592B2 (en) | 2018-05-24 |
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