NZ624593B2 - Method for producing substituted 5-fluoro-1h-pyrazolopyridines - Google Patents
Method for producing substituted 5-fluoro-1h-pyrazolopyridines Download PDFInfo
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- NZ624593B2 NZ624593B2 NZ624593A NZ62459312A NZ624593B2 NZ 624593 B2 NZ624593 B2 NZ 624593B2 NZ 624593 A NZ624593 A NZ 624593A NZ 62459312 A NZ62459312 A NZ 62459312A NZ 624593 B2 NZ624593 B2 NZ 624593B2
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- New Zealand
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- compound
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 24
- LTYNYHHABUSSHS-UHFFFAOYSA-N 5-fluoro-1h-pyrazolo[4,3-b]pyridine Chemical class FC1=CC=C2NN=CC2=N1 LTYNYHHABUSSHS-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 185
- 238000000034 method Methods 0.000 claims abstract description 73
- 239000012442 inert solvent Substances 0.000 claims abstract description 19
- 238000002329 infrared spectrum Methods 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims description 56
- 229940125898 compound 5 Drugs 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 abstract description 5
- 238000003756 stirring Methods 0.000 abstract description 4
- QZFHIXARHDBPBY-UHFFFAOYSA-N vericiguat Chemical compound N1=C(N)C(NC(=O)OC)=C(N)N=C1C(C1=CC(F)=CN=C11)=NN1CC1=CC=CC=C1F QZFHIXARHDBPBY-UHFFFAOYSA-N 0.000 abstract 4
- 229950005018 vericiguat Drugs 0.000 abstract 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 100
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 76
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 39
- 150000003839 salts Chemical class 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- -1 iodo compound Chemical class 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 229960004592 isopropanol Drugs 0.000 description 19
- 150000002825 nitriles Chemical class 0.000 description 19
- 238000001291 vacuum drying Methods 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 229910052783 alkali metal Inorganic materials 0.000 description 11
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- NBUKAOOFKZFCGD-UHFFFAOYSA-N 2,2,3,3-tetrafluoropropan-1-ol Chemical compound OCC(F)(F)C(F)F NBUKAOOFKZFCGD-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- RGXCTRIQQODGIZ-UHFFFAOYSA-O isodesmosine Chemical compound OC(=O)C(N)CCCC[N+]1=CC(CCC(N)C(O)=O)=CC(CCC(N)C(O)=O)=C1CCCC(N)C(O)=O RGXCTRIQQODGIZ-UHFFFAOYSA-O 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 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 6
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 5
- GMVPRGQOIOIIMI-DODZYUBVSA-N 7-[(1R,2R,3R)-3-hydroxy-2-[(3S)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]heptanoic acid 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 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 150000001204 N-oxides Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 150000004683 dihydrates Chemical class 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- UMFCIIBZHQXRCJ-NSCUHMNNSA-N trans-anol Chemical compound C\C=C\C1=CC=C(O)C=C1 UMFCIIBZHQXRCJ-NSCUHMNNSA-N 0.000 description 5
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 5
- 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
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 150000004682 monohydrates Chemical class 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000007363 ring formation reaction Methods 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
- 239000008096 xylene Substances 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 3
- 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 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229910052799 carbon 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
- 239000013078 crystal Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 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
- 239000001257 hydrogen Substances 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
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- 150000005229 pyrazolopyridines Chemical class 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N 1-nonene Chemical compound CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- JLFVIEQMRKMAIT-UHFFFAOYSA-N ac1l9mnz Chemical compound O.O.O JLFVIEQMRKMAIT-UHFFFAOYSA-N 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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
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- 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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- C07B2200/13—Crystalline forms, e.g. polymorphs
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- 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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- 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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- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C07C317/00—Sulfones; Sulfoxides
- C07C317/02—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms
- C07C317/04—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- C07D295/00—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
- 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
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
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- C07D295/00—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
- 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
- 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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- C07D295/00—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
- 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
- C07D295/037—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 with quaternary ring nitrogen atoms
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- C07—ORGANIC CHEMISTRY
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- C07D295/00—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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/067—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The disclosure relates to a method for producing a polymorphic form of Vericiguat (Methyl N-[4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate), 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, or by the IR spectrum of the compound exhibits band maxima at 1707, 1633, 1475 cm-1. Also disclosed methods of preparing the polymorph and medicaments containing it for the treatment and/or prophylaxis of cardiovascular disorders. The polymorph may be prepared by stirring Vericiguat in an inert solvent, at a temperature of 20°C - 120°C and isolating the resulting polymorph. 5.9, 6.9, 22.7, or by the IR spectrum of the compound exhibits band maxima at 1707, 1633, 1475 cm-1. Also disclosed methods of preparing the polymorph and medicaments containing it for the treatment and/or prophylaxis of cardiovascular disorders. The polymorph may be prepared by stirring Vericiguat in an inert solvent, at a temperature of 20°C - 120°C and isolating the resulting polymorph.
Description
Method for roducin substitutedS-fluoro-ll-l- 'razolo ridincs The present application relates to a novel and efficient process for preparing novel substituted 5- fluoro-lH—pyrazolopyridines 0f the formula (VI) N\ N\ / /N (v1) 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-fluor0—lH-pyrazolopyridines of the formula (VI) are suitable for ation of compound of the formula (I) \ N‘ | N N/ N \ NH2 2 NH (1), which serves for production of medicaments and for production of medicaments for treatment and/or prophylaxis of vascular disorders.
The compound ofthe formula (1) acts as a stimulator of soluble ate cyclase and can be used as an agent for prophylaxis and/or treatment of cardiovascular disorders, for example for ent of ension and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, of anthythmias, for treatment of thromboembolic disorders and mias such as myocardial infarction, stroke, transitory and ischaemic attacks, peripheral perfusion disorders, prevention of restenoses such as after thrombosis therapy, percutaneous transluminal angioplasty (PTA), percutaneous uminal coronary angioplasty (PTCA), bypass, and for treatment of arteriosclerosis, tic disorders and diseases of the urogenital system, for example prostate hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, ma, pulmonary hypertension, gastroparesis, scleroderrna and inence.
The compound of the formula (I) may be t 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 HI), 246°C (polymorph IV), 234°C (polymorph 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 (1) in Example 1 as a substance.
The crystal polymorph of the compound formula (I) in polymorph (I) is notable for stability 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 ation 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 a (1).
WO 03/095451, and disclose the synthesis of pyrazolopyridines 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—lH-pyrazolo[3,4-b]pyridineamine E.
Selective dechlorination of the nic acid A to give the compound B, uent conversion to the amide C, the reduction thereof to the nitrile and the final ation with hydrazine hydrate form the 5-fluoro-1H—pyrazolo[3,4-b]pyridine core. Scheme 1 below illustrates the synthesis. 2012/073276 _ 3 _ Scheme 1: O O F F F \ OH \ OH \ I) ii) NH2 —' ’ —" / / / CI N Cl N Cl N Cl A B C F 0" iii) \ iv) \ I NxN / F N Cl D E [1) Pd(OAc)2, PPh3, NEtg, HCOZH; ii) 1) (coc1)2, CHZClz, cat. DMF, 2) NH3 (g), dioxane, iii) TFAA, NEtg; iv) HZNNHzx H20, n-BuOH].
A disadvantage of this process is that, proceeding from o-lH-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 d 5-fluoro-lH-pyrazolopyridines of the formula (VI). This is illustrated by way of example in Scheme 2.
Scheme 2: iso e l I’F'Q CuCN KQ NaiD mylnitrite; F Br:© / N_ DMSO IN N_ —’ | \N.N —’F£):(N "—" I \ \ ,N N H F F G (VI) A further disadvantage is that the diazotization is conducted under anhydrous conditions and the diazonium salt has to be isolated, which necessitates erable safety precautions on conversion to the industrial scale and thus causes high tion costs.
A further disadvantage is that the alkylation with a benzyl derivative proceeds unselectively and the product is obtained in only a low yield after complex purification and separation of the isomers. _ 4 _ A further disadvantage is that, in the course of cyanation, toxic copper cyanide has to be d, 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 antage is that the preparation of 5-fluoro-lH-pyrazolopyridines of the formula (VI), according to the s 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 an efficient process with high yield for preparation of 5- fluoro-lH—pyrazolopyridines of the formula (VI) N\ N\ l N as a key ent for an efficient process with high yield for preparation of compound of the formula (I) and the N—oxides, salts, solvates, salts ofN—oxides and solvates of the N—oxides and salts thereof.
This object is achieved in accordance with the t invention, as follows. Scheme 3 below illustrates the individual reaction steps by way of example.
WO 76168 _ 5 _ Scheme 3: b F 2 /@ N\ R1 F a) N\ N R2/ / / 0 o O LCHS O O L0H (11) (III) (IV) Q F a l \N —’ N\ N / \ b) / F C) I N 0 CN (V) (VI) F: : / \ / d) e) NH2 / \ NH2 HN *" x HCI H2N \ (IX) (1) _ 6 _ [a): LiCl, MesogH, EtOH; b) formamide, NaOMe/MeOH, EtOH; c) POC13, CH3CN, lane; d) l. NaOMe/MeOH, 2. NH4Cl/EtOH; e) DMF, NEt3, phenylazomalononitrile; f) Pd/C, H2, DMF; g) iPrOH, methyl chloroformate, NEtg].
Step a) is already known for the tituted pyrazolopyridines through (WO 03/004503 (Example IIIb) and WO 03/095451 (Example 2A)): (H) H J [aa): CF3303H, 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 age 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 reaction time is considerably shorter ed to the prior art.
A r advantage is that the preparation of IV proceeds with high selectivity and the product is formed in high purity without significant duct formation, and no complex purification procedures are ed.
A further advantage is that IV is obtained by crystallization in high yield and purity.
Steps (1) — g) are already known for the unsubstituted pyrazolopyridines through WO 03/095451, and and can be used analogously.
Specifically, the process according to the invention for preparing a compound of the formula (VI) comprises WO 76168 N\ N‘ | N F (VI) which by the cyclization of the 5—aminopyrazole derivative (Ila) HZN \N \ / (Ha) in which T1 is (Cl-C4)-alkyl, in the presence of a suitable acid with the aldehyde (III) F IIRZ (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 7 ~--N N— ---N > ---N o \_/ \_/ 01‘ : a to give the ester of the formula (IVa) 2012/073276 _ g - N\ N‘ | N 0 \ (W3) in which T1 is as defined above, the subsequent reaction thereof with ammonia or ide to give the amide of the formula (V) | ‘N NH2 (V) and the subsequent dehydration to give the nitrile WI).
The present invention further provides for the use of the compound of the formula (VI) N\ N‘ I N (VI) for preparation of the compound of the formula (I) 2012/073276 and the N—oxides, salts, solvates, salts ofN—oxides and solvates of the es and salts thereof.
The present invention further provides for the use of the compound ofthe formula (III) z:337I (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 \‘~ I \ I \ N 7 ---N N— --~N > -—-N o \_/ \_/ _ 10 _ for preparation of the compound of the a (I) and the es, salts, solvates, salts of N-oxides and solvates of the N—oxides and salts thereof.
The present invention further es for the 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 (V1) is converted to the compound of the formula (VII) IN\ N‘ XHCI (VII), the latter is subsequently reacted in an inert solvent in the presence of a suitable base with the compound of the formula (VHIa) 2012/073276 WHIa) to give the compound of the formula (VIII) IN\ N‘ N/ N \ NH2 2 //N (V111), and then the latter is reduced in an inert solvent in the presence of a suitable reducing agent to give the compound (1X) | "N N R‘ \ NH2 (1X), then the latter is reacted in the presence of a suitable base in the presence or absence of a solvent with methyl chloroformate or with dimethyl onate to give the compound of the formula (I) \ N‘ I N N/ N \ NH2 (1), and optionally the resulting compound of the formula (I) is optionally ted 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 effected by methods known to those skilled in the art in a two-stage process, first to form the imino ester with sodium ide in methanol at 0°C to +40°C and then nucleophilic addition of one ammonia equivalent, for example ammonia or ammonium chloride, in acetic acid or an alcohol to form the amidine (VII) at +50 to +150°C.
Suitable ls for the conversion (VI) —> (VII) are alcohols such as methanol, ethanol, n- propanol, panol, n—butanol or tert-butanol.
Inert solvents for the process step (VII) + (VIIIa) —> (VIID are alcohols such as methanol, ethanol, n—propanol, isopropanol, nol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as hylforrnamide (DMF), dimethyl sulphoxide (DMSO), sulpholane, N,N’- dimethylpropyleneurea (DMPU), N—methylpyrrolidone (NMP), ne, acetonitrile or else water.
It is likewise le to use mixtures of the solvents mentioned. 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 ium hydrogencarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylarnine, diisopropylethylamine, pyridine, l,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) —> NIH) is generally ted 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, ed or reduced pressure (for example from 0.5 to 5 bar). In general, standard re is ed.
The compound of the formula (VDIa) can be prepared analogously to the literature L. F. Cavalieri, J. F. Tanker, A. Bendich, J. Am. Chem. Soc., 1949, 71, 533.
The reductions (VIII) —) (IX) are effected in the presence of a le 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 solvents 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 solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N’—dimethylpropyleneurea , N—methylpyrrolidone mMP), ne, acetonitrile or else water. It is likewise possible to use es of the solvents mentioned. Preference is given to DMF and pyridine. le catalysts for the sion (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 tin(II) de in a le acid, for example hydrogen chloride/hydrochloric acid, sulphuric acid, oric acid or acetic acid, within a temperature range of +20°C to +140°C.
Inert solvents for process step (DC) —> (I) are, for example, alcohols such as methanol, ethanol, n- propanol, panol, n—butanol or utanol, ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene or chlorobenzene, arbons such as benzene, xylene, toluene, hexane, cyclohexane or l oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), MN’-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 isopropanol and tetrahydrofuran.
Suitable bases for the process step (IX) —) (I) are alkali metal hydrides such as sodium hydride, alkali metal hydroxides, for example lithium hydroxide, sodium ide 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 potassium methoxide, sodium ethoxide or ium ethoxide or ium teIt-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8- diazabicyclo[5.4.0]undecene (DBU) or l,5-diazabicyclo[4.3.0]nonene (DBN). Preference is given to triethylamine.
The reaction (IX) —> (I) is generally conducted within a temperature range of -lO°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, standard pressure is employed.
Compounds of the formula (Ha) are known from the literature and can be prepared in analogy to Example 20A in WO 69. nds of the formula (III) are known from the literature H. ka, S. Yamashita and T.
Ishihara, t 353-354 (1993). The synthesis disclosed therein is illustrated in Scheme 4.
Scheme4: Q‘s/’0 F 00 //O /%F\ Cr\ J.) 8\ Cl + 5% _. r1 0 F . .
No2 F F K (XII) L \NV H \I I /N|\Bn (XVIb) M N m) I I H m\ _. /N / + My. o (IIIb) (Illa) [k) 3 eq dimethylbenzylamine, 130 — 140°C; 1) 10 eq CH31, reflux, m) 1M NaOH, 20°C; n) DMSO- H20 (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 achieved and, in this process, very large amounts (2.79 kg per kg of (XVIb)) of by-product (dimethyldibenzyl nitrobenzenesulphonate) are obtained, which have to be removed and disposed of.
A further disadvantage of this process is that, according to H. Yamanaka, H. Ganbayashi, M.
Kuwabara, K. Fukunishi and M. Nomura, Nippon Kagaku Kaishi (7) 1036-1043 (1988), proceeding from (XVIb), the alkylation es 10 equivalents of the carcinogenic alkylating agent methyl iodide.
A r disadvantage of this process is that, according to H. Yamanaka, S. Yamashita and T. ra, t 353-354 (1993), the reaction of O with morpholine forms not only the desired product (IIIb) but also 11% of the by-product , which necessitates a complex purification, the result being that the l synthesis for preparation of (IHb) gives only a low overall yield and causes high production costs.
The synthesis bed therein, however, is unsuitable for the preparation of the aldehydes of the formula (HI) on the industrial scale, and so a new and efficient synthesis has been developed, which is rated by way of e in Scheme 5.
SchemeS: Ow/OOMO F 0,00 F F ‘s\ /s’ F 0 ) F ‘s\ F>r >< Wed —* Fxo F F F F F F F F F (X) (XI) (XII) F F CH3803' (XIII) (XIV) | + 0fi F L, 0 \ F s) o F K/NWH CH3803' o (XV) (11121) [0) without solvent; p) dichloromethane or without solvent, morpholine; q) without solvent, methyl methanesulphonate; r) NaOH, water; s) morpholine/tiiethylamine.] 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 sis disclosed therein is illustrated in Scheme 6. _ 17 _ Scheme 6: (XIII) The sis described therein, however, for reasons including the low yield, is unsuitable for the preparation of the aldehydes of the formula (III) on the industrial scale.
The present ion further provides a process for preparing compounds of the formula (III) (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 s i ‘ i \ 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 formula (XI) without solvent and the resulting 2,2,3,3-tetrafluoropropy1 trifluoromethanesulphonate of the formula (XII) is reacted with a compound of the formula (XIIa) (XIIa) in which R1 and R2 are each as defined above to give a compound of the formula ) (XIIIa) in which R1 and R2 are each as defined above and with methyl methanesulphonate to give a compound of the formula (XIVa) CH3803' (XIVa) in which R1 and R2 are each as defined above and with sodium hydroxide to give a compound of the formula (XVa) R\l}|l+/\’/kl:2 R1 F CH3SO - 3 (XVa) in which R1 and R2 are each as defined above and finally converted under basic conditions to give the nd of the formula (III).
The present ion r preferentially provides a process for preparing compounds of the formula (Ma) (111a) wherein trifluoromethanesulphonic anhydride of the formula (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 reacted with morpholine to give a nd of the formula (XIII) (XIII) and with methyl methanesulphonate to give a compound of the formula (XIV) CH3803‘ (XIV) and with sodium ide to give a compound of the formula (XV) fN \ F 0Q F CH380'3 (XV) and finally with addition 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 y reduces the industrial complexity of the synthesis.
The yields of the resulting aldehydes of the formula (III) are much higher with the new synthesis process than in the prior art.
"Basic conditions" in the context of the invention for the process step (XIVa) to (XVa) means that the acid formed in the reaction is ged by auxiliary bases, for example sodium hydroxide, ium hydroxide, potassium carbonate, sodium ate, 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 ting agent. The on is conducted without solvent and ds virtually quantitatively, which achieves a high space-time yield.
A further advantage of this process is that the product (XIV) is not isolated, (XIV) is dissolved 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; on of the aqueous on with morpholine affords (Illa) as the sole product in high yield.
A r age of this process 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, preferably at +20°C to +100°C, at standard pressure, within, for example 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 hydrochloric acid.
Alkali metal salts are sodium chloride or m chloride. A preferred alkali metal salt is lithium chloride.
Inert solvents are, for example, ls such as methanol, ethanol, 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, e, xylene, hexane, cyclohexane or mineral oil fractions or other solvents, itrile or MN-dimethylformamide, or mixtures of solvents. Preference is given to ethanol, diethylene glycol dimethyl ether or dioxane.
The preferred formation 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 +1 30°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 iso-propanol. ence is given to ethanol. le 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 encarbonate or potassium hydrogencarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or ium tert-butoxide, or c 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 solvents 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 solvent, optionally in the presence of a suitable base, with a suitable dehydrating agent, for example orus oride, 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.
Preference is given to phosphorus oxychloride.
Inert solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, arbons such as benzene, e, 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, azabicyclo[5.4.0]undecene (DBU) or 1,5—diazabicyclo[4.3.0]nonene (DBN).
Preference is given to ne.
The compounds described in the context of the process according to the invention may also be in the form of the salts, solvates or solvates of the salts f.
The compounds described in the context of the process according to the invention may, depending on the structure, also be in the form of the tautomers thereof.
Preferred salts in the context of the invention are physiologically acceptable salts of the compounds used and prepared in the process according to the invention.
Physiologically acceptable salts of the compounds used and prepared in the process according to the invention include acid on salts of mineral acids, carboxylic acids and sulphonic acids, for e salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, esulphonic acid, sulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, ic acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. _ 22 _ Physiologically acceptable salts of the compounds used and prepared in the process according to the invention also include salts of customary bases, by way of example and with ence alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts d from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, hanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N—methylmorpholine, dihydroabiethylamine, arginine, lysine, ethylenediamine and methylpiperidine.
In the context of the invention, es refer to those forms of the compounds used and prepared in the process according to the invention which, in the solid or liquid state, form a x by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the nation is with water.
In the context of the present invention, the substituents, unless specified otherwise, are each defined as follows: Algl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms. Preferred examples e: , ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert—butyl.
The present invention is illustrated in detail below by non—limiting preferred examples and ative examples. Unless stated otherwise, all amounts given refer to percentages by weight. _ 23 _ The present invention provides a process for preparing compounds of the formula (VI) F (VI), characterized in that the compound of the formula (V) N\ N‘ | N is prepared by reaction of an ester of the formula (IVa) N N \ \ o \ (Na) in which T1 is (C1-C4)-a]kyl with formamide.
The present invention further es a s as described above, characterized in that an ester of the formula (IVa) is prepared by cyclization of the 5-aminopyrazole derivative (Ha) WO 76168 H2N \N \ / (Ha) in which T1 is (C1-C4)-a1ky1 in the ce of an acid and an alkali metal salt with an aldehyde of the a (III) (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 \ ‘ \ A \ N ' ' 'N N— ' ' ' N ' ' ‘ N O \_/ \_/ , , The present invention further provides a process as described above, characterized in that the aldehyde used in the cyclization reaction is the compound of the formula (IIIa) (111a).
The present invention further provides a process for preparing aldehydes of the formula (III) WO 76168 (III) in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, together with the en atom to which they are bonded, are characterized in that trifluoromethanesulphonic anhydride is d with 2,2,3,3-tetrafluoro propanol without solvent and the resulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate is reacted with a compound of the formula (XIIa) 2/NH (XIIa) in which R1 and R2 are each as defined above, to give a compound of the formula (XIIIa) 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) in which R1 and R2 are each as defined above and with sodium hydroxide to give a compound of the formula (XVa) R |+ R1 F CH3SO' in which R1 and R2 are each as defined above and finally converted under basic conditions to give the compound ofthe formula (HI).
The present invention further provides a process for preparing compounds of the formula (Ma) (IIIa), wherein trifluoromethanesulphonic ide of the formula (X) is reacted with 2,2,3,3-tetrafluoro— l-propanol of the formula (XI) t t and the resulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate of the formula (XII) is reacted with line to give a compound of the formula (XIH) 0d F F (XIII) and with methyl methanesulphonate to give a compound of the formula (XIV) CH3803' (XIV) and with sodium hydroxide to give a compound ofthe formula (XV) -27 _ (\NMYKF 0Q F CH3$O - 3 (XV) and finally with addition of morpholine to give the compound ofthe formula (Illa).
The present invention further provides a process for ing the compound of the formula (I) (I), WO 76168 characterized in that nds of the formula (VI) ‘\ \ / /N F (VI) are used, these being characterized in that they are prepared by the process ed above and the resulting compounds 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.
The present invention further provides a process for preparing the compound of the formula (I), characterized in that compounds of the formula WI) N\ N‘ | N F (VI) are used, these being characterized in that they are prepared by the processes specified above and the resulting compounds 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 f.
The t invention further provides a process for preparing the compound of the formula (1), characterized in that compounds of the formula (VI) IN\ N‘ F (VI) are used, these being terized in that they are prepared by the processes specified above and the resulting compounds of the formula (I) are optionally converted with the riate (i) solvents and/or (ii) acids or bases to the es, salts and/or solvates of the salts thereof.
The present invention further provides a process 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 WII) \ ‘ | N XHCI (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 N//N (VIHa) to give the compound of the formula (VIII) - 3o _ \ N‘ | N / N N \ \ NH2 (VIII), and then reducing the latter in an inert solvent in the presence of a suitable reducing agent to give the compound (]X) N N \ \ | N N/ N \ NH2 2 NH2 (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 nd of the a (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 salts thereof.
The present invention further provides the compound of the a (I) in crystalline form of polyrnorph I 2012/073276 H 0’ 3 (1), characterized in that the x-ray ctogram of the compound exhibits peak maxima of the 2 theta angle at 5.9, 6.9, 22.7.
The present invention filrther provides the nd of the formula (I) in polymorph (I) as described above, characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 5.9, 6.9, 16.2, 16.5, 24.1, 22.7, 24.7.
The present invention further provides the compound of the formula (I) in crystalline form of polymorph I H c’ 3 (I), characterized in that the IR spectrum of the compound exhibits band maxima at 1707, 1633, 1475 cm]. 2012/073276 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'l.
The invention further provides a process for preparing the compound of the formula (I) in crystalline form of polymorph 1, 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 a (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 acetate/ethanol/water, isopropanol, a mixture of isopropanol/water, methanol, a mixture of methanol/water, acetonitn'le, e, 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.
The present invention further provides a compound of the formula (I) in polymorph (I) as described above for treatment of ers.
The present ion further provides a ment comprising 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 2O a (I) in polymorph (I) as described above. Medicament comprising a compound of the a (I) in polymorph (I) as described above in more than 90 per cent by weight based on the total amount of the compound ofthe formula (I) t in polymorph (I) as described above.
The present invention fithher provides for the use of the compound of the formula (I) in polymorph (I) as described above for production of a medicament for treatment of cardiovascular disorders.
The present ion further provides the method for treatment of cardiovascular disorders by administering an effective amount of a compound of the formula (I) in rph (I) as described above.
The present invention further provides the compound of the formula (I) as the di-dimethyl sulphoxide solvate l E / / Me/ ‘Me N/ N \ NH2 HZNO NH [(8') # Me/ \Me (1), 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 ion further provides the compound of the formula (I) as the di-dimethyl sulphoxide e, characterized in that the x-ray diffractogram of the compound ts peak maxima ofthe 2 theta angle at 12.0, 16.6, 17.8, 18.8, 20.3, 21.7.
The present invention further provides the compound of the formula (I) as the di-dimethyl sulphoxide solvate | ‘N E / / Me/ \Me N/ N \ NH2 H2NO NH (IS? §< Me/ \Me (1), characterized in that the IR spectrum of the compound exhibits band maxima at 1720, 1628, 1481 cm".
The present invention further provides the compound of the formula (I) as the di-dimethyl sulphoxide solvate, terized in that the IR spectrum of the compound exhibits band maxima at 628,1481,1234,1041,1017 cm'l.
The present invention further provides a process for preparing the compound of the formula (I) as the di-dimethyl sulphoxide solvate in lline 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 yl sulphoxide and an inert solvent, for example ethyl acetate, is stirred at a temperature of - 120°C and the ethyl sulphoxide solvate is isolated. Preference is given to a temperature range of 20 to 90°C.
The present invention further provides the compound of the formula (XIV) CH3SO3' (XIV) and the salts, es and solvates of the salts thereof.
The present invention further provides the compound of the formula (XV) (\N \ F 0Q F CH3SO - and the salts, solvates and solvates of the salts thereof. _ 35 _ A. es Abbreviations: Ac acetyl CI chemical ionization (in MS) DCI direct chemical tion (in MS) DMF dimethylformamide DMSO dimethyl sulphoxide eq. lent(s) ESI electrospray ionization (in MS) Et ethyl GC/MS gas chromatography—coupled mass spectrometry sat. saturated h hour(s) 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 ature Rt retention time (in HPLC) SFC supercritical fluid chromatography THF tetrahydrofuran UV ultraviolet spectrometry v/v volume to volume ratio (of a solution) All x—ray ctometry data were obtained with the following acquisition parameters: Diffractometer system PANalytical XPERT-PRO Scan axis Gonio Anode material Cu K—Alphal [A] 1 .54060 K-Alpha2 [A] 1 .54443 K-A2 / K-Al ratio 0.50000 Scan Mode: Transmission Scan type: 2theta:omega 2theta figure: in 02° All infrared spectroscopy data were obtained with the following acquisition ters: Spectrometer: Perkin Elmer Spectrum One with diamond ATR unit Parameter: 32 scans Resolution: 2 cm'1 Example 1 2,2,3,3-Tetrafluoropropyl romethanesulphonate F O\\S//O /§(|\F F>Fr \o 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 d addition had ended, the reaction mixture was heated to 70°-75°C and d for 2 h. The e 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-tetrafluoro-1—propanol were cooled to 0°C and 106.8 g (0.379 mol) of trifluoromethanesulphonic anhydride were added dropwise 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 nd. 1H NMR (400 MHz, CD013): 6 = 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 Method A: 311.9 g (3.58 mol) of morpholine were dissolved in 290 m1 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 e 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 nd. 1H NMR (400 MHz, CDC13): 8 = 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 morpholine 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 e was stirred at 5° - 10°C for 30 min. The reaction mixture was heated to 40°C and stirred for 1 h. After cooling 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 nd.
Example 3 4-Methyl(2,2,3,3-tetrafluoropropyl)morpholin—4-ium methanesulphonate 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 isopropanol were added. After cooling to 0° - 5°C, the mixture was stirred for a r 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 theory) of the title compound. 1H NMR (400 MHz, D20): 5 = 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, l H) ppm. _ 39 _ Method B: .0 g (181.3 mmol) of methyl methanesulphonate were heated to 135°C and, at this temperature, .1 g (172.7 mmol) of the compound from e 2 were added dropwise. The mixture was stirred at 135°C for 3 h and then 40 m1 of water were added. Afier cooling to 50°C, the aqueous solution of the title compound was used in the subsequent stage (see Example 4).
Example 4 4-Methyl[2,3 ,3 -trifluoropropen-1 -y1]morpholinium methanesulphonate pN \ 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 mol) at 50° - 55°C, and the e was stirred at 50°C for 1 h. The on mixture was cooled to 20°C and the precipitated salts were filtered off with suction and washed with 5 ml of water. The s product solution (102.1 g; max. 172.7 mmol) was used in the subsequent stage (see Example 5).
For analytical purposes, a sample was concentrated and dried. 1H NMR (400 MHz, D20): 5 = 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-3 -(morpholin—4-yl)acry1aldehyde Method A: An aqueous solution 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 ylamine 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 mixture of 290 m1 of dichloromethane and 100 ml of triethylamine, and the combined c phases were d, washed with 250 m1 of sat. aqueous potassium carbonate solution and concentrated on a rotary ator at 40°C. 50 m1 of toluene were added and the mixture was concentrated r. This gave 34.2 g (81.9% of theory) of the title 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 on 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 e were added and the mixture was trated further. This gave 35.3 g (83.4% of theory) of the title compound. 1H NMR (500 MHz, CDC13): 5 = 3.51 - 3.60 (m, 4 H) 3.72 - 3.83 (m, 4 H) 6.16 (d, J=27.1Hz, 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 se 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 dichloromethane and 15 ml of triethylamine, and the combined organic phases were washed with 85 ml of sat. aqueous potassium carbonate solution and concentrated under reduced pressure at 45° - 50°C. 120 m1 of toluene and 60 m1 of toluene were distilled off.
The suspension was stirred at room ature overnight, and the product was filtered off with suction and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 19.2 g (68.3% of theory) of the title compound.
Example 6 Ethyl 5-fluoro-l -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridine-3 -carboxylate \ \ l/ N Method A: 22.3 g (84.8 mmol) of ethyl 5-amino-l-(2-fluorobenzyl)-lH-pyrazolecarboxylate (preparation described for Example 20A in WO 69) 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 temperature, the product was filtered off with suction, washed twice with 4.5 ml of ethanol and stirred with 325 m1 of water for l h. The solids were filtered off with suction, washed twice with 11.5 ml of water and dried in a vacuum drying cabinet 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-dfi): 5 = 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 (5 br., 1H) ppm.
Method B: 27.0 g (635.2 mmol) of lithium chloride and 42.2 g (254.1 mmol) of the compound from Example were initially charged in 75 ml of l and heated to reflux ature. At this temperature, a solution of 66.9 g (254.1 mmol) of ethyl 5—amino(2-fluorobenzyl)-lH-pyrazolecarboxylate (preparation described for Example 20A in WO 00/06569) and 33.0 ml (508.2 mmol) of methanesulphonic acid in 180 m1 of l were added within 10 min. The mixture was stirred at reflux ature for 2 h, then 120 ml of panol were added, the mixture was cooled to 62°C, 0.6 g of the title nd 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 suction, washed with 180 ml of water, stirred with 300 m1 of water for 0.5 h, filtered off with suction, washed with 300 m1 of water and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 65.1 g (80.7% of theory) of the title compound.
Method C: WO 76168 .42 g (20.6 mmol) of ethyl 5-amino(2-fluorobenzyl)-1H-pyrazolecarboxylate (preparation described for e 20A in WO 00/06569) were initially charged in 20 m1 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 Example 5 in 50 m1 of l at reflux temperature within 10 min.
The mixture was stirred at reflux temperature for 2 h, then 10 m1 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 nd.
Example 7 ro—1-(2-fluorobenzyl)-1H-pyrazolo[3,4—b]pyrid'me—3-carboxamide 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 on 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 nitrogen 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-dé): a = 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-l -(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3—carbonitrile W0 2013/076168 N\ N‘ l N 17.3 g (60.0 mmol) of the compound obtained in e 7 were heated to 103° - 107°C in 40.5 ml of lane 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 m1 of acetonitrile, then the mixture was stirred at 107°C for 1.5 h until sion was complete (HPLC). Thereafter, the mixture was cooled to room temperature, and 2.8 m1 of sulpholane/acetonitrile (5:1 vol/vol) and then 17.8 ml of water were added dropwise. The mixture 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 mixture 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 cabinet at 50°C under a gentle nitrogen stream. This gave 14.7 g (91.9% of theory) of the title compound.
MS (ESIpos): m/z = 271 (M+H)+ 1H NMR (400 MHZ, DMSO-d6): 8 = 5.87 (s, 2H), 7.17 — 7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H) ppm.
Example 9 -Fluoro- 1 uorobenzyl)- 1H-pyrazolo[3,4-b]pyridinecarboximidamide hydrochloride NH x HCI 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 ide in ol (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 1 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 ) of the title compound.
MS (ESIpos): m/z = 288 (M+H)+ 1H NMR (400 MHz, DMSO-d6): 8 = 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 m1 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 solution of 87.1 g (1.26 mol) of sodium nitrite in 222.5 ml of water was added dropwise within 1 h and rinsed in with 60 m1 of water, and the mixture was d 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 m1 of water (19 ml) was added dropwise within 45 min and rinsed in with 60 m1 of water, and a solution of 83.4 g (1.26 mol) of malononitrile in 233 m1 of ethanol was added se within 1 h. 68.5 ml of l 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 m1 of cold toluene.
The still-moist residue was dissolved in 872 g of DMF. This gave 1117.0 g of DMF on of the title compound.
Method B: _ 45 _ 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 m1 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 m1 of water, and the mixture was d 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 m1 of water was added dropwise within 45 min and rinsed in with 20 m1 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 m1 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 m1 of cold e. 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 solution of the title compound.
Example 11 2-[5-F1u0ro(2-fluorobenzyl)-1H-pyrazolo[3,4—b]pyridin—3-y1][(E)- phenyldiazenyl]pyrimidine-4,6-diamine \ N‘ I N N/\N \ NHZ 2 //N Method A: 448.2 g (1.38 mol) of the compound from Example 9 were suspended in 1059 ml of DMF. The mixture was heated to 85°C and 212 ml (1.52 mol) of triethylamine 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 m1 of DMF, and the mixture was stirred at 100°C ght.
The on mixture was cooled to RT, 656 m1 of water were added dropwise and the mixture was ~46- stirred at RT for 0.5 h, then cooled to 0° - 5°C and d 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 m1 of methanol, 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 ) of the title compound. 1H NMR (400 MHz, DMSO-dé): 5 = 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, l 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 m1 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 m1 of DMF were used to rinse it in and the mixture was stirred at 100°C for 20 h. The reaction e 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 methanol, 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 mrnol) 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 m1 (39.6 mmol) of triethylamine and 27.7 g of the sulpholane solution from Example 10 Method B was added dropwise at this temperature within 35 min. 2 m1 of sulpholane were used to rinse it in and the mixture was stirred at 100°C for 2.5 h. The reaction e was cooled to 60°C, 90 ml of panol 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 m1 of isopropanol, suction- dried 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—l ~(2-fluor0benzyl)-lH-pyrazolo[3,4-b]pyridin—3-yl]pyrimidine-4,5,6-triamine W0 2013/076168 \ \ l/ N N/ N \ NH2 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 ght. The mixture was filtered through kieselguhr 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 ol 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 suction, 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 subsequent stage. According to the ity of the water wash, the DMF content was in the range of 10 — 17% by .
Method B: .0 g of the DMF-containing solids from Method A were suspended in 220 m1 of water and filtered with suction through a suction filter. 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-dé): 6 = 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-l or0benzyl)-lH—pyrazolo[3,4-b]pyridinyl]pyrimidin-5— yl} carbamate N\ N\ | N N/ N \ NH2 HN\(0 0\CH3 Method A: 4.0 g (77.0% by weight, 8.36 mmol) of the compound from e 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 m1 of triethylamine were added dropwise within 0.5 h and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50°C for 1 h. Thereafter, the reaction mixture was cooled to RT and stirred at RT for l 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 m1 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 hot- filtered and the filter residue was washed with 1.9 ml of ethyl acetate". 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 r 1 h. The solids were filtered 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.
WO. 2013/076168 MS (ESIpos): m/z = 427 (M+H)+ 1H NMR (400 MHz, DMSO—dé): 5 = 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) According to the preparation s described, the cthyl sulnhoxide 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 a (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 (1).
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 m1 (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 m1 of water were added and the mixture was stirred for 2.5 h.
The solids were filtered 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 t.
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 m1 (14.1 mmol) of methyl chloroforrnate were added dropwise. The mixture was stirred at 35° - 40°C for 16.5 h, and 9.5 ml of ol 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 mixture 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 ol, 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 acetate 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 residue was washed with 4.4 ml of ethyl acetate. 138 m1 of ethyl acetate were heated to 50°C, and the combined filtrates were added dropwise and stirred at 45 - 50°C for l 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 t".
Method B: 2.0 g of the di-dimethyl sulphoxide 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 present in polymorph 1.
Method F: 0.5 g of the di—dimethyl sulphoxide solvate were stirred at reflux temperature in 12.5 ml of solvent for 17 h, cooled to RT and d for a further 1 h. The solids were filtered off with suction, washed with 2 m1 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 m1 of ethyl acetate/3.5 ml of ethanol/0.3 ml of water 2.) 12.5 ml of panol 3.) 12.5 ml of isopropanol/0.3 ml of water 4.) 12.5 ml ofmethanol .) 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 ions of the x-ray diffractogram. Table 3 shows the bands of the IR spectrum.
WO 76168 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 nd of the formula (I) can be prepared by processes described above. This affords the compound of the formula (I) in a crystal polymorph referred to hereinafter as polymorph I. rph I has a melting point of 257°C and a characteristic x-ray ctogram featuring the reflections (2 theta) 5.9, 6.9, 16.2, 16.5, 24.1 and 24.7, and a characteristic IR spectrum featuring the band maxima (in cm'l) 1707, 1633, 1566, 1475, 1255 and 1223 (Tables 1 and 3, s 1 and singly, four further polymorphs, a monohydrate, a dihydrate, a DMF/water solvate and a didimethyl sulphoxide solvate, and also a triacetic acid solvate of the compound of the formula (I) were found. The nd 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 melting point of 234°C. The monohydrate contains approx. 4.1% water, the dihydrate contains 7.8% water, the DMF/Water solvate contains 13.6% dimethylformamide and 0.9 % water, the di-DMSO solvate contains 26.8% dimethyl sulphoxide and the triacetic acid solvate ns 29.7% acetate. Each of the crystalline forms mentioned has a teristic x-ray diffractogram and IR spectrum (Tables 2 and 3, Figures 1 - 4, 6 - 14).
Table 1: X—rax diffractomet_rx for polmomhs I to V Polymorph I Polymorph H Polymorph III Polymorph IV rph V "m- ~ 00 L») QUIKIIUJ . - b-fi-HN 23.5 N00 [\J 24.4 ' 26.3 27.9 28.3 29.3 .3 Table 2: X-rax diffractometlx for polmogph hydrates and es Monohydrate Dihydrate DMF/water Acetic acid [2 theta] [2 theta] solvate solvate [2 theta] [2 theta] U1 \0 00 N U] U) .9 11.0 7 _N \O U) "--10.0 .7 11.0 24.1 24.4 24.8 .5 26.5 WO 76168 258 33.4 261 33 9 Table 3: IR spectra of polmorphs I to V Band maxima Polymorph I Polymorph H Polymorph III rph IV Polymorph V [cm 1]- [cm 1]- [cm 1]- [cm4 ] [ml] 899 903 913 936 933 935 955 1059 958 954 1058 1072 1031 1034 1077 1112 1067 1059 1104 1157 1082 1075 1161 1057 1208 1111 1103 1207 1083 1223 1202 1161 1255 1223 1206 1305 1249 1319 1264 1237 1353 1305 1253 1370 1349 1278 1435 1368 1319 1475 1436 1355 1566 1456 1370 1620 1480 1424 1633 1566 1437 1707 1620 1458 2956 1704 1476 3130 2953 1489 3277 3132 1570 3332 3278 1587 WO 76168 Monohydrate Dihydrate DMF/water Acetic acid [cm'l] [cm'l] solvate solvate [0111.1] ' [cm’l] 761 760 745 778 762 774 774 771 811 777 810 809 812 873 801 834 835 846 902 835 873 874 867 953 872 912 913 896 918 953 937 932 941 Figure 1: IR spectrum of the compound of the a (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 a (I) as the di—DMSO solvate, DMF/water e and drate 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 polymorph 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 diffractogram of the compound of the formula (I) in polymorph IV Figure 9: X-ray diffractogram of the compound of the formula (I) in polymorph V Figure 10: X—ray diffractogram 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 a (I) as the dihydrate
Claims (15)
1. Compound of the formula (I) in crystalline form of rph I N N 2 NH 3 (I), 5 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.
2. Compound according to Claim 1, characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 5.9, 6.9, 16.2, 16.5, 24.1, 22.7, 24.7. 10 3. 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.
4. Compound according to Claim 3, characterized in that the IR spectrum of the compound 5 exhibits band maxima at 1707, 1633, 1566, 1475, 1255, 1223 cm-1.
5. Process for preparing the compound of the formula (I) N N 2 NH 3 (I), in crystalline form of polymorph I, terized in that the compound of the formula (I), present 10 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 rph I.
6. Compound in crystalline form of polymorph I according to any one of Claims 1 to 4 for treatment of ers. 15
7. Medicament comprising a compound in crystalline form of polymorph I according to any one of Claims 1 to 4 and no greater tions of any other form of the compound of the formula (I).
8. Medicament comprising a nd in crystalline form of polymorph I according to any one of Claims 1 to 4 in more than 90 per cent by weight based on the total amount of the 20 compound of the formula (I) present.
9. Use of the compound in crystalline form of polymorph I according to any one of Claims 1 to 4 for production of a medicament for treatment of cardiovascular disorders.
10. A compound according to claim 1, substantially as herein described or exemplified.
11. A compound according to claim 3, substantially as herein described or exemplified.
12. A process according to claim 5, substantially as herein described or exemplified.
13. A ment according to claim 7, substantially as herein described or exemplified.
14. A medicament according to claim 8, substantially as herein described or exemplified. 5
15. A use according to claim 9, ntially as herein described or exemplified.
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