SK285215B6 - Spôsob prípravy sildenafilu a jeho medziprodukty - Google Patents
Spôsob prípravy sildenafilu a jeho medziprodukty Download PDFInfo
- Publication number
- SK285215B6 SK285215B6 SK1385-99A SK138599A SK285215B6 SK 285215 B6 SK285215 B6 SK 285215B6 SK 138599 A SK138599 A SK 138599A SK 285215 B6 SK285215 B6 SK 285215B6
- Authority
- SK
- Slovakia
- Prior art keywords
- tertiary
- compound
- alkanol
- formula
- ethanol
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 title claims description 26
- 229960003310 sildenafil Drugs 0.000 title claims description 8
- 239000000543 intermediate Substances 0.000 title description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract 2
- 150000002367 halogens Chemical class 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 13
- 239000002184 metal Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 239000012442 inert solvent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 125000006529 (C3-C6) alkyl group Chemical group 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229910052987 metal hydride Inorganic materials 0.000 claims description 4
- 150000004681 metal hydrides Chemical class 0.000 claims description 4
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 3
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- JYUXDXWXTPSAEL-UHFFFAOYSA-N 1,4-dioxane;oxolane Chemical compound C1CCOC1.C1COCCO1 JYUXDXWXTPSAEL-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000011737 fluorine Chemical group 0.000 claims 1
- 229910044991 metal oxide Inorganic materials 0.000 claims 1
- 150000004706 metal oxides Chemical class 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 239000002585 base Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- BMLPAJIEDKJHSB-UHFFFAOYSA-N 2-methyl-4-nitro-5-propylpyrazole-3-carboxamide Chemical compound CCCC1=NN(C)C(C(N)=O)=C1[N+]([O-])=O BMLPAJIEDKJHSB-UHFFFAOYSA-N 0.000 description 5
- PZMXDLWWQHYXGY-UHFFFAOYSA-N 4-amino-1-methyl-3-propylpyrazole-5-carboxamide Chemical compound CCCC1=NN(C)C(C(N)=O)=C1N PZMXDLWWQHYXGY-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- -1 alkaline earth metal salt Chemical class 0.000 description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- CLHNTBSDCJLCKV-UHFFFAOYSA-N 2-chloro-5-chlorosulfonylbenzoic acid Chemical compound OC(=O)C1=CC(S(Cl)(=O)=O)=CC=C1Cl CLHNTBSDCJLCKV-UHFFFAOYSA-N 0.000 description 2
- TWHOPPVZRQGQPO-UHFFFAOYSA-N 2-fluoro-5-(4-methylpiperazin-4-ium-1-yl)sulfonylbenzoate Chemical compound C1CN(C)CCN1S(=O)(=O)C1=CC=C(F)C(C(O)=O)=C1 TWHOPPVZRQGQPO-UHFFFAOYSA-N 0.000 description 2
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 2
- WKHHHZDKDHGOOA-UHFFFAOYSA-N 2-methoxy-5-(4-methylpiperazin-1-yl)sulfonylbenzoic acid Chemical compound C1=C(C(O)=O)C(OC)=CC=C1S(=O)(=O)N1CCN(C)CC1 WKHHHZDKDHGOOA-UHFFFAOYSA-N 0.000 description 2
- CISMZCVQNVNWJW-UHFFFAOYSA-N 5-chlorosulfonyl-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC(S(Cl)(=O)=O)=CC=C1F CISMZCVQNVNWJW-UHFFFAOYSA-N 0.000 description 2
- OUBZCDOQEMLMAB-UHFFFAOYSA-N 5-chlorosulfonyl-2-methoxybenzoic acid Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1C(O)=O OUBZCDOQEMLMAB-UHFFFAOYSA-N 0.000 description 2
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical compound COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- PXQSTAPXZKXDIT-UHFFFAOYSA-N 2-chloro-5-(4-methylpiperazin-4-ium-1-yl)sulfonylbenzoate Chemical compound C1CN(C)CCN1S(=O)(=O)C1=CC=C(Cl)C(C(O)=O)=C1 PXQSTAPXZKXDIT-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- YJESALUAHUVISI-UHFFFAOYSA-N 3,5-dimethylhexan-2-one Chemical compound CC(C)CC(C)C(C)=O YJESALUAHUVISI-UHFFFAOYSA-N 0.000 description 1
- ZZLCFHIKESPLTH-UHFFFAOYSA-N 4-Methylbiphenyl Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 description 1
- OMNAXWNQKWRJQM-UHFFFAOYSA-N 4-[[2-chloro-5-(4-methylpiperazin-1-yl)sulfonylbenzoyl]amino]-2-methyl-5-propylpyrazole-3-carboxamide Chemical compound CCCC1=NN(C)C(C(N)=O)=C1NC(=O)C1=CC(S(=O)(=O)N2CCN(C)CC2)=CC=C1Cl OMNAXWNQKWRJQM-UHFFFAOYSA-N 0.000 description 1
- ZRSDFTNDDQYARE-UHFFFAOYSA-N 4-[[2-methoxy-5-(4-methylpiperazin-1-yl)sulfonylbenzoyl]amino]-2-methyl-5-propylpyrazole-3-carboxamide Chemical compound CCCC1=NN(C)C(C(N)=O)=C1NC(=O)C1=CC(S(=O)(=O)N2CCN(C)CC2)=CC=C1OC ZRSDFTNDDQYARE-UHFFFAOYSA-N 0.000 description 1
- JLIQOBRCRLKVPG-UHFFFAOYSA-N 5-[2-chloro-5-(4-methylpiperazin-1-yl)sulfonylphenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)Cl)=CC=1S(=O)(=O)N1CCN(C)CC1 JLIQOBRCRLKVPG-UHFFFAOYSA-N 0.000 description 1
- HXXSYMNSLDJBEU-UHFFFAOYSA-N 5-[2-methoxy-5-(4-methylpiperazin-1-yl)sulfonylphenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OC)=CC=1S(=O)(=O)N1CCN(C)CC1 HXXSYMNSLDJBEU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OUPYODDWWCXJGQ-UHFFFAOYSA-N CCCC1=NN(C)C(C(N)=O)=C1NC(=O)C1=CC(S(=O)(=O)N2CCN(C)CC2)=CC=C1F Chemical compound CCCC1=NN(C)C(C(N)=O)=C1NC(=O)C1=CC(S(=O)(=O)N2CCN(C)CC2)=CC=C1F OUPYODDWWCXJGQ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229910052790 beryllium Inorganic materials 0.000 description 1
- ATBAMAFKBVZNFJ-UHFFFAOYSA-N beryllium atom Chemical compound [Be] ATBAMAFKBVZNFJ-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- OIYLDISFBUJSNS-UHFFFAOYSA-N non-5-enal Chemical compound CCCC=CCCCC=O OIYLDISFBUJSNS-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D295/22—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 hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Reproductive Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9822238.3A GB9822238D0 (en) | 1998-10-12 | 1998-10-12 | Process for preparation of pyrazolo[4,3-D]pyrimidin-7-ones and intermediates thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SK138599A3 SK138599A3 (en) | 2000-05-16 |
| SK285215B6 true SK285215B6 (sk) | 2006-09-07 |
Family
ID=10840421
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK1385-99A SK285215B6 (sk) | 1998-10-12 | 1999-10-08 | Spôsob prípravy sildenafilu a jeho medziprodukty |
Country Status (48)
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000078760A1 (fr) * | 1999-06-21 | 2000-12-28 | The Biochemical Pharmaceutical Factory Of Zhuhai Sez | Procede de preparation de sildenafil, agent et procede d'obtention d'un comprime mixte a base de sildenafil et de chlorhydrate d'apomorphine |
| US6667398B2 (en) | 2000-06-22 | 2003-12-23 | Pfizer Inc | Process for the preparation of pyrazolopyrimidinones |
| IL153532A0 (en) * | 2000-06-22 | 2003-07-06 | Pfizer | Process for the preparation of pyrazolopyrimidinones |
| EP1176147A1 (en) * | 2000-07-28 | 2002-01-30 | Pfizer Limited | Process for the preparation of pyrazolo[4,3-d]pyrimidin-7-ones and intermediates thereof |
| EP1176142A1 (en) * | 2000-07-28 | 2002-01-30 | Pfizer Inc. | Process for the preparation of pyrazoles |
| US6407259B1 (en) | 2000-07-28 | 2002-06-18 | Pfizer Inc. | Process for the preparation of pyrazoles |
| PE20020394A1 (es) | 2000-08-18 | 2002-06-21 | Agouron Pharma | Compuestos de pirazol y composiciones farmaceuticas que los contienen, que modulan y/o inhiben la actividad de erab/hadh2 |
| IL162602A0 (en) | 2001-12-20 | 2005-11-20 | Applied Research Systems | Pyrrolidine derivatives as prostaglandin modulators |
| AU2002367023A1 (en) * | 2001-12-21 | 2003-07-30 | Cytokinetics, Inc. | Compositions and methods for treating heart failure |
| EP1719772A1 (en) | 2002-05-31 | 2006-11-08 | Schering Corporation | Process for preparing xanthine phosphodiesterase v inhibitors and precursors thereof |
| WO2004072079A1 (en) * | 2003-02-11 | 2004-08-26 | Pfizer Limited | Hydrated and anhydrous sildenafil hemi-citrate compound |
| EP1605752B1 (en) * | 2003-03-27 | 2011-09-14 | Cytokinetics, Inc. | Sulfonamides for the treatment of congestive heart failure, their compositions and uses. |
| CN100360531C (zh) * | 2003-12-18 | 2008-01-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 用于预防或治疗阳萎和性冷淡的新吡唑并嘧啶类化合物 |
| US20070010525A1 (en) * | 2005-06-27 | 2007-01-11 | Meyer Jackson | Method and compositions for modulating neuropeptide hormone secretion |
| NL2000291C2 (nl) * | 2005-11-10 | 2009-02-17 | Pfizer Prod Inc | 1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H- pyrazool(4,3-d)pyrimidine-5-yl)piperidine-4-carbonzuur en zouten daarvan. |
| WO2007141805A2 (en) * | 2006-06-05 | 2007-12-13 | Matrix Laboratories Limited | Novel process for the preparation of sildenafil citrate |
| CZ308056B6 (cs) * | 2015-07-20 | 2019-11-27 | Ustav Experimentalni Botaniky Av Cr V V I | 5-Substituované-7-[4-(substituované)benzyl]amino-3-isopropylpyrazolo[4,3-d]pyrimidiny, jejich použití jako antirevmatika, a farmaceutické přípravky |
| WO2017168174A1 (en) | 2016-04-02 | 2017-10-05 | N4 Pharma Uk Limited | New pharmaceutical forms of sildenafil |
| CN107759603B (zh) * | 2016-08-18 | 2020-09-01 | 四川科伦药物研究院有限公司 | 一种杂环化合物的制备方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3992441A (en) * | 1972-12-26 | 1976-11-16 | Pfizer Inc. | Sulfamylbenzoic acids |
| GB9013750D0 (en) * | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
| GB9612514D0 (en) * | 1996-06-14 | 1996-08-14 | Pfizer Ltd | Novel process |
| EA002057B1 (ru) * | 1997-04-25 | 2001-12-24 | Пфайзер Инк. | ПИРАЗОЛОПИРИМИДИНОНЫ, КОТОРЫЕ ИНГИБИРУЮТ ЦИКЛИЧЕСКИЙ ГУАНОЗИН-3',5'-МОНОФОСФАТ-ФОСФОДИЭСТЕРАЗУ ТИПА 5 (cGMP PDE5), ДЛЯ ЛЕЧЕНИЯ СЕКСУАЛЬНОГО РАССТРОЙСТВА |
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1998
- 1998-10-12 GB GBGB9822238.3A patent/GB9822238D0/en not_active Ceased
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1999
- 1999-09-22 CU CU1999142A patent/CU22928A3/es unknown
- 1999-09-22 TW TW088116306A patent/TW589314B/zh not_active IP Right Cessation
- 1999-09-27 RS YUP-489/99A patent/RS49762B/sr unknown
- 1999-10-05 GT GT199900172A patent/GT199900172A/es unknown
- 1999-10-06 CZ CZ0353299A patent/CZ296816B6/cs not_active IP Right Cessation
- 1999-10-07 IL IL15292399A patent/IL152923A/en not_active IP Right Cessation
- 1999-10-07 AP APAP/P/1999/001672A patent/AP1233A/en active
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- 1999-10-07 PE PE1999001016A patent/PE20001086A1/es not_active Application Discontinuation
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- 1999-10-07 IL IL13227399A patent/IL132273A/en not_active IP Right Cessation
- 1999-10-07 CR CR6118A patent/CR6118A/es unknown
- 1999-10-08 SK SK1385-99A patent/SK285215B6/sk not_active IP Right Cessation
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- 1999-10-08 CA CA002285733A patent/CA2285733C/en not_active Expired - Lifetime
- 1999-10-08 UA UA99105491A patent/UA66787C2/xx unknown
- 1999-10-08 US US09/415,440 patent/US6207829B1/en not_active Expired - Fee Related
- 1999-10-09 CN CNA031427383A patent/CN1473831A/zh active Pending
- 1999-10-09 CN CNB991239180A patent/CN1207295C/zh not_active Expired - Fee Related
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- 1999-10-11 BG BG103794A patent/BG63205B1/bg unknown
- 1999-10-11 DZ DZ990212A patent/DZ2912A1/xx active
- 1999-10-11 KR KR10-1999-0043836A patent/KR100380954B1/ko not_active Expired - Fee Related
- 1999-10-11 ES ES99307996T patent/ES2237049T3/es not_active Expired - Lifetime
- 1999-10-11 PT PT99307996T patent/PT994115E/pt unknown
- 1999-10-11 DE DE69923906T patent/DE69923906T2/de not_active Expired - Lifetime
- 1999-10-11 AU AU53581/99A patent/AU756463B2/en not_active Ceased
- 1999-10-11 NO NO19994943A patent/NO313700B1/no not_active IP Right Cessation
- 1999-10-11 ZA ZA9906412A patent/ZA996412B/xx unknown
- 1999-10-11 EG EG126999A patent/EG22630A/xx active
- 1999-10-11 HU HU9903469A patent/HU226162B1/hu not_active IP Right Cessation
- 1999-10-11 BR BR9905092-7A patent/BR9905092A/pt not_active IP Right Cessation
- 1999-10-11 TN TNTNSN99189A patent/TNSN99189A1/fr unknown
- 1999-10-11 ID IDP990941A patent/ID23351A/id unknown
- 1999-10-11 EA EA199900822A patent/EA003774B1/ru not_active IP Right Cessation
- 1999-10-12 HR HR990318A patent/HRP990318B1/xx not_active IP Right Cessation
- 1999-10-12 PL PL335959A patent/PL198150B1/pl not_active IP Right Cessation
- 1999-10-12 EE EEP199900507A patent/EE04192B1/xx not_active IP Right Cessation
- 1999-10-12 UY UY25750A patent/UY25750A1/es not_active Application Discontinuation
- 1999-10-12 TR TR1999/02541A patent/TR199902541A2/xx unknown
- 1999-10-12 SG SG1999005097A patent/SG118060A1/en unknown
- 1999-10-12 JP JP29009999A patent/JP3721021B2/ja not_active Expired - Fee Related
- 1999-10-12 CO CO99064776A patent/CO5150214A1/es unknown
- 1999-10-12 GE GEAP19995027A patent/GEP20022700B/en unknown
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2001
- 2001-01-16 US US09/761,376 patent/US20010009962A1/en not_active Abandoned
-
2002
- 2002-09-23 US US10/253,029 patent/US20030069422A1/en not_active Abandoned
- 2002-11-18 IL IL15292402A patent/IL152924A0/xx unknown
- 2002-11-18 IL IL15292802A patent/IL152928A0/xx active IP Right Grant
- 2002-11-18 IL IL15292602A patent/IL152926A0/xx unknown
- 2002-11-18 IL IL15292702A patent/IL152927A0/xx unknown
- 2002-11-18 IL IL15292302A patent/IL152923A0/xx unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed due to non-payment of maintenance fees |
Effective date: 20111008 |