HU223950B1 - Eljárás a racém, valamint az R-(-)- és S-(+)-N-[4-ciano-3-(trifluor-metil)-fenil]-3-[(4-fluor-fenil)-szulfonil]-2-hidroxi-2-metil-propánsavamid előállítására - Google Patents
Eljárás a racém, valamint az R-(-)- és S-(+)-N-[4-ciano-3-(trifluor-metil)-fenil]-3-[(4-fluor-fenil)-szulfonil]-2-hidroxi-2-metil-propánsavamid előállítására Download PDFInfo
- Publication number
- HU223950B1 HU223950B1 HU9901937A HUP9901937A HU223950B1 HU 223950 B1 HU223950 B1 HU 223950B1 HU 9901937 A HU9901937 A HU 9901937A HU P9901937 A HUP9901937 A HU P9901937A HU 223950 B1 HU223950 B1 HU 223950B1
- Authority
- HU
- Hungary
- Prior art keywords
- racemic
- formula
- cyano
- optically pure
- trifluoromethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 50
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000003568 thioethers Chemical class 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- OKIHXNKYYGUVTE-UHFFFAOYSA-N 4-Fluorothiophenol Chemical compound FC1=CC=C(S)C=C1 OKIHXNKYYGUVTE-UHFFFAOYSA-N 0.000 claims abstract description 11
- -1 sulfonic acid halide Chemical class 0.000 claims abstract description 11
- PMDYLCUKSLBUHO-UHFFFAOYSA-N 4-amino-2-(trifluoromethyl)benzonitrile Chemical compound NC1=CC=C(C#N)C(C(F)(F)F)=C1 PMDYLCUKSLBUHO-UHFFFAOYSA-N 0.000 claims abstract description 9
- IIBBSRFFFOOJBY-UHFFFAOYSA-N n-[4-cyano-3-(trifluoromethyl)phenyl]-2,3-dihydroxy-2-methylpropanamide Chemical compound OCC(O)(C)C(=O)NC1=CC=C(C#N)C(C(F)(F)F)=C1 IIBBSRFFFOOJBY-UHFFFAOYSA-N 0.000 claims abstract description 8
- CIJRBLJATSUYTM-UHFFFAOYSA-N 3,4-dihydroxy-3-methylbutanoic acid Chemical compound OCC(O)(C)CC(O)=O CIJRBLJATSUYTM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract description 7
- 150000003459 sulfonic acid esters Chemical class 0.000 claims abstract description 7
- AUQOJOMQBSXVBP-UHFFFAOYSA-N n-[4-cyano-3-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3,2-dioxathiolane-4-carboxamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C1(C)COS(=O)O1 AUQOJOMQBSXVBP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 15
- 238000007254 oxidation reaction Methods 0.000 claims description 15
- 239000003444 phase transfer catalyst Substances 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 230000003647 oxidation Effects 0.000 claims description 12
- 239000002609 medium Substances 0.000 claims description 10
- RLYHGDXBALNOJK-UHFFFAOYSA-N 4-methyl-2-oxo-1,3,2-dioxathiolane-4-carbonyl chloride Chemical compound ClC(=O)C1(C)COS(=O)O1 RLYHGDXBALNOJK-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
- 239000002253 acid Substances 0.000 claims description 9
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical group OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 9
- 150000008282 halocarbons Chemical class 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 150000003512 tertiary amines Chemical class 0.000 claims description 8
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical group [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 4
- 150000004982 aromatic amines Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000000864 peroxy group Chemical group O(O*)* 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052720 vanadium Inorganic materials 0.000 claims description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 239000004215 Carbon black (E152) Substances 0.000 claims 2
- 229930195733 hydrocarbon Natural products 0.000 claims 2
- 150000002430 hydrocarbons Chemical class 0.000 claims 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims 1
- 230000006103 sulfonylation Effects 0.000 claims 1
- 238000005694 sulfonylation reaction Methods 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
- 229960000997 bicalutamide Drugs 0.000 abstract description 11
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 abstract description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 17
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- DGADNPLBVRLJGD-UHFFFAOYSA-N 2,3-dihydroxy-2-methylpropanoic acid Chemical compound OCC(O)(C)C(O)=O DGADNPLBVRLJGD-UHFFFAOYSA-N 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- DGADNPLBVRLJGD-SCSAIBSYSA-N (2r)-2,3-dihydroxy-2-methylpropanoic acid Chemical compound OC[C@](O)(C)C(O)=O DGADNPLBVRLJGD-SCSAIBSYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- CTYJERNWLVBMTF-UHFFFAOYSA-N 3-(4-fluorophenyl)sulfanyl-2-hydroxy-2-methylpropanoic acid Chemical compound OC(=O)C(O)(C)CSC1=CC=C(F)C=C1 CTYJERNWLVBMTF-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- GCGWWKKSGPETMI-UHFFFAOYSA-N n-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfanyl-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CSC1=CC=C(F)C=C1 GCGWWKKSGPETMI-UHFFFAOYSA-N 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- HBJAYXGUOOININ-SCSAIBSYSA-N (2s)-3-bromo-2-hydroxy-2-methylpropanoic acid Chemical compound BrC[C@](O)(C)C(O)=O HBJAYXGUOOININ-SCSAIBSYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000006735 epoxidation reaction Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- UXEPFHXAGWAYPF-UHFFFAOYSA-N dioxathiolane Chemical class C1CSOO1 UXEPFHXAGWAYPF-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002360 explosive Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- OSYXXQUUGMLSGE-UHFFFAOYSA-N methyl 2-methyloxirane-2-carboxylate Chemical compound COC(=O)C1(C)CO1 OSYXXQUUGMLSGE-UHFFFAOYSA-N 0.000 description 3
- ADWWGHQIQLUIHA-UHFFFAOYSA-N methyl 3-(4-fluorophenyl)sulfanyl-2-hydroxy-2-methylpropanoate Chemical compound COC(=O)C(C)(O)CSC1=CC=C(F)C=C1 ADWWGHQIQLUIHA-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 150000002924 oxiranes Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 229960003604 testosterone Drugs 0.000 description 3
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical compound CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 2
- 229960002074 flutamide Drugs 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 2
- JFUFHTFAGLUHNE-UHFFFAOYSA-M sodium;2,3-dihydroxy-2-methylpropanoate Chemical compound [Na+].OCC(O)(C)C([O-])=O JFUFHTFAGLUHNE-UHFFFAOYSA-M 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- CMPGARWFYBADJI-UHFFFAOYSA-L tungstic acid Chemical compound O[W](O)(=O)=O CMPGARWFYBADJI-UHFFFAOYSA-L 0.000 description 2
- JEIWMMMVZOQQHT-TYICEKJOSA-N (1r)-1,2,2-trimethylcyclopentane-1,3-dicarbonyl chloride Chemical compound CC1(C)C(C(Cl)=O)CC[C@@]1(C)C(Cl)=O JEIWMMMVZOQQHT-TYICEKJOSA-N 0.000 description 1
- SJAYUJDJZUWFDO-SSDOTTSWSA-N (2r)-1-(2-methylprop-2-enoyl)pyrrolidine-2-carboxylic acid Chemical compound CC(=C)C(=O)N1CCC[C@@H]1C(O)=O SJAYUJDJZUWFDO-SSDOTTSWSA-N 0.000 description 1
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- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
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- VYKVTAIYHHOYBV-UHFFFAOYSA-N [3-[4-cyano-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxopropyl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC(C)(O)C(=O)NC1=CC=C(C#N)C(C(F)(F)F)=C1 VYKVTAIYHHOYBV-UHFFFAOYSA-N 0.000 description 1
- RXVVINDYSQZHCQ-UHFFFAOYSA-N [3-[4-cyano-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxopropyl] methanesulfonate Chemical compound CS(=O)(=O)OCC(O)(C)C(=O)NC1=CC=C(C#N)C(C(F)(F)F)=C1 RXVVINDYSQZHCQ-UHFFFAOYSA-N 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
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- 239000000051 antiandrogen Substances 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
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- 229910021641 deionized water Inorganic materials 0.000 description 1
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- RUOCORIYQAUTEF-UHFFFAOYSA-N hydrogen peroxide;(2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate Chemical compound OO.FC(F)(F)C(=O)OC(=O)C(F)(F)F RUOCORIYQAUTEF-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
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- 208000037819 metastatic cancer Diseases 0.000 description 1
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- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 1
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- 239000008399 tap water Substances 0.000 description 1
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/10—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms two oxygen atoms and one sulfur atom, e.g. cyclic sulfates
Abstract
A találmány tárgya új eljárás az ismert (I) képletű racém, valamint azR-(–)- és az S-(+)-N-[4-ciano-3-(trifluor-metil)-- fenil]-3-[(4-fluor-fenil)-szulfonil]-2-hidroxi-2-metil-propánsavamid (Bicalutamide)előállítására. A találmány szerint úgy járnak el, hogy racém vagyoptikailag tiszta 2,3-dihidroxi-2-metil-propánkarbonsavat tionil-kloriddal reagáltatnak, majd a kapott vegyületet 4-ciano-3-trifluor-metil-anilinnel reagáltatják, majd a kapott (V) képletű 4-{[4-ciano-3-(trifluor-metil)-anilino]-karbonil}-4-metil-1,3,2-dioxatiolán-2-onthidrolizálják, majd a keletkezett (IV) képletű N-[4-ciano-3-(trifluor-metil)-fenil]-2,3-dihidroxi-2-metil-propánsavamidot egy R–SO2–Xáltalános képletű szulfonsav-halogeniddel – ahol R metil-, p-tolil-vagy p-bróm-fenil-csoportot, X pedig halogénatomot jelent –szulfonilezik, majd a kapott (III) általános képletű szulfonsav-észter-származékot valamely bázis jelenlétében 4-fluor-tiofenollalreagáltatják, végül a kapott racém vagy optikailag tiszta (II) képletűtioéterszármazékot oxidálják. ŕ
Claims (16)
1. Új eljárás az ismert (I) képletű racém, valamint az (la) képletű R-(-)- és az (lb) képletű S-(+)-N-[4-ciano3- (trifluor-metil)-fenil]-3-[(4-fluor-fenil)-szulfonil]-2hidroxi-2-metil-propánsavamid előállítására, azzal jellemezve, hogy racém vagy optikailag tiszta (VII) képletű 2,3dihidroxi-2-metil-propán-karbonsavat valamely halogénezett szénhidrogén vagy aromás szénhidrogénoldószerben egy aromás amin bázis jelenlétében tionil-kloriddal reagáltatunk, a kapott racém vagy optikailag tiszta (VI) képletű
4- klór-karbonil-4-metil-1,3,2-dioxatiolán-2-ont egy tercier aminbázis jelenlétében inért oldószerben -40 és 0 °C közötti hőmérsékleten 4-ciano-3-trifluor-metilanilinnel reagáltatjuk, a kapott racém vagy optikailag tiszta (V) képletű 4{[4-ciano-3-(trifluor-metil)-anilino]-karbonil}-4-metil1,3,2-dioxatiolán-2-ont vizes bázikus közegben hidrolizáljuk, a keletkezett racém vagy optikailag tiszta (IV) képletű N-[4-ciano-3-(trifluor-metil)-fenilj-2,3-dihidroxi-2metil-propánsavamidot valamely halogénezett szénhidrogén-oldószerben, egy tercier aminbázis jelenlétében egy R-SO2-X általános képletű szulfonsav-halogeniddel - ahol R metil-, p-tolil- vagy
40 p-bróm-fenil-csoportot, X pedig halogénatomot jelent szulfonilezzük, a kapott racém vagy optikailag tiszta (III) általános képletű szulfonsav-észter-származékot - ahol R metil-, p-tolil- vagy p-bróm-fenil-csoportot jelent - valamely
45 bázis jelenlétében 4-fluor-tiofenollal reagáltatjuk, végül a kapott racém vagy optikailag tiszta (II) képletű tioéterszármazékot
i) valamely szervetlen peroxisóval víz és valamely vízzel elegyedő vagy nem elegyedő oldószer keveréké50 ben, utóbbi esetben valamely fázistranszfer katalizátor jelenlétében, vagy ii) vizes hidrogén-peroxid-oldattal
a) valamely 1-4 szénatomos alifás karbonsavban, vagy
55 β) vizes-bázisos közegben, kívánt esetben vízzel elegyedő szerves oldószerek jelenlétében, vagy
γ) valamely vízzel nem elegyedő szerves oldószerben fázistranszfer katalizátor és egy, a vanádium- vagy a krómcsoportba tartozó fémből levezethető sav
60 sójának jelenlétében oxidáljuk.
HU 223 950 Β1
2. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (VII) képletű 2,3dihidroxi-2-metil-propánkarbonsav tionil-kloriddal történő reagáltatását halogénezett szénhidrogén-oldószerként diklór-metánban, kloroformban vagy diklór-etánban, vagy aromás szénhidrogén-oldószerként benzolban, toluolban vagy xilolban hajtjuk végre aromás aminbázisként piridin jelenlétében.
3. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (VI) képletű 4-klórkarbonil-4-metil-1,3,2-dioxatiolán-2-ont tercier aminbázisként trietil-amin jelenlétében reagáltatjuk a 4-ciano3-trifluor-metil-anilinnel.
4. A 3. igénypont szerinti eljárás, azzal jellemezve, hogy inért oldószerként egy halogénezett vagy egy aromás szénhidrogén- vagy egy éter típusú oldószert alkalmazunk.
5. A 3. igénypont szerinti eljárás, azzal jellemezve, hogy a reagáltatást -15 és 0 °C közötti hőmérsékleten hajtjuk végre.
6. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (V) képletű 4-{[4ciano-3-(trifluor-metil)-anilino]-karbonil}-4-metil-1,3,2dioxatiolán-2-on hidrolizálását valamely alkálifémhidroxidot tartalmazó vizes közegben hajtjuk végre.
7. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (IV) képletű N-[4ciano-3-(trifluor-metil)-fenil]-2,3-dihidroxi-2-metil-propánsavamidot halogénezett szénhidrogén-oldószerként diklór-metánban, tercier aminbázisként piridin jelenlétében szulfonilezzük egy R-SO2-X általános képletű szulfonsav-halogeniddel, ahol R jelentése az 1. igénypontban megadott.
8. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (III) általános képletű szulfonsav-észter-származékok - ahol R jelentése az 1. igénypontban megadott - és a 4-fluor-tiofenol reagáltatását bázisként egy szervetlen bázis, előnyösen nátrium-hidroxid jelenlétében, előnyösen izopropilalkoholos oldatban végezzük.
9. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (II) képletű tioéterszármazékot szervetlen peroxisóként a 2KHSO5.KHSO4.K2SO4 összetételű sóval (Oxone®) oxidáljuk.
10. A 9. igénypont szerinti eljárás, azzal jellemezve, hogy az oxidációt metanol és víz elegyében hajtjuk végre.
11. A 9. igénypont szerinti eljárás, azzal jellemezve, hogy az oxidációt diklór-metán és víz keverékében fázistranszfer katalizátor jelenlétében hajtjuk végre.
12. A 9. igénypont szerinti eljárás, azzal jellemezve, hogy az oxidációt etil-acetát és víz keverékében fázistranszfer katalizátor jelenlétében hajtjuk végre.
13. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (II) képletű tioéterszármazékot 1-4 szénatomos alifás karbonsavként ecetsavban vagy hangyasavban oxidáljuk vizes hidrogén-peroxid-oldattal.
14. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (II) képletű tioéterszármazékot vizes-bázisos közegként vizes alkálifém-karbonát-oldatban, kívánt esetben vízzel elegyedő szerves oldószerként acetonitril és/vagy valamely 1-4 szénatomos alkanol, előnyösen metanol jelenlétében oxidáljuk vizes hidrogén-peroxid-oldattal.
15. Az 1. igénypont szerinti eljárás, azzal jellemezve, hogy a racém vagy optikailag tiszta (II) képletű tioéterszármazékot vízzel nem elegyedő szerves oldószerként egy halogénezett szénhidrogén-oldószerben, előnyösen diklór-metánban fázistranszfer katalizátorként egy kvatemer ammóniumsó alkalmazásával, nátrium-volframát jelenlétében oxidáljuk vizes hidrogén-peroxid-oldattal.
16. A 11., 12. és 15. igénypont szerinti eljárás, azzal jellemezve, hogy fázistranszfer katalizátorként tetrabutil-ammónium-hidrogén-szulfátot, cetil-trimetilammónium-kloridot vagy tetrabutil-ammónium-kloridot használunk.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9901937A HU223950B1 (hu) | 1999-06-10 | 1999-06-10 | Eljárás a racém, valamint az R-(-)- és S-(+)-N-[4-ciano-3-(trifluor-metil)-fenil]-3-[(4-fluor-fenil)-szulfonil]-2-hidroxi-2-metil-propánsavamid előállítására |
| US10/030,665 US7199257B1 (en) | 1999-06-10 | 2000-05-26 | Process for the synthesis of N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropionamide |
| ES00937111T ES2188550T3 (es) | 1999-06-10 | 2000-05-26 | Procedimiento para la sintesis de n-(4-ciano-3-trifluorometil-fenil)-3-(4-fluorofenil-sulfonil)-2-hidroxi-2-metil-propionamida. |
| EP00937111A EP1189898B1 (en) | 1999-06-10 | 2000-05-26 | Process for the synthesis of n-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropionamide |
| PCT/HU2000/000049 WO2001000608A1 (en) | 1999-06-10 | 2000-05-26 | Process for the synthesis of n-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropionamide |
| DE60001657T DE60001657T2 (de) | 1999-06-10 | 2000-05-26 | Verfahren zur herstellung von n-(4-cyan-3-trifluormethylphenyl)-3-(4-flurophenylsulfonyl)-2-hydroxy-2-methylpropionamid |
| AU52397/00A AU5239700A (en) | 1999-06-10 | 2000-05-26 | Process for the synthesis of n-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenyl-sulfon l)-2-hydroxy-2-methyl-propionamide |
| AT00937111T ATE234294T1 (de) | 1999-06-10 | 2000-05-26 | Verfahren zur herstellung von n-(4-cyan-3- trifluormethylphenyl)-3-(4-flurophenylsulfonyl) 2-hydroxy-2-methylpropionamid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9901937A HU223950B1 (hu) | 1999-06-10 | 1999-06-10 | Eljárás a racém, valamint az R-(-)- és S-(+)-N-[4-ciano-3-(trifluor-metil)-fenil]-3-[(4-fluor-fenil)-szulfonil]-2-hidroxi-2-metil-propánsavamid előállítására |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| HU9901937D0 HU9901937D0 (en) | 1999-08-30 |
| HUP9901937A2 HUP9901937A2 (hu) | 2001-04-28 |
| HU223950B1 true HU223950B1 (hu) | 2005-03-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU9901937A HU223950B1 (hu) | 1999-06-10 | 1999-06-10 | Eljárás a racém, valamint az R-(-)- és S-(+)-N-[4-ciano-3-(trifluor-metil)-fenil]-3-[(4-fluor-fenil)-szulfonil]-2-hidroxi-2-metil-propánsavamid előállítására |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US7199257B1 (hu) |
| EP (1) | EP1189898B1 (hu) |
| AT (1) | ATE234294T1 (hu) |
| AU (1) | AU5239700A (hu) |
| DE (1) | DE60001657T2 (hu) |
| ES (1) | ES2188550T3 (hu) |
| HU (1) | HU223950B1 (hu) |
| WO (1) | WO2001000608A1 (hu) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7102026B2 (en) | 2001-06-13 | 2006-09-05 | Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság | Process for preparing and isolating rac-bicalutamide and its intermediates |
| US6737550B2 (en) | 2001-06-13 | 2004-05-18 | Biogal Gryogyszergyar Rt. | Process for preparing rac-bicalutamide and its intermediates |
| CN1602299A (zh) | 2001-12-13 | 2005-03-30 | 住友化学工业株式会社 | 比卡鲁胺晶体及其制造方法 |
| DE10222104A1 (de) | 2002-05-17 | 2003-12-04 | Helm Ag | Verfahren zur Herstellung von N-(4'-Cyano-3'-trifluormethyl)-3-(4"-fluorphenylsulfonyl)-2-hydroxy-2-methylpropionamid |
| US20040063782A1 (en) * | 2002-09-27 | 2004-04-01 | Westheim Raymond J.H. | Bicalutamide forms |
| US6818766B2 (en) * | 2002-10-02 | 2004-11-16 | Synthon Bv | Process for making bicalutamide and intermediates thereof |
| US20050020675A1 (en) * | 2003-02-21 | 2005-01-27 | Parthasaradhi Reddy Bandi | Bicalutamide polymorphs |
| US20050008691A1 (en) | 2003-05-14 | 2005-01-13 | Arturo Siles Ortega | Bicalutamide compositions |
| JP2007521224A (ja) * | 2003-06-25 | 2007-08-02 | テバ ジョジセルジャール ザ−トケルエン ムケド レ−スベニュタ−ルシャシャ−グ | Ｒａｃ−ビカルタミドの精製及び単離方法 |
| JP4322621B2 (ja) | 2003-10-16 | 2009-09-02 | 住友化学株式会社 | ４’−シアノ−３−［（４−フルオロフェニル）スルホニル］−２−ヒドロキシ−２−メチル−３’−トリフルオロメチルプロピオンアニリドの製造方法 |
| US20080177109A1 (en) * | 2005-03-29 | 2008-07-24 | Usv Limited | Novel Process for Preparation of Bicalutamide |
| WO2007013094A2 (en) * | 2005-04-15 | 2007-02-01 | Sun Pharmaceutical Industries Limited | A process for preparation of antiandrogen compound |
| CA2513356A1 (en) * | 2005-07-26 | 2007-01-26 | Apotex Pharmachem Inc. | Process for production of bicalutamide |
| CA2635461A1 (en) * | 2005-12-27 | 2007-07-05 | Dabur Pharma Limited | An improved process for preparation of bicalutamide |
| CN101462988B (zh) * | 2007-12-21 | 2014-01-01 | 中国医学科学院药物研究所 | 一种比卡鲁胺的合成工艺 |
| WO2012042532A1 (en) * | 2010-09-29 | 2012-04-05 | Shilpa Medicare Limited | Process for preparing bicalutamide |
| CN102086167B (zh) * | 2010-12-09 | 2013-05-08 | 济南大学 | 一种乙磺酰基乙腈的制备方法 |
| CN102321000A (zh) * | 2011-07-21 | 2012-01-18 | 宁波人健药业集团有限公司 | 氧化制备比卡鲁胺的方法 |
| CN102351762A (zh) * | 2011-07-21 | 2012-02-15 | 宁波人健药业集团有限公司 | 用n-(4-氰基-3-三氟甲基苯基)-3-(4-氟苯硫基)-2-甲基-2-羟基丙酰胺制备比卡鲁胺的方法 |
| CN108069887B (zh) * | 2016-11-17 | 2021-04-20 | 山西振东制药股份有限公司 | 一种(r)-比卡鲁胺中间体的制备方法 |
| CN109336798B (zh) * | 2018-11-19 | 2021-11-16 | 常州新星联生物科技有限公司 | 一种比卡鲁胺硫醚中间体的制备方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100172B1 (en) | 1982-07-23 | 1987-08-12 | Imperial Chemical Industries Plc | Amide derivatives |
| CA2181358A1 (en) | 1994-01-21 | 1995-07-27 | Nancy M. Gray | Methods and compositions for treating androgen-dependent diseases using optically pure r-(-)-casodex |
| US6019957A (en) | 1997-06-04 | 2000-02-01 | The University Of Tennessee Research Corporation | Non-steroidal radiolabeled agonist/antagonist compounds and their use in prostate cancer imaging |
| CN1602299A (zh) * | 2001-12-13 | 2005-03-30 | 住友化学工业株式会社 | 比卡鲁胺晶体及其制造方法 |
| US6818766B2 (en) * | 2002-10-02 | 2004-11-16 | Synthon Bv | Process for making bicalutamide and intermediates thereof |
-
1999
- 1999-06-10 HU HU9901937A patent/HU223950B1/hu active IP Right Grant
-
2000
- 2000-05-26 US US10/030,665 patent/US7199257B1/en not_active Expired - Fee Related
- 2000-05-26 EP EP00937111A patent/EP1189898B1/en not_active Expired - Lifetime
- 2000-05-26 AU AU52397/00A patent/AU5239700A/en not_active Abandoned
- 2000-05-26 AT AT00937111T patent/ATE234294T1/de active
- 2000-05-26 DE DE60001657T patent/DE60001657T2/de not_active Expired - Lifetime
- 2000-05-26 WO PCT/HU2000/000049 patent/WO2001000608A1/en active IP Right Grant
- 2000-05-26 ES ES00937111T patent/ES2188550T3/es not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9901937A2 (hu) | 2001-04-28 |
| HU9901937D0 (en) | 1999-08-30 |
| EP1189898A1 (en) | 2002-03-27 |
| ES2188550T3 (es) | 2003-07-01 |
| EP1189898B1 (en) | 2003-03-12 |
| WO2001000608A8 (en) | 2001-06-21 |
| WO2001000608A1 (en) | 2001-01-04 |
| DE60001657D1 (de) | 2003-04-17 |
| US7199257B1 (en) | 2007-04-03 |
| DE60001657T2 (de) | 2003-12-04 |
| AU5239700A (en) | 2001-01-31 |
| ATE234294T1 (de) | 2003-03-15 |
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Owner name: RICHTER GEDEON NYRT., HU Free format text: FORMER OWNER(S): RICHTER GEDEON VEGYESZETI GYAR RT., HU |