LT5282B - Intermediates in producing phenoxyacetic acid derivatives and method of using the same - Google Patents
Intermediates in producing phenoxyacetic acid derivatives and method of using the same Download PDFInfo
- Publication number
- LT5282B LT5282B LT2005019A LT2005019A LT5282B LT 5282 B LT5282 B LT 5282B LT 2005019 A LT2005019 A LT 2005019A LT 2005019 A LT2005019 A LT 2005019A LT 5282 B LT5282 B LT 5282B
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- Lithuania
- Prior art keywords
- general formula
- compound represented
- compound
- acid
- ethyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 11
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical class OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 title abstract description 10
- 239000000543 intermediate Substances 0.000 title abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 208000008589 Obesity Diseases 0.000 abstract description 2
- 206010046543 Urinary incontinence Diseases 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 201000001421 hyperglycemia Diseases 0.000 abstract description 2
- 235000020824 obesity Nutrition 0.000 abstract description 2
- 102000012367 Beta 3 adrenoceptor Human genes 0.000 abstract 1
- 206010052402 Gastrointestinal hypermotility Diseases 0.000 abstract 1
- 206010036018 Pollakiuria Diseases 0.000 abstract 1
- 108040005346 beta3-adrenergic receptor activity proteins Proteins 0.000 abstract 1
- 208000018936 intestinal hypermotility Diseases 0.000 abstract 1
- 230000037036 intestinal hypermotility Effects 0.000 abstract 1
- 230000004936 stimulating effect Effects 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000002904 solvent Substances 0.000 description 18
- 239000002253 acid Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 150000002373 hemiacetals Chemical class 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- NKTOLZVEWDHZMU-UHFFFAOYSA-N 2,5-xylenol Chemical compound CC1=CC=C(C)C(O)=C1 NKTOLZVEWDHZMU-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- UMDSCNIUVCSCST-UHFFFAOYSA-N ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate Chemical compound CCOC(=O)COC1=CC(C)=C(CC(OC)OC)C=C1C UMDSCNIUVCSCST-UHFFFAOYSA-N 0.000 description 4
- WCMIHKIZLBYABS-UHFFFAOYSA-N ethyl 2-[4-(2-ethoxy-2-hydroxyethyl)-2,5-dimethylphenoxy]acetate Chemical compound CCOC(O)CC1=CC(C)=C(OCC(=O)OCC)C=C1C WCMIHKIZLBYABS-UHFFFAOYSA-N 0.000 description 4
- -1 hemiacetal compound Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- LOFUWVSJBJFQPY-UHFFFAOYSA-N 4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol Chemical compound COC(OC)C(O)C1=CC(C)=C(O)C=C1C LOFUWVSJBJFQPY-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- HHTRUCKBVLAMMY-UHFFFAOYSA-N ethyl 2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate Chemical compound CCOC(=O)COC1=CC(C)=C(C(O)C(OC)OC)C=C1C HHTRUCKBVLAMMY-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- JAYBQRKXEFDRER-UHFFFAOYSA-N 4-(2-amino-1-hydroxypropyl)phenol Chemical compound CC(N)C(O)C1=CC=C(O)C=C1 JAYBQRKXEFDRER-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- JAYBQRKXEFDRER-RCOVLWMOSA-N 4-Hydroxynorephedrine Chemical compound C[C@H](N)[C@H](O)C1=CC=C(O)C=C1 JAYBQRKXEFDRER-RCOVLWMOSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Išradėjai intensyviai tyrinėjo naują tarpinį junginį, kuris tinkamai ir didelės išeigos gali būti paverčiamas (X) bendros formulės fenoksiacto rūgšties dariniu arba jo farmaciškai priimtina druska, ir atrado, kad fenoksiacto rūgšties darinys (X) labai didelės išeigos gali būti gaunamas iš naujo hemiacetalio junginio, išreikšto bendra formule (I). Be to, išradėjai atrado (I) hemiacetalio junginio iš 2,5-ksilenolio gavimo būdą patogiais būdais. Remiantis šiais atradimais, buvo atliktas šis išradimas.The inventors have intensively investigated a novel intermediate which can be converted into a phenoxyacetic acid derivative of the general formula (X) or a pharmaceutically acceptable salt thereof in a suitable and high yield, and discovered that the phenoxyacetic acid derivative (X) can be obtained in very high yield from a new hemiacetal compound. expressed by the general formula (I). In addition, the inventors have discovered a method for preparing the hemiacetal compound (I) from 2,5-xylene in convenient ways. Based on these discoveries, the present invention was made.
Taigi, šis išradimas pateikia:Thus, the present invention provides:
(1) junginį, išreikštą bendra formule (I):(1) A compound represented by the general formula (I):
kurioje kiekvienas R1 ir R2 nepriklausomai yra žemesniojo alkilo grupė;wherein each of R 1 and R 2 is independently lower alkyl;
(2) junginį pagal aukščiau pateiktą (1), kurioje R1 ir R2 yra etilo grupė;(2) a compound according to the above (1), wherein R 1 and R 2 are ethyl;
(3) junginio, išreikšto bendra formule (I):(3) of the compound represented by the general formula (I):
kurioje kiekvienas R1 ir R2 nepriklausomai yra žemesniojo alkilo grupė, gavimo būdą, kuris apima pakopas:wherein each of R 1 and R 2 is independently a lower alkyl group, the process comprising the steps of:
(a) junginio, išreikšto formule (II):(a) Compound of Formula (II):
R3Q (ii) poveikįjunginiu, išreikštu bendra formule (III)R 3 Q (ii) Exposure to a compound represented by the general formula (III)
-CHO-CHO
R3O'R 3 O '
(III) kurioje R3 yra žemesniojo alkilo grupė, siekiant gauti junginį išreikštą bendra formule (IV):(III) wherein R 3 is a lower alkyl group to give a compound represented by the general formula (IV):
kurioje R3 yra toks, kaip apibūdinta aukščiau;wherein R 3 is as defined above;
(b) minėto junginio, išreikšto bendra formule (IV), poveikį junginiu, išreikštu bendra formule (V):(b) the effect of said compound represented by the general formula (IV) with the compound represented by the general formula (V):
ZCH2CO2R1 (V) kurioje Z yra chloro, bromo arba jodo atomas ir R1 yra toks, kaip apibūdintaZCH 2 CO 2 R 1 (V) wherein Z is a chlorine, bromine or iodine atom and R 1 is as defined
kurioje R1 ir R2 yra tokie, kaip apibūdinta aukščiau;wherein R 1 and R 2 are as defined above;
(c) minėto junginio, išreikšto bendra formule (VI), redukavimą, siekiant gauti junginį išreikštą bendra formule (VII):(c) reducing said compound represented by general formula (VI) to obtain a compound represented by general formula (VII):
(VII) kurioje R1 ir R3 yra tokie, kaip apibūdinta aukščiau;(VII) wherein R 1 and R 3 are as defined above;
(d) minėto junginio, išreikšto bendra formule (VII), hidrolizavimą, siekiant gauti junginį, išreikštą bendra formule (VIII):(d) hydrolyzing said compound of general formula (VII) to obtain a compound of general formula (VIII):
kurioje R1 yra toks, kaip apibūdinta aukščiau; ir (e) minėto junginio, išreikšto bendra formule (VIII), poveikį R2-OH, kurioje R2 yra toks, kaip apibūdinta aukščiau;wherein R 1 is as defined above; and (e) reacting said compound of general formula (VIII) with R 2 -OH wherein R 2 is as defined above;
(4) būdą, remiantis aukščiau aprašytu (3), kur R1 ir R2 yra etilo grupė ir R3 yra metilo grupė;(4) the method according to the above (3), wherein R 1 and R 2 are ethyl and R 3 is methyl;
(5) junginį, išreikštą bendra formule (IV):(5) a compound represented by the general formula (IV):
(IV) kurioje R3 yra žemesniojo alkilo grupė;(IV) wherein R 3 is lower alkyl;
(6) junginį pagal aukščiau pateiktą (5), kur R3 yra metilo grupė;(6) a compound according to the above (5), wherein R 3 is a methyl group;
(7) junginį, išreikštą bendra formule (VI):(7) compound represented by the general formula (VI):
(VI) kurioje kiekvienas R1 ir R3 nepriklausomai yra žemesniojo alkilo grupė;(VI) wherein each of R 1 and R 3 is independently lower alkyl;
(8) junginį, išreikštą bendra formule (VII):(8) a compound represented by the general formula (VII):
kurioje kiekvienas R1 ir R3 nepriklausomai yra žemesniojo alkilo grupė;wherein each of R 1 and R 3 is independently lower alkyl;
(9) junginį, pagal aukščiau pateiktą (7) arba (8), kur R1 yra etilo grupė ir R3 yra metilo grupė;(9) a compound according to (7) or (8) above, wherein R 1 is ethyl and R 3 is methyl;
(10) junginį, išreikštą bendra formule (VIII):(10) a compound represented by the general formula (VIII):
(VII)(VII)
(VIII) kurioje R1 yra žemesniojo alkilo grupė;(VIII) wherein R 1 is lower alkyl;
(11) junginį pagal 10 punktą, kurioje R1 yra etilo grupė;(11) The compound of claim 10, wherein R 1 is ethyl;
(12) junginio, išreikšto bendra formule (X):(12) a compound represented by the general formula (X):
(X) kurioje R1 yra žemesniojo alkilo grupė, arba jo farmaciškai priimtinos druskos gavimo būdą, kuris apima junginio, išreikšto bendra formule (I):(X) wherein R 1 is a lower alkyl group, or a pharmaceutically acceptable salt thereof, which process comprises the preparation of a compound represented by the general formula (I):
kurioje R1 yra toks, kaip apibūdinta aukščiau, ir R2 yra žemesniojo alkilo grupė, poveikio junginiu, išreikštu formule (IX):wherein R 1 is as defined above and R 2 is a lower alkyl group, by the action of the compound represented by formula (IX):
pakopą, dalyvaujant reduktoriui, ir po to minėto (X) junginio farmaciškai priimtinos druskos pasirinktinai sudarymą;a step, in the presence of a reducing agent, and optionally forming a pharmaceutically acceptable salt of said compound (X);
(13) būdą pagal aukščiau aprašytą (12), kur R1 ir R2 yra etilo grupė.(13) A process according to the above (12), wherein R 1 and R 2 are ethyl.
Šiame išradime terminas “žemesniojo alkilo grupė reiškia linijinės arba šakotos grandinės alkilo grupę, turinčią 1-6 anglies atomus, tokią kaip metilo, etilo, propilo, izopropilo, butilo, izobutilo, antr-butilo grupę ir panašiai.In the present invention, the term "lower alkyl group" means a straight or branched chain alkyl group containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and the like.
GERIAUSIAS IŠRADIMO VYKDYMO BŪDASBEST MODE FOR CARRYING OUT THE INVENTION
Šio išradimo junginys, išreikštas bendra formule (I), gali būti gaunamas pakopomis (a) - (e), kaip pavaizduota sekančioje schemoje:The compound of the present invention represented by the general formula (I) may be obtained in steps (a) to (e) as depicted in the following scheme:
kurioje R1, R2, R3 ir Z yra tokie, kaip apibūdinta aukščiau.wherein R 1 , R 2 , R 3 and Z are as defined above.
(Pakopa a)(Tier a)
Fenolio darinys, išreikštas bendra formule (IV), gali būti gaunamas, veikiant 2,5-ksilenolį, išreikštą formule (II), junginiu, išreikštu bendra formule (III), dalyvaujant šarminio metalo hidroksido vandeniniam tirpalui, tokiam kaip natrio hidroksido vandeninis tirpalas. Panaudotas junginio (III) ir šarminio metalo hidroksido kiekis vidutiniškai svyruoja nuo maždaug 1 iki maždaug 3 molinių ekvivalentų, skaičiuojant nuo 1 molio 2,5-ksilenolio (II). Reakcija vidutiniškai yra vykdoma nuo maždaug 10 iki maždaug 70°C temperatūros nuo 1 iki 10 valandų laikotarpiu. Po reakcijos pabaigos reakcijos tirpalas yra neutralizuojamas praskiesta rūgštimi, tokia kaip praskiesta druskos rūgštis. Po to nusodintieji kristalai yra filtruojami ir džiovinami, siekiant gauti (IV) bendros formulės fenolio darinį.The phenol derivative represented by the general formula (IV) may be obtained by the action of 2,5-xylenol represented by the formula (II), a compound represented by the general formula (III) in the presence of an aqueous alkali metal hydroxide such as aqueous sodium hydroxide. The amount of compound (III) and alkali metal hydroxide used ranges from about 1 to about 3 molar equivalents on average, based on 1 mol of 2,5-xylene (II). The reaction is carried out on average at about 10 to about 70 ° C for a period of from 1 to 10 hours. After the completion of the reaction, the reaction solution is neutralized with dilute acid such as dilute hydrochloric acid. The precipitated crystals are then filtered and dried to give the phenol derivative of general formula (IV).
(Pakopa b)(Step b)
Fenolio darinys (IV) yra veikiamas halogenacto rūgšties esteriu, kurio bendra formulė (V), dalyvaujant bazei inertiniame tirpiklyje, siekiant gauti junginį išreikštą bendra formule (VI). Reakcijoje panaudoti inertiniai tirpikliai apima eterius, tokius kaip tetrahidrofuranas arba panašiai, ketonus, tokius kaip acetonas, metilo etilo ketonas arba panašiai, acetonitrilą, N,Ndimetilformamidą, Ν,Ν-dimetilacetamidą arba panašiai. Tirpikliai gali būti panaudoti pavieniui arba kaip dviejų arba kelių tirpiklių mišinys. Reakcijoje panaudota bazė apima natrio karbonatą, kalio karbonatą, cezio karbonatą ir panašiai. Halogenacto rūgšties esteris (V) apima CICH2CO2R1, BrCH2, CO2R1 arba ICH2CO2R1. Panaudotas halogenacto rūgšties (V) ir bazės kiekis vidutiniškai svyruoja nuo maždaug 1 iki maždaug 5 molinių ekvivalentų, skaičiuojant nuo 1 molio fenolio darinio (IV). Halogenacto rūgšties esteris (V) ir bazė vidutiniškai yra naudojami ekvimoliniu santykiu, tačiau bet kuris iš jų gali būti naudojamas pertekliumi. Reakcija vidutiniškai yra vykdoma nuo maždaug 0 iki maždaug 100°C temperatūros nuo 1 iki 24 valandų laikotarpiu. Po reakcijos pabaigos reakcijos mišinio ekstrahavimas ir po to koncentravimas įprastais būdais įgalina gauti junginį kurio bendra formulė (VI).The phenol derivative (IV) is treated with a haloacetic acid ester of the general formula (V) in the presence of a base in an inert solvent to give the compound represented by the general formula (VI). Inert solvents used in the reaction include ethers such as tetrahydrofuran or the like, ketones such as acetone, methyl ethyl ketone or the like, acetonitrile, N, N-dimethylformamide, Ν, Ν-dimethylacetamide or the like. Solvents can be used singly or as a mixture of two or more solvents. The base used in the reaction includes sodium carbonate, potassium carbonate, cesium carbonate and the like. Haloacetic acid ester (V) includes CICH2CO2R 1, BrCH2, CO 2 R 1 or R 2 ICH2CO first The amount of haloacetic acid (V) and base used is on average from about 1 to about 5 molar equivalents based on 1 mol of phenolic derivative (IV). The haloacetic acid ester (V) and base are used in equimolar proportions on average, but any of these can be used in excess. The reaction is carried out on average at about 0 to about 100 ° C for a period of from 1 to 24 hours. Upon completion of the reaction, extraction of the reaction mixture and subsequent concentration in a conventional manner affords the compound of general formula (VI).
(Pakopa c)(Step c)
Junginio (VI) redukcija, naudojant reduktorių inertiniame tirpiklyje įgalina gauti acetalio darinį kurio bendra formulė (VII). Reakcijoje naudojami inertiniai tirpikliai apima eterius, tokius kaip tetrahidrofuranas, 1,2dimetoksietanas, dioksanas arba panašiai, organinius karboksirūgšties esterius, tokius kaip etilo acetatas arba panašiai, acetonitrilą arba panašiai. Tirpikliai gali būti naudojami pavieniui arba kaip dviejų arba kelių tirpiklių mišinys. Reakcijoje naudojami reduktoriai apima natrio jodidą/trialkilchlorsilaną, tokį kaip chlortrimetilsilanas, chlortrietilsilanas, t-butildimetilchlorsilanas arba panašiai, kurių panaudotas kiekis vidutiniškai svyruoja nuo maždaug 2 iki maždaug 6 molinių ekvivalentų, skaičiuojant nuo 1 molio junginio (VI). Reakcija vidutiniškai yra vykdoma nuo maždaug -30 iki maždaugReduction of compound (VI) using a reducing agent in an inert solvent enables the acetal derivative of general formula (VII) to be obtained. Inert solvents used in the reaction include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane or the like, organic carboxylic acid esters such as ethyl acetate or the like, acetonitrile or the like. Solvents can be used singly or as a mixture of two or more solvents. Reducers used in the reaction include sodium iodide / trialkylchlorosilane such as chlorthrimethylsilane, chlorthriethylsilane, t-butyldimethylchlorosilane, or the like, which are used in an amount ranging from about 2 to about 6 molar equivalents on average per mole of compound (VI). The reaction is run on average from about -30 to about
30°C temperatūros nuo 10 minučių iki 12 valandų laikotarpiu. Po reakcijos pabaigos reakcijos mišinio ekstrahavimas ir po to koncentravimas įprastais būdais įgalina gauti acetalio darinį kurio bendra formulė (VII).30 ° C for 10 minutes to 12 hours. Upon completion of the reaction, the reaction mixture is extracted and then concentrated in a conventional manner to afford the acetal derivative of general formula (VII).
(Pakopa d)(Step d)
Acetalio darinio (VII) hidrolizė, naudojant rūgštį tinkamame tirpiklyje įgalina gauti aldehido darinį išreikštą bendra formule (VIII). Hidrolizės reakcijoje naudojamas tirpiklis apima eterius, tokius kaip tetrahidrofuranas,Hydrolysis of the acetal derivative (VII) using an acid in a suitable solvent affords the aldehyde derivative represented by the general formula (VIII). The solvent used in the hydrolysis reaction includes ethers such as tetrahydrofuran,
1,2-dimetoksietanas, dioksanas arba panašiai, ketonus, tokius kaip acetonas arba panašiai, acetonitrilas arba panašiai. Tirpikliai gali būti naudojami pavieniui arba kaip dviejų arba kelių tirpiklių mišinys. Tirpikliai taip pat gali būti naudojami derinyje su vandeniu. Reakcijoje naudojama rūgštis apima 5 - 20% perchlorato rūgštį 1-10% druskos rūgštį 1-10% sieros rūgštį ptoluensulfonrūgštį trifluoracto rūgštį arba panašiai, kurios panaudotas kiekis vidutiniškai svyruoja nuo maždaug 0,1 iki maždaug 2,5 molinių ekvivalentų, skaičiuojant nuo 1 molio acetalio darinio (VII). Hidrolizės reakcija yra vykdoma vidutiniškai nuo maždaug 0 iki maždaug 50°C temperatūros nuo 0,5 iki 24 valandų periodu. Po reakcijos pabaigos reakcijos mišinio ekstrahavimas ir po to koncentravimas įprastais būdais įgalina gauti aldehido darinį (VIII).1,2-dimethoxyethane, dioxane or the like, ketones such as acetone or the like, acetonitrile or the like. Solvents can be used singly or as a mixture of two or more solvents. Solvents can also be used in combination with water. The acid used in the reaction comprises 5-20% perchloric acid 1-10% hydrochloric acid 1-10% sulfuric acid ptoluenesulfonic acid trifluoroacetic acid, or the like, in an amount ranging from about 0.1 to about 2.5 molar equivalents on average per mol. acetal derivative (VII). The hydrolysis reaction is carried out at an average temperature of about 0 to about 50 ° C for a period of from 0.5 to 24 hours. Upon completion of the reaction, extraction of the reaction mixture and subsequent concentration in the usual manner affords the aldehyde derivative (VIII).
(Pakopa e)(Tier e)
Šio išradimo hemiacetalio darinys, išreikštas bendra formule (I), gali būti gaunamas, aldehidą (VIII) veikiant R2OH, pasirinktinai dalyvaujant rūgščiai, tokiai kaip acto rūgštis arba panašiai. Papildoma R2OH reakcija į aldehido darinį (VIII) vyksta greitai, ir po to vykstanti kristalizacija iš tinkamo tirpiklio įgalina gauti hemiacetalio darinį kurio bendra formulė (I). Naudojamo R2OH kiekis vidutiniškai svyruoja maždaug nuo 1 iki maždaug 10 molinių ekvivalentų, skaičiuojant nuo 1 molio aldehido (VIII). Tuo atveju, kai naudojama rūgštis, panaudotas rūgšties kiekis vidutiniškai svyruoja nuo maždaug 0,01 iki maždaug 0,1 molinių ekvivalentų, skaičiuojant nuo 1 molio aldehido (VIII). Kristalizavimo tirpikliai apima sumaišytą tirpiklį iš R2OH derinyje su n-heksanu, n-heptanu, cikloheksanu arba panašiai. Hemiacetalio darinys (I) pasižymi geromis kristalinėmis savybėmis ir gali būti laikomas tam tikrose sąlygose, pavyzdžiui, žemiau 10°C, ilgą periodą. Atitinkamai, hemiacetalis yra tinkamas komercinei gamybai.The hemiacetal derivative of the present invention represented by the general formula (I) may be obtained by reacting the aldehyde (VIII) with R 2 OH, optionally in the presence of an acid such as acetic acid or the like. The additional reaction of R 2 OH to the aldehyde derivative (VIII) proceeds rapidly and subsequent crystallization from a suitable solvent enables the hemiacetal derivative of general formula (I) to be obtained. The amount of R 2 OH used ranges, on average, from about 1 to about 10 molar equivalents, based on 1 mol of aldehyde (VIII). In the case where an acid is used, the amount of acid used ranges on average from about 0.01 to about 0.1 molar equivalents based on 1 mol of aldehyde (VIII). Crystallization solvents include a mixed solvent of R 2 OH in combination with n-hexane, n-heptane, cyclohexane or the like. The hemiacetal derivative (I) has good crystalline properties and can be stored under certain conditions such as below 10 ° C for a long period. Accordingly, hemiacetal is suitable for commercial production.
Bendros (X) formulės fenoksiacto rūgšties darinio, kuris yra tinkamas panaudoti kaip vaistas, gamybos būdas, naudojant bendros (I) formulės hemiacetalio darinį, yra detalizuotas sekančioje schemoje:The process for preparing a phenoxyacetic acid derivative of the general formula (X) which is suitable for use as a medicament using the hemiacetal derivative of the general formula (I) is detailed in the following scheme:
(ix) kurioje R1 ir R2 yra tokie, kaip apibūdinta aukščiau.(ix) wherein R 1 and R 2 are as defined above.
Fenoksiacto rūgšties darinys, išreikštas bendra formule (X), gali būti gaunamas hemiacetalio darinį, kurio bendra formulė (I), veikiant aminu, kurio formulė (IX), dalyvaujant reduktoriui inertiniame tirpiklyje. Reakcijoje naudojami inertiniai tirpikliai apima eterius, tokius kaip tetrahidrofuranas, 1,2dimetoksietanas, dioksanas arba panašiai, halogenintus angliavandenilius, tokius kaip metileno chloridas, 1,2-dichloretanas arba panašiai, organines karboksirūgštis, tokias kaip acto rūgštis arba panašiai, angliavandenilius, tokius kaip toluenas arba panašiai, alkoholius, tokius kaip metanolis, etanolis arba panašiai, acetonitrilą arba panašiai. Tirpikliai gali būti naudojami pavieniui arba kaip dviejų arba kelių tirpiklių mišinys. Reakcijoje naudojami reduktoriai apima šarminių metalų hidroboranus, tokius kaip NaBFU, NaBH3CN, NaBH(OAc)3, NaBH(0Me)3 arba panašiai, boranus, tokius kaip BH3 · piridinas, BH3 · Ν,Ν-dietilanilinas arba panašiai. Jeigu būtina, šie reduktoriai gali būti naudojami pasirinktinai dalyvaujant rūgščiai, tokiai, kaip acto rūgštis, p-toluensulfonrūgštis, metansulfonrūgštis, sieros rūgštis, druskos rūgštis, arba bazei, tokiai kaip trietilaminas arba panašiai. Alternatyviai, reakcija gali būti vykdoma vandenilio aplinkoje, dalyvaujant metalų katalizatoriui, tokiam kaip 5-10% paladis ant anglies, Raney-Ni, platinos oksidas, paladžio juodžiai, 10% platina ant anglies (sulfidinta) arba panašiai. Tuo atveju, kai naudojami šarminių metalų hidroboranai arba boranai, kaip reduktoriai, tokio reduktoriaus naudojamas kiekis vidutiniškai svyruoja nuo maždaug 0,5 iki maždaug 5 molinių ekvivalentą, skaičiuojant nuo 1 molio hemiacetalio darinio (I). Reakcija yra vykdoma vidutiniškai nuo maždaug 0 iki maždaug 60°C temperatūros nuo 1 iki 48 valandų periodu. Po reakcijos pabaigos, jeigu reikalaujama, netirpios medžiagos yra nufiltruojamos, ir reakcijos mišinio ekstrahavimas ir po to koncentravimas įprastais būdais įgalina gauti fenoksiacto rūgšties darinį, kurio bendra formulė (X). Alternatyviai reakcija gali būti vykdoma aminą (IX) veikiant aldehidu, kurio bendra formulė (VIII), vietoj hemiacetalio darinio (I).The phenoxyacetic acid derivative represented by the general formula (X) may be obtained by the action of a hemiacetal derivative of the general formula (I) on an amine of the formula (IX) in the presence of a reducing agent in an inert solvent. Inert solvents used in the reaction include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane or the like, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane or the like, organic carboxylic acids such as acetic acid or the like, hydrocarbons such as toluene. or the like, alcohols such as methanol, ethanol or the like, acetonitrile or the like. Solvents can be used singly or as a mixture of two or more solvents. Reducers used in the reaction include alkali metal hydroboranes such as NaBFU, NaBH 3 CN, NaBH (OAc) 3 , NaBH (0Me) 3 or the like, boranes such as BH 3 · pyridine, BH 3 · Ν, Ν-diethylaniline or the like. If necessary, these reducing agents may be used optionally in the presence of an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, or a base such as triethylamine or the like. Alternatively, the reaction may be carried out in a hydrogen atmosphere in the presence of a metal catalyst such as 5-10% palladium on carbon, Raney-Ni, platinum oxide, palladium on carbon, 10% platinum on carbon (sulfide) or the like. In the case of alkali metal hydroboranes or boranes as reducing agents, the amount of such reducing agent used will on average vary from about 0.5 to about 5 molar equivalents based on 1 mol of the hemiacetal derivative (I). The reaction is carried out at an average temperature of about 0 to about 60 ° C for a period of from 1 to 48 hours. After completion of the reaction, insoluble materials, if required, are filtered off and the reaction mixture is extracted and then concentrated in a conventional manner to afford the phenoxyacetic acid derivative of general formula (X). Alternatively, the reaction may be carried out by reacting the amine (IX) with an aldehyde of general formula (VIII) instead of the hemiacetal derivative (I).
Fenoksiacto rūgšties darinys (X) pasirinktinai gali būti paverčiamas jo farmaciškai priimtinos rūgšties adityvine druska įprastais būdais. Tokių druskų pavyzdžiai apima rūgšties adityvines druskas, sudarytas su neorganinėmis rūgštimis, tokiomis kaip druskos rūgštis, vandenilio bromidas, vandenilio jodidas, sieros rūgštis, fosforo rūgštis ir panašiai; rūgšties adityvines druskas, sudarytas su organinėmis rūgštimis, tokiomis kaip skruzdžių rūgštis, acto rūgštis, metansulfonrūgštis, benzensulfonrūgštis, p-toluensulfonrūgštis, propiono rūgštis, citrinų rūgštis, gintaro rūgštis, vyno rūgštis, fumaro rūgštis, sviesto rūgštis, oksalo rūgštis, malono rūgštis, maleino rūgštis, pieno rūgštis, obuolių rūgštis, anglies rūgštis, glutamo rūgštis, asparto rūgštis ir panašiai.The phenoxyacetic acid derivative (X) can optionally be converted into its pharmaceutically acceptable acid addition salt by conventional means. Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like; acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, malic acid, acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and the like.
Aminas, išreikštas formule (IX), gali būti gaunamas pasirinktinai atskiriant komerciškai tinkamą amino enantiomerų mišinį įprastais būdais. Alternatyviai, aminas (IX) gali būti gaunamas būdais, aprašytais “J. Med. Chem. 1997, 20 (7), p. 978-981”.The amine represented by formula (IX) may be obtained by optional separation of a commercially available mixture of amino enantiomers by conventional means. Alternatively, the amine (IX) can be obtained by the methods described in “J. Med. Chem. 1997, 20 (7), p. 978-981 ".
Šio išradimo junginys, išreikštas bendra formule (I), jo tarpiniai junginiai (IV), (VI), (VII) ir (VIII) taip pat ir fenoksiacto rūgšties darinys, kurio bendra formulė (X), gali būti pasirinktinai izoliuoti arba išgryninti, taikant standartines izoliavimo arba gryninimo technikas, tokias kaip tirpiklio ekstrahavimas, rekristalizacija, chromatografija ir panašiai.The compound of the present invention represented by the general formula (I), its intermediates (IV), (VI), (VII) and (VIII) as well as the phenoxyacetic acid derivative of the general formula (X) can be optionally isolated or purified, by standard isolation or purification techniques such as solvent extraction, recrystallization, chromatography, and the like.
PAVYZDŽIAIEXAMPLES
Sekantys pavyzdžiai iliustruoja išradimą detaliau. Tačiau, bet kuriuo atveju, tai nereiškia, kad jie buvo sudaryti kaip apribojantys šio išradimo apimtį.The following examples illustrate the invention in more detail. However, this does not mean that they are intended to limit the scope of the present invention.
PAVYZDYSEXAMPLE
4-(1-hidroksi-2,2-dimetoksietil)-2,5-dimetilfenolis4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenol
5,2% natrio hidroksido (630g), 2,5-ksilenolio (100g) vandeninio tirpalo, 60% glioksalio dimetilacetalio (213g) vandenilio tirpalo ir vandens (200g) suspensija maišant buvo kaitinama prie 55°C 5 valandas. Reakcijos mišinys buvo vėsinamas ledo vonioje ir iš eilės į mišinį buvo pridėta acetanitrilo (90g) ir 7,4% druskos rūgšties (380g). Nusodintieji kristalai buvo nufiltruoti, siekiant gauti 4-(1-hidroksi-2,2-dimetoksietil)-2,5-dimetilfenolį (150g). 1H-NMR(DMSOd6) δ min. d.: 2,06 (3H, s), 2,15 (3H, s), 3,08 (3H, s), 3,35 (3H, s), 4,23 (1H, d, J=6,7Hz), 4,55 (1H, dd, J=6,7, 4,4Hz), 4,96 (1H, d, J=4,4Hz), 6,49 (1H, s), 7,03(1 H, s), 8,96(1 H, s).A suspension of 5.2% sodium hydroxide (630g), 2,5-xylene xenol (100g) in water, 60% glyoxal dimethylacetal (213g) in water and water (200g) was heated at 55 ° C for 5 hours with stirring. The reaction mixture was cooled in an ice bath and acetanitrile (90g) and 7.4% hydrochloric acid (380g) were added successively. The precipitated crystals were filtered to give 4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenol (150 g). 1 H-NMR (DMSOd 6 ) δ min. d: 2.06 (3H, s), 2.15 (3H, s), 3.08 (3H, s), 3.35 (3H, s), 4.23 (1H, d, J = 6) , 7Hz), 4.55 (1H, dd, J = 6.7, 4.4Hz), 4.96 (1H, d, J = 4.4Hz), 6.49 (1H, s), 7.03 (1H, s), 8.96 (1H, s).
PAVYZDYSEXAMPLE
Etilo 2-[4-(1-hidroksi-2,2-dimetoksietil)-2,5-dimetil-fenoksi]acetatasEthyl 2- [4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethyl-phenoxy] acetate
Į Ν,Ν-dimetilformamidą (81g) kambario temperatūroje maišant buvo pridėta 4-(1-hidroksi-2,2-dimetoksietil)-2,5-dimetilfenolio (20,Og), kalio karbonato (15,8g) ir etilo chloracetato (12,4g). Mišinys buvo maišomas kambario temperatūroje valandą ir po to maišomas prie 71°C 2 valandas. Reakcijos mišinys buvo praskiestas etilo acetatu, plaunamas vandeniu ir sūrymu ir džiovinamas bevandeniu natrio sulfatu. Organinis sluoksnis buvo koncentruojamas sumažintame slėgyje, ir į nuosėdas buvo pridėtas etilo acetato ir heksano mišinys. Nusodintieji kristalai buvo surinkti filtravimu, siekiant gauti etilo 2-[4-(1 -hidroksi-2,2-dimetoksietil)-2,5-dimetilfenoksijacetatą (21,3g).4- (1-Hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenol (20, Og), potassium carbonate (15.8g), and ethyl chloroacetate ( 12.4g). The mixture was stirred at room temperature for 1 hour and then stirred at 71 ° C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and a mixture of ethyl acetate and hexane was added to the residue. The precipitated crystals were collected by filtration to give ethyl 2- [4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (21.3 g).
1H-NMR(CDCI3) δ min. d.: 1,28 (3H, t, J=7,1Hz), 2,26 (3H, s), 2,32 (3H, s), 2,54 (1H, d, J=2,3Hz), 3,22 (3H, s), 3,50 (3H, s), 4,27 (2H, q, J=7,1Hz), 4,32 (1H, d, J=6,6Hz), 4,61 (2H, s), 4,80 (1H, dd, J=6,6, 2,3Hz), 6,48 (1H, s), 7,25 (1H, s). 1 H-NMR (CDCl 3 ) δ min. d: 1.28 (3H, t, J = 7.1Hz), 2.26 (3H, s), 2.32 (3H, s), 2.54 (1H, d, J = 2.3Hz) , 3.22 (3H, s), 3.50 (3H, s), 4.27 (2H, q, J = 7.1Hz), 4.32 (1H, d, J = 6.6Hz), 4 , 61 (2H, s), 4.80 (1H, dd, J = 6.6, 2.3Hz), 6.48 (1H, s), 7.25 (1H, s).
PAVYZDYSEXAMPLE
Etilo 2-[4-(2,2-dimetoksietil)-2,5-dimetilfenoksi]acetatasEthyl 2- [4- (2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate
Į maišomą natrio jodido (72g) ir chlortrimetiisilano (52g) acetonitrile (180g) suspensiją lašinant buvo pridėta etilo 2-[4-(1-hidroksi-2,2-dimetoksietil)-2,5-dimetilfenoksi]acetato (50g) acetonitrile (80g) tirpalo ledo-druskos vonioje. Mišinys buvo maišomas 30 minučių ir po to buvo pridėta tolueno (400g) ir piridino (25g). Reakcijos mišinys iš eilės buvo plaunamas vandeniniu natrio tiosulfato tirpalu, citrinų rūgšties vandeniniu tirpalu, natrio bikarbonato vandeniniu tirpalu ir sūrymu. Organinis sluoksnis buvo džiovinamas bevandeniu natrio sulfatu ir koncentruojamas sumažintame slėgyje, siekiant gauti etilo 2-[4-(2,2-dimetoksietil)-2,5-dimetilfenoksi]acetatą (43g).Ethyl 2- [4- (1-hydroxy-2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (50g) acetonitrile was added dropwise to a stirred suspension of sodium iodide (72g) and chlorotrimethisilane (52g) in acetonitrile (180g). 80g) in an ice-salt bath solution. The mixture was stirred for 30 minutes and then toluene (400g) and pyridine (25g) were added. The reaction mixture was washed successively with aqueous sodium thiosulfate solution, aqueous citric acid solution, aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 2- [4- (2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (43g).
1H-NMR(CDCI3) δ min. d.: 1,30 (3H, t, J=7,1Hz), 2,24 (3H, s), 2,27 (3H, s), 2,82 (2H, d, J=5,6Hz), 3,33 (6H, s), 4,27 (2H, q, J=7,1Hz), 4,47 (1H, t, J=5,6Hz), 4,60 (2H, s), 6,50 (1H, s), 6,97 (1H, s). 1 H-NMR (CDCl 3 ) δ min. d: 1.30 (3H, t, J = 7.1Hz), 2.24 (3H, s), 2.27 (3H, s), 2.82 (2H, d, J = 5.6Hz) , 3.33 (6H, s), 4.27 (2H, q, J = 7.1Hz), 4.47 (1H, t, J = 5.6Hz), 4.60 (2H, s), 6 , 50 (1H, s), 6.97 (1H, s).
PAVYZDYSEXAMPLE
Etilo 2-[4-(2-formilmetil)-2,5-dimetilfenoksi]acetatasEthyl 2- [4- (2-formylmethyl) -2,5-dimethylphenoxy] acetate
Etilo 2-[4-(2,2-dimetoksietil)-2,5-dimetilfenoksi]acetatas (23,7g) maišant buvo ištirpintas acetonitrile (110g) ir buvo pridėta 10% perchlorato rūgšties (120g) ir po to mišinys buvo maišomas valandą kambario temperatūroje. Reakcijos mišinys buvo paskirstytas tarp tolueno (190g) ir vandens (120g). Organinis sluoksnis iš eilės buvo plaunamas vandeniu, vandeniniu natrio bikarbonato tirpalu ir sūrymu ir džiovinamas bevandeniu natrio sulfatu, po ko sekė koncentravimas sumažintame slėgyje. Po nuosėdų ištirpinimo etanolyje (96g), tirpiklis buvo pašalintas sumažintame slėgyje. Nuosėdos vėl buvo ištirpintos etanoliu (96g), ir tirpiklio pašalinimas sumažintame slėgyje davė etilo 2-[4-(2-formilmetil)-2,5-dimetilfenoksi]acetatą (20,8g).Ethyl 2- [4- (2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (23.7g) was dissolved in acetonitrile (110g) with stirring and 10% perchloric acid (120g) was added and the mixture was stirred for one hour. at room temperature. The reaction mixture was partitioned between toluene (190g) and water (120g). The organic layer was washed successively with water, aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. After dissolving the precipitate in ethanol (96g), the solvent was removed under reduced pressure. The residue was redissolved in ethanol (96g) and removal of the solvent under reduced pressure gave ethyl 2- [4- (2-formylmethyl) -2,5-dimethylphenoxy] acetate (20.8g).
1H-NMR(CDCI3) 6 mln.d.: 1,30 (3H, t, J=7,1Hz), 2,20 (3H, s), 2,25 (3H, s), 3,59 (2H, d, J=2,4Hz), 4,27 (2H, q, J=7,1Hz), 4,62 (2H, s), 6,56 (1H, s), 6,94 (1H, s), 9,66 (1H, t, J=2,4Hz). 1 H-NMR (CDCl 3 )? Ppm: 1.30 (3H, t, J = 7.1Hz), 2.20 (3H, s), 2.25 (3H, s), 3.59 (2H, d, J = 2.4Hz), 4.27 (2H, q, J = 7.1Hz), 4.62 (2H, s), 6.56 (1H, s), 6.94 (1H , s), 9.66 (1H, t, J = 2.4Hz).
PAVYZDYSEXAMPLE
Etilo 2-[4-(2-etoksi-2-hidroksietil)-2,5-dimetilfenoksi]acetatasEthyl 2- [4- (2-ethoxy-2-hydroxyethyl) -2,5-dimethylphenoxy] acetate
Etilo 2-[4-(2,2-dimetoksietil)-2,5-dimetilfenoksi]acetatas (43g) maišant buvo ištirpintas acetonitrile (190g). Į susidariusį tirpalą buvo pridėta 10% perchlorato rūgšties (216g), ir mišinys buvo maišomas valandą kambario temperatūroje. Reakcijos mišinys buvo paskirstytas tarp tolueno (340g) ir vandens. (200g). Organinis sluoksnis iš eilės buvo plaunamas vandeniu, vandeniniu natrio bikarbonato tirpalu ir sūrymu ir džiovinamas bevandeniu natrio sulfatu, po ko sekė koncentravimas sumažintame slėgyje. Nuosėdos buvo ištirpintos etanolyje (180g), ir tirpiklis buvo pašalintas sumažintame slėgyje. Nuosėdos buvo ištirpintos su heksanu (86g) ir etanoliu (37g). Pridėjus kristaliklių, tirpalas buvo maišomas prie 0 - 10°C 2 valandas. Buvo pridėta heksano (220g) ir susidariusi suspensija buvo maišoma prie 0 - 10°C 2 valandas. Nusodinti kristalai buvo filtruojami, siekiant gauti etilo 2-[4-(2-etoksi2-hidroksietil)-2,5-d imetilfenoksi]acetatą (21 g).Ethyl 2- [4- (2,2-dimethoxyethyl) -2,5-dimethylphenoxy] acetate (43g) was dissolved in acetonitrile (190g) with stirring. To the resulting solution was added 10% perchloric acid (216g) and the mixture was stirred for one hour at room temperature. The reaction mixture was partitioned between toluene (340g) and water. (200g). The organic layer was washed successively with water, aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The precipitate was dissolved in ethanol (180g) and the solvent was removed under reduced pressure. The precipitate was dissolved with hexane (86g) and ethanol (37g). After the addition of crystallizers, the solution was stirred at 0 - 10 ° C for 2 hours. Hexane (220g) was added and the resulting suspension was stirred at 0-10 ° C for 2 hours. The precipitated crystals were filtered to give ethyl 2- [4- (2-ethoxy2-hydroxyethyl) -2,5-dimethylphenoxy] acetate (21 g).
1H-NMR(DMSO-de) 6 min. d.: 1,06 (3H, t, J=7,0Hz), 1,21 (3H, t, J=7,1Hz), 2,11 (3H, s), 2,19 (3H, s), 2,50-2,80 (2H, m), 3,20-3,40 (1H, m), 1 H-NMR (DMSO-d e) 6 min. d: 1.06 (3H, t, J = 7.0Hz), 1.21 (3H, t, J = 7.1Hz), 2.11 (3H, s), 2.19 (3H, s) , 2.50-2.80 (2H, m), 3.20-3.40 (1H, m),
3,60 - 3,70 (1H, m), 4,16 (2H, q, J=7,1Hz), 4,50 - 4,70 (1H, m), 4,73 (2H, s),3.60-3.70 (1H, m), 4.16 (2H, q, J = 7.1Hz), 4.50-4.70 (1H, m), 4.73 (2H, s),
5,98 (1H, d, J= 7,6Hz), 6,59 (1H, s), 6,93 (1H, s).5.98 (1H, d, J = 7.6Hz), 6.59 (1H, s), 6.93 (1H, s).
PAVYZDYSEXAMPLE
Etilo (-)-2-[4-[2-[[(1 S,2R)-2-hidroksi-2-(4-hidroksifenil)-1-metiletil]amino] etil]-2,5-dimetilfenoksi]acetatasEthyl (-) - 2- [4- [2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] -2,5-dimethylphenoxy] acetate
Etilo 2-[4-(2-etoksi-2-hidroksietil)-2,5-dimetilfenoksi]acetato (5,4g), 10% paladžio-anglies (50% drėgmė, 1,4g), (1R,2S)-2-amino-1-(4hidroksifenil)propan-1 -olio (3,0g) ir tetrahidrofurano (30g) suspensija buvo maišoma vandenilio atmosferoje prie 40°C 3 valandas. Po to, kai katalizatorius buvo pašalintas filtravimu, filtratas buvo koncentruojamas sumažintame slėgyje. Nuosėdos buvo ištirpintos toluene ir iš eilės plaunamos vandeniu, natrio bikarbonato vandeniniu tirpalu ir sūrymu. Organinis sluoksnis buvo džiovinamas bevandeniu natrio sulfatu, ir tirpiklis buvo pašalintas sumažintame slėgyje, siekiant gauti etilo (-)-2-[4-[2-[[( 1 S,2R)-2-hidroksi-2-(4hidroksi-fenil)-1 -metiletil]amino]etil]-2,5-dimetilfenoksi]acetatą (7,3g).Ethyl 2- [4- (2-ethoxy-2-hydroxyethyl) -2,5-dimethylphenoxy] acetate (5.4g), 10% Palladium Carbon (50% Humidity, 1.4g), (1R, 2S) - A suspension of 2-amino-1- (4-hydroxyphenyl) propan-1-ol (3.0g) and tetrahydrofuran (30g) was stirred under a hydrogen atmosphere at 40 ° C for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The precipitate was dissolved in toluene and washed successively with water, aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl (-) - 2- [4- [2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxy-phenyl)]. -1-methylethyl] amino] ethyl] -2,5-dimethylphenoxy] acetate (7.3 g).
1H-NMR(CDCI3) 6 min. d.: 0,98 (3H, d, J=6,4Hz), 1,34 (3H, t, J=7,1 Hz), 1 H-NMR (CDCl 3 ) 6 min. d: 0.98 (3H, d, J = 6.4Hz), 1.34 (3H, t, J = 7.1Hz),
2,18 (3H, s), 2,22 (3H, s), 2,60 - 3,00 (5H, m), 4,31 (2H, q, J=7,1Hz), 4,49 (1H, d, J=5,6Hz), 4,62 (2H, s), 6,41 (1H, s), 6,69 (2H, d, J=8,5Hz), 6,78 (1H, s), 7,05 (2H, d, J=8,5Hz).2.18 (3H, s), 2.22 (3H, s), 2.60 - 3.00 (5H, m), 4.31 (2H, q, J = 7.1Hz), 4.49 ( 1H, d, J = 5.6Hz), 4.62 (2H, s), 6.41 (1H, s), 6.69 (2H, d, J = 8.5Hz), 6.78 (1H, s), 7.05 (2H, d, J = 8.5Hz).
PAVYZDYSEXAMPLE
Etilo (-)-2-[4-[2-[[(1 S,2R)-2-hidroksi-2-(4-hidroksifenii)-1 -metiletiljamino] etil]-2,5-dimetilfenoksi]acetato hidrochloridasEthyl (-) - 2- [4- [2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethylamino] ethyl] -2,5-dimethylphenoxy] acetate hydrochloride
Etilo 2-[4-(2-etoksi-2-hidroksietil)-2,5-dimetilfenoksi]acetato (68,7g),Ethyl 2- [4- (2-ethoxy-2-hydroxyethyl) -2,5-dimethylphenoxy] acetate (68.7 g),
10% paladžio-anglies (50% drėgmė, 17g), (1R, 2S)-2-amino-1-(4hidroksifenil)propan-1-olio (38,Og) ir tetrahidrofurano (380g) suspensija buvo maišoma vandenilio atmosferoje prie 40°C 5 valandas. Po katalizatoriaus pašalinimo filtravimu, filtratas buvo koncentruojamas sumažintame slėgyje. Nuosėdos buvo ištirpintos toluene ir plaunamos iš eilės vandeniu, vandeniniu natrio bikarbonato tirpalu ir sūrymu. Organinis sluoksnis buvo džiovinamas bevandeniu natrio sulfatu, ir tirpiklis buvo pašalintas sumažintame slėgyje. Nuosėdos buvo ištirpintos toluene (200g) ir etanolyje (21 g) ir buvo prilašinta 20 masės % vandenilio chlorido etanolyje (37,3g). Nusodintieji kristalai buvo filtruojami, siekiant gauti etilo (-)-2-[4-[2-[[(1 S,2R)-2-hidroksi-2-(4hidroksifenil)-1-metiletil]amino]etil]-2,5-dimetilfenoksi]acetato hidrochloridą (70,2g).A suspension of 10% palladium-carbon (50% humidity, 17g), (1R, 2S) -2-amino-1- (4-hydroxyphenyl) propan-1-ol (38.0 g) and tetrahydrofuran (380g) was stirred under a hydrogen atmosphere at 40 ° C. ° C for 5 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. The precipitate was dissolved in toluene and washed successively with water, aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The precipitate was dissolved in toluene (200g) and ethanol (21g) and added dropwise to 20% w / w hydrogen chloride in ethanol (37.3g). The precipitated crystals were filtered to give ethyl (-) - 2- [4- [2 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] -2. 5-dimethylphenoxy] acetate hydrochloride (70.2 g).
1H-NMR(DMSO-d6) δ mln. d.: 0,96 (3H, d, J=6,6Hz), 1,21 (3H, t, 1 H-NMR (DMSO-d 6 ) δ million. d: 0.96 (3H, d, J = 6.6Hz), 1.21 (3H, t,
J=7,1 Hz), 2,15 (3H, s), 2,25 (3H, s), 2,8 - 3,2 (4H, m), 4,16 (2H, q, J=7,1Hz),J = 7.1 Hz), 2.15 (3H, s), 2.25 (3H, s), 2.8 - 3.2 (4H, m), 4.16 (2H, q, J = 7 , 1Hz),
4,76 (2H, s), 4,9 - 5,1 (1H, m), 5,8 - 6,0 (1H, m), 6,68 (1H, s), 6,76 (2H, d, J=8,5Hz), 6,96 (1 H, s), 7,17 (2H, d, J=8,5Hz), 8,5 - 9,0 (2H, br), 9,41 (1 H, s)..4.76 (2H, s), 4.9-5.1 (1H, m), 5.8-6.0 (1H, m), 6.68 (1H, s), 6.76 (2H, d, J = 8.5Hz), 6.96 (1H, s), 7.17 (2H, d, J = 8.5Hz), 8.5-9.0 (2H, br), 9.41 (1H, s) ..
PRAMONINIS PRITAIKYMASINDUSTRIAL ADAPTATION
Iš komerciškai naudingo 2,5-ksilenolio per hemiacetalio darinį, išreikštą šio išradimo bendra formule (I), įprastais būdais gali būti gaunamas aukšto grynumo bendros (X) formulės fenoksiacto rūgšties darinys arba jo farmaciškai priimtina druska. Taigi, minėtas hemiacetalio darinys (I) yra tinkamas panaudoti kaip tarpinis junginys gamybai vaisto, skirto nutukimo, hiperglikemijos, ligų, sukeltų žarnyno hiperkinezija, polakiurijos, šlapimo nelaikymo, depresijos arba tulžies akmenligės gydymui arba profilaktikai.The commercially useful 2,5-xylenol via the hemiacetal derivative represented by the general formula (I) of the present invention can, in conventional manner, provide a high-purity phenoxyacetic acid derivative of the general formula (X) or a pharmaceutically acceptable salt thereof. Thus, said hemiacetal derivative (I) is useful as an intermediate in the manufacture of a medicament for the treatment or prevention of obesity, hyperglycemia, diseases caused by intestinal hyperkinesia, polycuria, urinary incontinence, depression or gallstones.
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| WO2000002846A1 (en) | 1998-07-08 | 2000-01-20 | Kissei Pharmaceutical Co., Ltd. | Phenoxyacetic acid derivatives and medicinal compositions containing the same |
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| WO2000002846A1 (en) | 1998-07-08 | 2000-01-20 | Kissei Pharmaceutical Co., Ltd. | Phenoxyacetic acid derivatives and medicinal compositions containing the same |
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