WO2005051935A1 - Method for preparing phenyl heterocycles as cyclooxygenase-2 inhibitor - Google Patents
Method for preparing phenyl heterocycles as cyclooxygenase-2 inhibitor Download PDFInfo
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- WO2005051935A1 WO2005051935A1 PCT/KR2004/000130 KR2004000130W WO2005051935A1 WO 2005051935 A1 WO2005051935 A1 WO 2005051935A1 KR 2004000130 W KR2004000130 W KR 2004000130W WO 2005051935 A1 WO2005051935 A1 WO 2005051935A1
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 title claims abstract description 11
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- 238000007273 lactonization reaction Methods 0.000 claims abstract description 11
- 238000006467 substitution reaction Methods 0.000 claims abstract description 11
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 10
- 239000003999 initiator Substances 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- 239000000376 reactant Substances 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 claims description 11
- 230000002209 hydrophobic effect Effects 0.000 claims description 10
- 239000002798 polar solvent Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 230000000881 depressing effect Effects 0.000 claims description 9
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 229960002163 hydrogen peroxide Drugs 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 230000000994 depressogenic effect Effects 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 claims description 3
- 229910000166 zirconium phosphate Inorganic materials 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 229940083608 sodium hydroxide Drugs 0.000 claims 1
- 235000011121 sodium hydroxide Nutrition 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 238000003912 environmental pollution Methods 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 6
- 150000002367 halogens Chemical class 0.000 abstract description 6
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 abstract description 3
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 19
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical group C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 11
- 229960000371 rofecoxib Drugs 0.000 description 10
- 230000003247 decreasing effect Effects 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- IRDHYTJELMYUOR-UHFFFAOYSA-N 3-(4-fluorophenyl)-4-phenyl-2h-furan-5-one Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 IRDHYTJELMYUOR-UHFFFAOYSA-N 0.000 description 4
- UZLXCHVDUBCZMH-UHFFFAOYSA-N 3-(4-methylsulfanylphenyl)-4-phenyl-2h-furan-5-one Chemical compound C1=CC(SC)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 UZLXCHVDUBCZMH-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- AFBSVSJJWQSFSK-UHFFFAOYSA-N 3-(4-bromophenyl)-4-phenyl-2h-furan-5-one Chemical compound C1=CC(Br)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 AFBSVSJJWQSFSK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229960003424 phenylacetic acid Drugs 0.000 description 3
- 239000003279 phenylacetic acid Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052755 nonmetal Inorganic materials 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XMCRWEBERCXJCH-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1Cl XMCRWEBERCXJCH-UHFFFAOYSA-N 0.000 description 1
- FKJSFKCZZIXQIP-UHFFFAOYSA-N 2-bromo-1-(4-bromophenyl)ethanone Chemical compound BrCC(=O)C1=CC=C(Br)C=C1 FKJSFKCZZIXQIP-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000037093 Menstruation Disturbances Diseases 0.000 description 1
- 206010027339 Menstruation irregular Diseases 0.000 description 1
- 208000036831 Moderate mental retardation Diseases 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 231100000544 menstrual irregularity Toxicity 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 230000010309 neoplastic transformation Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- 239000010955 niobium Substances 0.000 description 1
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
Definitions
- the present invention relates to a method for preparing phenyl heterocycle as cyclooxygenase-2 inhibitor useful in the treatment of other cyclooxygenase mediated diseases, which is environmentally harmonious and has an improved productivity. More particularly, it relates to a method for preparing phenyl heterocycle as cyclooxygenase-2 inhibitor, characterized in providing a high-purity compound of Formula 5 with the low cost of production and a simple process, which is harmless to human and environmental pollution due to not generating a halogen gas when preparing, and comprising the steps of lactonization reaction with a compound of Formula 1 as an initiator; substitution reaction; and oxidation reaction.
- Cyclooxygenase is a non-steroidal antHnflammatory drug(NSAID) exerting antiin- flammatory, analgesic and antipyretic activity, which is rapidly and readily inducible by a number of functional groups including mitogens, endotoxin, hormones, cytokines and growth factors in comparison with a conventional cyclooxygenase- 1.
- NSAID non-steroidal antHnflammatory drug
- the above compound has been studying due to having excellent anti-cancer effects as well as a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effect, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
- the representative drug as cyclooxygenase-2 inhibitor is a rofecoxib.
- the rofecoxib is effective in alleviating symptoms related to a rheumatism heat, an influenza or other viral infection, a pain of influenza and neck, a menstrual irregularity, a headache, a toothache, a sprain and a fracture, a myositis, a neuralgia, a synovitis, an arthritis including an articular rheumatism and an osteoarthritis, a gout and a ankylosing, a bursitis, a burn; a pain, a heat and a inflammation including an injury after a surgical and dental operation.
- the rofecoxib can be used effectively to treat cancer due to being able to inhibit hormone induced uterine contractions, cellular neoplastic transformations and certain type of cancer growth through inhibition of prostaglandin G/H syntase.
- the rofecoxib is very excellent drug having various adaptability and excellent effect of medicine, which can be used in the treatment of dementia related Alzheimer's disease, dementia including a geriatric imbecility, a premature old age.
- Korean Pat. No. 10-0215358 and Korean Pat. Publication No. 2000-0022382 disclose that a method for preparing a rofecoxib such as Reaction Scheme 1.
- bromination reaction of Reaction Scheme 1 toxic chemicals such as aluminum chloride and bromine are used, so that it is not easy to control reaction, and can produce a gas which can affect environmental pollution and is dangerous to human body.
- bromine is known as a compound causing fatal damage in man's sexual organs.
- step of lactonization since a chromatography method is carried out by using silica gel when refining after reaction, a refining process needs a lot of time and cost of production is increased due to using an expensive silica gel.
- a conventional method for preparing a rofecoxib is comprised of three steps for a synthesis process.
- a noxious material to man's sexual organs such as bromine and non-environmentally harmonious material such as aluminum chloride are used in manufacturing process, so that it is danger in safety and there is possibility of environmental destruction.
- non-environmentally harmonious material such as aluminum chloride
- the present invention has been made in view of the above problems, and it is an object of the present invention to provide a method for preparing phenyl het- erocycles as a cyclooxygenase-2 inhibitor characterized in providing a high-purity compound of Formula 5 with the low cost of production and a simple process, which is harmless to human and environmental pollution due to not generating a halogen gas when preparing, and comprising the steps of lactonization reaction with a compound of Formula 1 as an initiator; substitution reaction; and oxidation reaction
- a method for preparing phenyl heterocycles as cyclooxygenase-2 inhibitor is comprised of the steps of lactonization reaction with a compound of Formula 1 as an initiator; substitution reaction; and oxidation reaction.
- X and X' are F, Cl or Br.
- the step of lactonization reaction to produce a compound of Formula 3 is comprised of the steps of agitating 1.0 equivalent of a compound of Formula 2, 1.0-1.5 equivalents of a compound of Formula 1 based on 1.0 equivalent of a compound of Formula 2, and a hydrophobic polar solvent at room temperature in the presence of 1.1-2.0 equivalents of a strong base for 1-2 hours, in which the hydrophobic polar solvent is selected from the group consisting of acetonitrile and methanol, and the polar base is selected from the group consisting of sodi- umhydroxide, potassium hydroxide, triethylamine and pyridine; removing the hydrophobic polar solvent by depression and distillation, after cooling the compound of Formula 1 and the compound of Formula 2 to 0 °C and 2.5 ⁇ 4 equivalents of l,8-diazabicyclo[5,4,0]undec-7-ene is dropwised therein, followed by agitation; oxidizing 50 ⁇ 60 mi of the reactant to pH
- the step of substitution reaction to produce a compound of Formula 4 is comprised of the steps of agitating 1.0 equivalent of the compound of Formula 3 and 1.0 ⁇ 1.5 equivalents of sodium thiomethoxide based on 1.0 equivalent of the compound of Formula 3 in an organic solvent at 50 ⁇ 60 °C for 1 ⁇ 2 hours, wherein the organic solvent is selected from the group consisting of hexamethylphosphoramide(HMPA), acetonitrile and methanol; cooling a reactant of the compound of Formula 3 and sodium thiomethoxide to room temperature and water is added thereto and the reactant is left for 7 ⁇ 10 hours for the crystallization; and recrystallizing the obtained solid with an ethanol.
- HMPA hexamethylphosphoramide
- the step of oxidation reaction to produce a compound of Formula 5 is comprised of the steps of agitating 1.0 equivalent of the compound of Formula 4 and 2.1 ⁇ 3 equivalents of metha-chloroperoxybezoic acid based on 1.0 equivalent of the compound of Formula 4 or 2.1 ⁇ 2.5 equivalents of 30 ⁇ 40% hydrogenperoxide in the presence of 0.01 ⁇ 0.05 equivalents of a catalyst at 40 ⁇ 45 °C for 0.5 ⁇ 1 hours, wherein the catalyst is selected from the group consisting of sodium tungstate-2 hydrate, acetic acid, sodium molybdate-2 hydrate and sodium vanadate; and cooling a reactant of the compound of Formula 4 and hydrogenperoxide to 0 °C ; and recrystallizing the obtained solid with an ethanol. Best Mode
- a method for preparing a rofecoxib in accordance with the present invention has a manufacturing process of the following Reaction Scheme 2.
- a method for preparing a rofecoxib employs the compound of Formula 1 linking with a halogen, as an initiator, so that a halogenization reaction is not needed to carry out, which does not produce a harmful gas.
- the method according to the present invention has advantages in low cost of production as well as being harmless to human and environmental pollution due to not generating a halogen gas in manufacturing process in comparison with a conventional method.
- the step of lactonization reaction produces a compound of Formula 3, by the steps of agitating a compound of Formula 2 and a compound of Formula 1 in a hydrophobic polar solvent at room temperature in the presence of a strong base for 1 ⁇ 2 hours; dropwising 2.5 ⁇ 4 equivalents of DBU in the reactant, followed by agitation for 1 ⁇ 2 hours; removing a hydrophobic polar solvent by depressing and distillating; oxidizing the reactant to pH 3 ⁇ 4 which is then washed, followed by depression and distillation; and adding an ethanol to the depressed and distilled reactant which is then cooled to 0 °C and agitated for 1 ⁇ 2 hours, followed by recrystallization.
- a yield of the compound of Formula 3 produced by the above method is 75 ⁇ 85%.
- a strong base employed in the present invention is selected from the group consisting of sodium hydroxide, potassium hydroxide, triethylamine and pyridine and 1.1 ⁇ 2.0 equivalents of the strong base based on 1.0 equivalent of Formula 2 is employed.
- a yield of Formula 3 is decreased, and in case of using more than 2.0 equivalents of the strong base based on 1 equivalent a compound of Formula 2, a yield of Formula 3 is relatively decreased, because Formula 2 is bonded to X or both of X and X', not X', of Formula 1, so that a separation and a refinement is difficult.
- the amount of the compound of Formula 1 used is 1.0 ⁇ 1.5 equivalents based on 1.0 equivalent of the compound of Formula 2. In case of using less than 1.0 equivalent of a compound of Formula 1, a yield of Formula 3 is decreased, and in case of using more than 1.5 equivalents of Formula 1, a yield of Formula 3 is relatively decreased because Formula 2 is bonded to X or both of X and X', not X', of Formula 1, so that a separation and a refinement is difficult.
- the amount of an ethanol, used for a recrystallization in the lactonization reaction is 5 ⁇ 10 parts by weight based on a compound of Formula 1. In case of using less than 5 parts by weight and more than 10 parts by weight, a yield of Formula 3 is decreased, and it is difficult to obtain a high purity of compound.
- the compound of Formula 1 is lactonized by using an ethanol, so that a high purity of a compound of Formula 3 is simply and rapidly produced.
- the organic solvent is selected from the group consisting of hexamethylphos- phoramide(HMPA), acetonitrile and methanol.
- the amount of the sodium thiomethoxide is 1.0 ⁇ 1.5 equivalents based on 1.0 equivalent of a compound of Formula 3. In case of using less that 1.0 equivalent of sodium thiomethoxide , a yield of Formula 4 is decreased, which causes a lowering of the total yield.
- the amount of an ethanol, used for a recrystallization in the substitution reaction is 5 ⁇ 10 parts by weight based on a compound of Formula 3. In case of using less than 5 parts by weight and more than 10 parts by weight, a yield of Formula 4 is decreased, and it is difficult to obtain a high purity of compound.
- a thiomethyl group is introduced to a compound of Formula 3 by using a sodium thiomethoxide and an organic solvent, so that a reaction time is shortened to 1 ⁇ 2 hours, and a compound of Formula 4 can be synthesized by carrying out a simple recrystallization using an ethanol.
- a compound of Formula 5 is obtained by the steps of agitating 1.0 equivalent of the compound of Formula 4 and 2.1 ⁇ 3 equivalents of metha-chloroperoxybezoic acid based on 1.0 equivalent of the compound of Formula 4 or 2.1 ⁇ 2.5 equivalents of 30 ⁇ 40% hydrogen peroxide in the presence of a catalyst at 40 ⁇ 45 °C for 0.5 ⁇ 1 hours; and cooling a reactant of the compound of Formula 4 and hydrogen peroxide to 0 °C ; and recrystallizing the obtained solid with an ethanol to produce a compound of Formula 5.
- a yield of Formula 5 is 95 ⁇ 100%.
- the catalyst can be a metal catalyst and a non-metal catalyst in which the metal catalyst is AM M O , wherein A is a hydrogen or an alkali metal such as lithium, M 1 2 6 1 and M are independent variants each other, which are selected from the group 2 consisting of vanadium, niobium, tantalum, molybdenum and tungsten. And also, an acetic acid as a non-metal catalyst can be used.
- More preferable catalysts are selected from the group consisting of sodium tungstate-2 hydrate, acetic acid, sodium molybdate-2 hydrate and sodium vanadate, and the amount of a catalyst used is 0.01 ⁇ 0.05 equivalents based on 1.0 equivalent of Formula 4.
- the catalyst used in the present invention can shorten reaction times by accelerating an oxidation reaction.
- the amount of an ethanol, used for a recrystallization in the recrystallization is 5 ⁇ 10 parts by weight based on a compound of Formula 4 as an initiator. In case of using less than 5 parts by weight and more than 10 parts by weight, a yield of Formula 5 is decreased, and it is difficult to obtain a high purity of compound.
- a reactant was cooled to 0 °C , and 44.8 mi (300mmol, 3 equivalents) of DBU was slowly dropwised, followed by agitating for 1 hour. After terminating the reaction, acetonitrile was removed by depressing and distillating. The amount of a remained reactant was about 55 mi , and the reactant was oxidized to pH 3.5 by using IN hydrochloric acid solution, which was then extracted twice with 100 mi of chloroform, and an organic layer was washed three times with 50 mi of water. The organic layer was dried with magnesium sulfate, followed by filtration, and then a desired compound was obtained by depressing and distillating.
- a reactant was cooled to 0 °C , and 10.3 mi (69.1mmol, 3 equivalents) of DBU was slowly dropwised, followed by agitating for 1 hour. After terminating the reaction, acetonitrile was removed by depressing and distillating. The amount of a remained reactant was about 55 mi , and the reactant was oxidized to pH 3.5 by using IN hydrochloric acid solution, which is then extracted twice with 100 mi of chloroform, and an organic layer was washed three times with 50 mi of water. The organic layer was dried with magnesium sulfate, followed by filtration, and then a desired compound was obtained by depressing and distillating.
- the amount of a remained reactant was about 55 mi , and the reactant was oxidized to pH 3.5 by using IN hydrochloric acid solution, which was then extracted twice with 100 mi of chloroform, and an organic layer was washed three times with 50 mi of water. The organic layer was dried with magnesium sulfate, followed by filtration, and then a desired compound was obtained by depressing and distillating.
- a method for preparing phenyl heterocycle as cyclo oxygenase-2 inhibitor in accordance with the present invention has advantages in providing a high-purity compound with the low cost of production and a simple-speedy refinement by using a recrystallization method, which is harmless to human and environmental pollution due to not generating a halogen gas when preparing.
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Abstract
The present invention relates to a method for preparing phenyl heterocycle as cyclooxygenase-2 inhibitor useful in the treatment of other cyclooxygenase meditated diseases, which is environmentally harmonious and has an improved productivity. More particularly, it relates to a method for preparing phenyl heterocycle as cyclooxygenase-2 inhibitor, characterized in providing a high-purity compound of Formula 5 with the low cost of production and a simple process, which is harmless to human and environmental pollution due to not generating a halogen gas when preparing, and comprising the steps of lactonization reaction with a compound of Formula 1 as an initiator; substitution reaction; and oxidation reaction.
Description
Description METHOD FOR PREPARING PHENYL HETEROCYCLES AS CYCLOOXYGENASE-2 INHIBITOR Technical Field
[1] The present invention relates to a method for preparing phenyl heterocycle as cyclooxygenase-2 inhibitor useful in the treatment of other cyclooxygenase mediated diseases, which is environmentally harmonious and has an improved productivity. More particularly, it relates to a method for preparing phenyl heterocycle as cyclooxygenase-2 inhibitor, characterized in providing a high-purity compound of Formula 5 with the low cost of production and a simple process, which is harmless to human and environmental pollution due to not generating a halogen gas when preparing, and comprising the steps of lactonization reaction with a compound of Formula 1 as an initiator; substitution reaction; and oxidation reaction.
[2] [Formula 1]
[3] wherein, X and X' are F, Cl, or Br.
[4] [Formula 5]
[5] Cyclooxygenase is a non-steroidal antHnflammatory drug(NSAID) exerting antiin- flammatory, analgesic and antipyretic activity, which is rapidly and readily inducible by a number of functional groups including mitogens, endotoxin, hormones, cytokines and growth factors in comparison with a conventional cyclooxygenase- 1.
[6] Also, the above compound has been studying due to having excellent anti-cancer effects as well as a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effect, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
[7] The representative drug as cyclooxygenase-2 inhibitor is a rofecoxib. The rofecoxib is effective in alleviating symptoms related to a rheumatism heat, an influenza or other viral infection, a pain of influenza and neck, a menstrual irregularity,
a headache, a toothache, a sprain and a fracture, a myositis, a neuralgia, a synovitis, an arthritis including an articular rheumatism and an osteoarthritis, a gout and a ankylosing, a bursitis, a burn; a pain, a heat and a inflammation including an injury after a surgical and dental operation.
[8] Also, the rofecoxib can be used effectively to treat cancer due to being able to inhibit hormone induced uterine contractions, cellular neoplastic transformations and certain type of cancer growth through inhibition of prostaglandin G/H syntase. In addition, the rofecoxib is very excellent drug having various adaptability and excellent effect of medicine, which can be used in the treatment of dementia related Alzheimer's disease, dementia including a geriatric imbecility, a premature old age.
[9] Korean Pat. No. 10-0215358 and Korean Pat. Publication No. 2000-0022382 disclose that a method for preparing a rofecoxib such as Reaction Scheme 1.
[10] [Reaction Scheme 1]
[11] But, in Reaction Scheme 1, cost of production is increased by using an expensive reagent such as 44nethylthioacetophenone as an initiator. Also, as an oxidizer, magnesium monoperoxyphthalate (hereinafter, referred to as 'MMPP') 6 hydrate is used or methachloro perbenzoic acid(hereinafter, referred to as 'MCPBA') is used, but those reagents are also very expensive and especially, the MMPP have to use large amount of more than 2 equivalents in reaction process, which has low purity of reagent and is unstable material, so that it is not easy to treat when mass-producing.
[12] Also, in bromination reaction of Reaction Scheme 1, toxic chemicals such as aluminum chloride and bromine are used, so that it is not easy to control reaction, and
can produce a gas which can affect environmental pollution and is dangerous to human body. In particular, bromine is known as a compound causing fatal damage in man's sexual organs.
[13] In step of lactonization, since a chromatography method is carried out by using silica gel when refining after reaction, a refining process needs a lot of time and cost of production is increased due to using an expensive silica gel.
[14] As described above, a conventional method for preparing a rofecoxib is comprised of three steps for a synthesis process. In the synthesis process, a noxious material to man's sexual organs such as bromine and non-environmentally harmonious material such as aluminum chloride are used in manufacturing process, so that it is danger in safety and there is possibility of environmental destruction. And there were problems to increase cost of production and need long time of manufacturing process and refining due to carrying out column chromatography using an expensive material such as 44nethylthioacetophenone. Disclosure
[15] Therefore, the present invention has been made in view of the above problems, and it is an object of the present invention to provide a method for preparing phenyl het- erocycles as a cyclooxygenase-2 inhibitor characterized in providing a high-purity compound of Formula 5 with the low cost of production and a simple process, which is harmless to human and environmental pollution due to not generating a halogen gas when preparing, and comprising the steps of lactonization reaction with a compound of Formula 1 as an initiator; substitution reaction; and oxidation reaction
[16] [Formula 1]
[17] wherein, X and X' are F, Cl or Br.
[18] [Formula 5]
[19] The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description. [20] A method for preparing phenyl heterocycles as cyclooxygenase-2 inhibitor is
comprised of the steps of lactonization reaction with a compound of Formula 1 as an initiator; substitution reaction; and oxidation reaction. [21] [Formula 1]
[22] wherein, X and X' are F, Cl or Br.
[23] [Formula 5]
[24] The step of lactonization reaction to produce a compound of Formula 3 is comprised of the steps of agitating 1.0 equivalent of a compound of Formula 2, 1.0-1.5 equivalents of a compound of Formula 1 based on 1.0 equivalent of a compound of Formula 2, and a hydrophobic polar solvent at room temperature in the presence of 1.1-2.0 equivalents of a strong base for 1-2 hours, in which the hydrophobic polar solvent is selected from the group consisting of acetonitrile and methanol, and the polar base is selected from the group consisting of sodi- umhydroxide, potassium hydroxide, triethylamine and pyridine; removing the hydrophobic polar solvent by depression and distillation, after cooling the compound of Formula 1 and the compound of Formula 2 to 0 °C and 2.5 ~ 4 equivalents of l,8-diazabicyclo[5,4,0]undec-7-ene is dropwised therein, followed by agitation; oxidizing 50 ~ 60 mi of the reactant to pH 3 ~ 4, in which the hydrophobic polar solvent is removed; depressing and distilling after washing the oxidized reactant; and adding an ethanol to the depressed and distilled reactant which is then cooled to 0 °C and agitated for 1 ~ 2 hours, followed by recrystallization.
[25] [Formula 2]
[26] [Formula 3]
[28] [Formula 4]
[29] The step of oxidation reaction to produce a compound of Formula 5 is comprised of the steps of agitating 1.0 equivalent of the compound of Formula 4 and 2.1 ~ 3 equivalents of metha-chloroperoxybezoic acid based on 1.0 equivalent of the compound of Formula 4 or 2.1 ~ 2.5 equivalents of 30 ~ 40% hydrogenperoxide in the presence of 0.01 ~ 0.05 equivalents of a catalyst at 40 ~ 45 °C for 0.5 ~ 1 hours, wherein the catalyst is selected from the group consisting of sodium tungstate-2 hydrate, acetic acid, sodium molybdate-2 hydrate and sodium vanadate; and cooling a reactant of the compound of Formula 4 and hydrogenperoxide to 0 °C ; and recrystallizing the obtained solid with an ethanol. Best Mode
[30] Hereinafter, the present invention is described in detail as follows.
[31] A method for preparing a rofecoxib in accordance with the present invention has a manufacturing process of the following Reaction Scheme 2.
[32] [Reaction Scheme 2]
[33] As shown in the above Reaction Scheme 2, a method for preparing a rofecoxib employs the compound of Formula 1 linking with a halogen, as an initiator, so that a halogenization reaction is not needed to carry out, which does not produce a harmful gas. The method according to the present invention has advantages in low cost of production as well as being harmless to human and environmental pollution due to not generating a halogen gas in manufacturing process in comparison with a conventional method.
[34] The step of lactonization reaction produces a compound of Formula 3, by the steps of agitating a compound of Formula 2 and a compound of Formula 1 in a hydrophobic polar solvent at room temperature in the presence of a strong base for 1 ~ 2 hours; dropwising 2.5 ~ 4 equivalents of DBU in the reactant, followed by agitation for 1 ~ 2 hours; removing a hydrophobic polar solvent by depressing and distillating; oxidizing the reactant to pH 3 ~ 4 which is then washed, followed by depression and distillation; and adding an ethanol to the depressed and distilled reactant which is then cooled to 0 °C and agitated for 1 ~ 2 hours, followed by recrystallization. A yield of the compound of Formula 3 produced by the above method is 75 ~ 85%.
[35] A strong base employed in the present invention is selected from the group consisting of sodium hydroxide, potassium hydroxide, triethylamine and pyridine and 1.1 ~ 2.0 equivalents of the strong base based on 1.0 equivalent of Formula 2 is employed. In case of using less than 1.1 equivalent of the strong base based on 1 equivalent of a compound of Formula 2, a yield of Formula 3 is decreased, and in case of using more than 2.0 equivalents of the strong base based on 1 equivalent a compound of Formula 2, a yield of Formula 3 is relatively decreased, because Formula 2 is bonded to X or both of X and X', not X', of Formula 1, so that a separation and a
refinement is difficult.
[36] The amount of the compound of Formula 1 used is 1.0 ~ 1.5 equivalents based on 1.0 equivalent of the compound of Formula 2. In case of using less than 1.0 equivalent of a compound of Formula 1, a yield of Formula 3 is decreased, and in case of using more than 1.5 equivalents of Formula 1, a yield of Formula 3 is relatively decreased because Formula 2 is bonded to X or both of X and X', not X', of Formula 1, so that a separation and a refinement is difficult.
[37] The amount of an ethanol, used for a recrystallization in the lactonization reaction, is 5 ~ 10 parts by weight based on a compound of Formula 1. In case of using less than 5 parts by weight and more than 10 parts by weight, a yield of Formula 3 is decreased, and it is difficult to obtain a high purity of compound.
[38] As described above, in the step of lactonization step forming a lactone, the compound of Formula 1 is lactonized by using an ethanol, so that a high purity of a compound of Formula 3 is simply and rapidly produced.
[39] In the step of substitution reaction, sodium thiomethoxide is mixed with a compound of Formula 3 in an organic solvent for 1 ~ 2 hours at 50 ~ 60 °C , and the reactant is cooled to room temperature, and water is added, and then the reactant is left for 7 ~ 10 hours to be crystallized, and the crystallized reactant is recrystallized with an ethanol to produce a compound of Formula 4. In this reaction, a yield of Formula 4 is 75 ~ 85%.
[40] The organic solvent is selected from the group consisting of hexamethylphos- phoramide(HMPA), acetonitrile and methanol. The amount of the sodium thiomethoxide is 1.0 ~ 1.5 equivalents based on 1.0 equivalent of a compound of Formula 3. In case of using less that 1.0 equivalent of sodium thiomethoxide , a yield of Formula 4 is decreased, which causes a lowering of the total yield.
[41] The amount of an ethanol, used for a recrystallization in the substitution reaction, is 5 ~ 10 parts by weight based on a compound of Formula 3. In case of using less than 5 parts by weight and more than 10 parts by weight, a yield of Formula 4 is decreased, and it is difficult to obtain a high purity of compound.
[42] As described above, in the substitution reaction, a thiomethyl group is introduced to a compound of Formula 3 by using a sodium thiomethoxide and an organic solvent, so that a reaction time is shortened to 1 ~ 2 hours, and a compound of Formula 4 can be synthesized by carrying out a simple recrystallization using an ethanol.
[43] In the step of oxidation reaction, a compound of Formula 5 is obtained by the steps of agitating 1.0 equivalent of the compound of Formula 4 and 2.1 ~ 3 equivalents of
metha-chloroperoxybezoic acid based on 1.0 equivalent of the compound of Formula 4 or 2.1 ~ 2.5 equivalents of 30 ~ 40% hydrogen peroxide in the presence of a catalyst at 40 ~ 45 °C for 0.5 ~ 1 hours; and cooling a reactant of the compound of Formula 4 and hydrogen peroxide to 0 °C ; and recrystallizing the obtained solid with an ethanol to produce a compound of Formula 5. In this reaction, a yield of Formula 5 is 95 ~ 100%. [44] The catalyst can be a metal catalyst and a non-metal catalyst in which the metal catalyst is AM M O , wherein A is a hydrogen or an alkali metal such as lithium, M 1 2 6 1 and M are independent variants each other, which are selected from the group 2 consisting of vanadium, niobium, tantalum, molybdenum and tungsten. And also, an acetic acid as a non-metal catalyst can be used.
[45] More preferable catalysts are selected from the group consisting of sodium tungstate-2 hydrate, acetic acid, sodium molybdate-2 hydrate and sodium vanadate, and the amount of a catalyst used is 0.01 ~ 0.05 equivalents based on 1.0 equivalent of Formula 4. The catalyst used in the present invention can shorten reaction times by accelerating an oxidation reaction.
[46] The amount of an ethanol, used for a recrystallization in the recrystallization, is 5 ~ 10 parts by weight based on a compound of Formula 4 as an initiator. In case of using less than 5 parts by weight and more than 10 parts by weight, a yield of Formula 5 is decreased, and it is difficult to obtain a high purity of compound.
[47] As described above, in the step of oxidation reaction according to the present invention, a 30 ~ 40% hydrogen peroxide and a catalyst are employed, so that a shortening of reaction time and a high yield thereof can be achieved, and a final product (rofecoxib) can be synthesized by carrying out a simple refinement using an ethanol.
[48] The present invention will be explained in detail by the following examples but is not limited thereto.
[49] Example 1
[50] Preparation of 3-fphenyl)-4-f4-chlorophenyl)-2f5H)-furanone
[51] 19.3g (102mmol, 1.02 equivalents) of 2,4-dichloroacetophenone and 13.6g (lOOmmol) of phenyl acetic acid were dissolved in 150 mi of acetonitrile, and 15.3 mi (l lOmmol, 1.1 equivalents) triethylamine was added therein, followed by agitating for 1 hour at room temperature.
[52] A reactant was cooled to 0 °C , and 44.8 mi (300mmol, 3 equivalents) of DBU was slowly dropwised, followed by agitating for 1 hour. After terminating the reaction, acetonitrile was removed by depressing and distillating. The amount of a remained
reactant was about 55 mi , and the reactant was oxidized to pH 3.5 by using IN hydrochloric acid solution, which was then extracted twice with 100 mi of chloroform, and an organic layer was washed three times with 50 mi of water. The organic layer was dried with magnesium sulfate, followed by filtration, and then a desired compound was obtained by depressing and distillating.
[53] 50 mi of ethanol was added in the compound, which is then cooled to 0 °C , and agitated for 1 hour, followed by filtration, and 21.6g of 3-(phenyl)-4(4-fluorophenyl)-2-(5H)-furanone was obtained.
[54] 1 H-NMR(CDC1 ) = δ5.16(2H,s), 7.27 ~ 7.35(4H,m), 7.4(5H,s) 3
[55] Example 2
[56] Preparation of 3-(phenyl)-4-(4-fluorophenyl)-2-(5H)- furanone
[57] 5g (23mmol, 1.02 equivalents) of 4-fluorophenylacylbromide and 3.1g (22.8mmol) of phenyl acetic acid were dissolved in 50 mi of acetonitrile, and 3.5 mi (25mmol, 1.1 equivalents) of triethylamine was added therein, followed by agitating for 1 hour at room temperature.
[58] A reactant was cooled to 0 °C , and 10.3 mi (69.1mmol, 3 equivalents) of DBU was slowly dropwised, followed by agitating for 1 hour. After terminating the reaction, acetonitrile was removed by depressing and distillating. The amount of a remained reactant was about 55 mi , and the reactant was oxidized to pH 3.5 by using IN hydrochloric acid solution, which is then extracted twice with 100 mi of chloroform, and an organic layer was washed three times with 50 mi of water. The organic layer was dried with magnesium sulfate, followed by filtration, and then a desired compound was obtained by depressing and distillating.
[59] 50 mi of ethanol was added in the compound, which is then cooled to 0 °C , and agitated for 1 hour, followed by filtration, and 4.7g of 3-(phenyl)-4(4-fluorophenyl)-2-(5H)-furanone was obtained.
[60] 1H-NMR(CDC1 ) = δ5.16(2H,s), 7.03 ~ 7.07(2H,m), 7.28 ~ 7.35(2H,m), 3 7.39(5H,s) [61] Example 3
[62] Preparation of 3-(phenyl)-4-(4-bromophenyl)-2-(5H)- furanone
[63] 7.7g (27.7mmol, 1.02 equivalents) of 2,4'-dibromoacetophenone and 3.7g (27.7mmol) of phenyl acetic acid were dissolved in 70 mi of acetonitrile, and 4.2 mi (29.9mmol, 1.1 equivalents) of triethylamine was added therein, followed by agitating for 1 hour at room temperature. [64] A reactant was cooled to 0 °C , and 12.2 mi (81.5mmol, 3 equivalents) of DBU was
slowly dropwised, followed by agitating for 1 hour. After terminating the reaction, acetonitrile was removed by depressing and distillating. The amount of a remained reactant was about 55 mi , and the reactant was oxidized to pH 3.5 by using IN hydrochloric acid solution, which was then extracted twice with 100 mi of chloroform, and an organic layer was washed three times with 50 mi of water. The organic layer was dried with magnesium sulfate, followed by filtration, and then a desired compound was obtained by depressing and distillating.
[65] 50 mi of ethanol was added in the compound, which is then cooled to 0 °C , and then agitated for 1 hour, followed by filtration, and 7g of 3-(phenyl)-4(4-bromophenyl)-2-(5H)-furanone was obtained.
[66] 'H-NMR^DCl ) = δ5.15(2H,s), 7.16 ~ 7.2(2H,d), 7.4(5H,s), 7.45 ~ 7.5(2H,d) 3
[67] Example 4
[68] Preparation of 3-(phenyl)-4-(4-methylthiophenyl)-2-(5H)-furanone
[69] lOg (37mmol) of 3-(phenyl)-4-(4<;hlorophenyl)-2-(5H)-furanone and 2.85g (40.7mmol, 1.1 equivalents) of sodium thiomethoxide were added in 50 mi of HMPA in the presence of a nitrogen, and the reactant was slowly heated to 55 °C , and agitated for 1.5 hours. After terminating a reaction, the reactant was cooled to room temperature, and 250 mi of water was slowly added, and the reactant was left for 8 hours, and the produced solid was removed and washed with water, and 50 mi of ethanol was added thereto, and then 8.3g of a yellow solid compound was obtained.
[70] 'H-NMR^DCl ) = δ2.47(3H,s), 5.16(2H,s), 7.27 ~ 7.35(4H,m) , 7.4(5H,s) 3
[71] Example 5
[72] 3-(phenyl)-4-(4-methylthiophenyl)-2-(5H)-furanone
[73] lg (3.94mmol) of 3-(phenyl)-4-(4-fluorophenyl)-2-(5H)-furanone and 0.3g (4.33mmol, 1.1 equivalents) of sodium thiomethoxide were added in 5 mi of HMPA in the presence of a nitrogen , and the reactant was slowly heated to 55 °C , and agitated for 1.5 hours. After terminating a reaction, the reactant was cooled to room temperature, and 25 mi of water was slowly added, and the reactant was left for 8 hours, and the produced solid was removed and washed with water and 10 mi of ethanol was added thereto, and then 0.9g of a yellow solid compound was obtained.
[74] 'H-NMR^DCl )=δ2.47(3H,s), 5.16(2H,s), 7.27 ~ 7.35(4H,m) , 7.4(5H,s) 3
[75] Example 6
[76] 3-(phenyl)-4-(4-methylthiophenyl)-2-(5H)-furanone
[77] lg (3.17mmol) of 3-(phenyl)-4-(4-bromophenyl)-2-(5H)- furanone and 0.24g (3.49mmol, 1.1 equivalents) of sodium thiomethoxide were added in 5 mi of HMPA in
the presence of a nitrogen, and the reactant was slowly heated to 55 °C , and agitated for 1.5 hours. After terminating a reaction, the reactant was cooled to room temperature, and 25 mi of water was slowly added, and the reactant was left for 8 hours, and the produced solid was removed and washed with water and 10 mi of ethanol was added thereto, and then 0.53g of a yellow solid compound was obtained. [78] 'H-NMR^DCl )=δ2.47(3H,s), 5.16(2H,s), 7.27 ~ 7.35(4H,m) , 7.4(5H,s) 3
[79] Example 7
[80] 3- henyl)-4-rr4-methylsulfonyl)phenyll-2-r5H)-furanone
[81] 2g (7. lmmol) of 3-(phenyl)-4-(4-methylthiophenyl)-2-(5H)-furanone and 0.05g (0.02 equivalents) of sodium tungstate were added in 15 mi of methanol, followed by agitation. 1.52g (15.6mmol, 2.2 equivalents) of 35% hydrogen peroxide solution was slowly dropwised. After finishing the dropwise, the reactant was slowly heated to 42 °C , and agitated for 1 hour. After terminating a reation, the reactant was cooled to 0 °C , and a solid was removed, and 20 mi of ethanol was added thereto, and then 2.2g of a desired solid compound was obtained.
[82] 1 H-NMR(CD COCD ) = δ3.16(3H,s), 5.38(2H,s), 7.41(5H,s), 7.66 ~ 7.7(2H,d) , 3 3 7.94 ~ 7.99(2H,d) Industrial Applicability
[83] A method for preparing phenyl heterocycle as cyclo oxygenase-2 inhibitor in accordance with the present invention has advantages in providing a high-purity compound with the low cost of production and a simple-speedy refinement by using a recrystallization method, which is harmless to human and environmental pollution due to not generating a halogen gas when preparing.
[84] Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
Claims
[1] 1. A method for preparing phenyl heterocycle as cyclo oxygenase-2 inhibitor comprising the steps of: lactonization reaction with a compound of Formula 1 as an initiator; substitution reaction; and oxidation reaction to prepare a compound of Formula 5. [Formula 1]
[2] 2. The method according to Claim 1, wherein said lactonization reaction to produce a compound of Formula 3 is comprised of the steps of agitating 1.0 equivalent of a compound of Formula 2, 1.0 ~ 1.5 equivalents of a compound of Formula 1 based on 1.0 equivalent of a compound of Formula 2, and a hydrophobic polar solvent at room temperature in the presence of 1.1 ~ 2.0 equivalents of a strong base for 1 ~ 2 hours, in which the hydrophobic polar solvent is selected from the group consisting of acetonitrile and methanol, and the polar base is selected from the group consisting of sodiumhydroxide, potassium hydroxide, triethylamine and pyridine; removing the hydrophobic polar solvent by depression and distillation, after cooling the compound of Formula 1 and the compound of Formula 2 to 0 °C and 2.5 ~ 4 equivalents of l,8-diazabicyclo[5,4,0]undec-7-ene is dropwised therein, followed by agitating; oxidizing 50 ~ 60 mi of the reactant, in which the hydrophobic polar solvent is removed, to pH 3 ~ 4; depressing and distilling after washing the oxidized reactant; and adding an ethanol to the depressed and distilled reactant which is then cooled to 0°C and agitated for 1~2 hours, followed by recrystallization. [Formula 2]
[Formula 3]
[3] 3. The method according to Claim 1, wherein said substitution reaction to produce a compound of Formula 4 is comprised of the steps of agitating 1.0 equivalent of the compound of Formula 3 and 1.0 ~ 1.5 equivalents of sodiumthiomethoxide based on 1.0 equivalent of the compound of Formula 3 in an organic solvent at 50 ~ 60 °C for 1 ~ 2 hours, wherein the organic solvent is selected from the group consisting of hexamethylphosphoramide(HMPA), acetonitrile and methanol; cooling a reactant of the compound of Formula 3 and sodium thiomethoxide to room temperature and water is added thereto and the reactant is left for 7 ~ 10 hours for the crystallization; and recrystallizing the obtained solid with an ethanol. [Formula 4]
[4] 4. The method according to Claim 1, wherein said oxidation reaction to produce a compound of Formula 5 is comprised of the steps of agitating 1.0 equivalent of the compound of Formula 4 and 2.1 ~ 3 equivalents of meta-chloroperoxybenzoic acid based on 1.0 equivalent of the compound of Formula 4 or 2.1 ~ 2.5 equivalents of 30 ~ 40% hydrogenperoxide in the presence of 0.01 ~ 0.05 equivalents of a catalyst at 40 ~ 45 °C for 0.5 ~ 1 hours, wherein the catalyst is selected from the group consisting of sodium tungstate-2 hydrate, acetic acid, sodium molybdate-2 hydrate and sodium vanadate; cooling a reactant of the compound of Formula 4 and hydrogenperoxide to 0 °C ; and recrystallizing the obtained solid with an ethanol.
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| KR1020030085341A KR20050051729A (en) | 2003-11-28 | 2003-11-28 | Process for preparing phenyl heterocycles as a cyclooxygenase-2 inhibitor |
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| US9132126B2 (en) | 2011-04-19 | 2015-09-15 | Il-Yang Pharm. Co., Ltd. | Phenyl-isoxazole derivatives and preparation process thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995018799A1 (en) * | 1994-01-10 | 1995-07-13 | Merck Frosst Canada Inc. | Phenyl heterocycles as cox-2 inhibitors |
| WO2003030812A2 (en) * | 2001-10-10 | 2003-04-17 | Shasun Chemicals And Drugs Limited | 1-[(4-methyl thio)phenyl]-2-(phenyl acetoxy)-1-ethanone and a process for preparing the same |
-
2003
- 2003-11-28 KR KR1020030085341A patent/KR20050051729A/en not_active Application Discontinuation
-
2004
- 2004-01-27 WO PCT/KR2004/000130 patent/WO2005051935A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995018799A1 (en) * | 1994-01-10 | 1995-07-13 | Merck Frosst Canada Inc. | Phenyl heterocycles as cox-2 inhibitors |
| WO2003030812A2 (en) * | 2001-10-10 | 2003-04-17 | Shasun Chemicals And Drugs Limited | 1-[(4-methyl thio)phenyl]-2-(phenyl acetoxy)-1-ethanone and a process for preparing the same |
Non-Patent Citations (1)
| Title |
|---|
| SYNLETT, vol. 12, 2000, pages 1749 - 1752 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9132126B2 (en) | 2011-04-19 | 2015-09-15 | Il-Yang Pharm. Co., Ltd. | Phenyl-isoxazole derivatives and preparation process thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20050051729A (en) | 2005-06-02 |
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