WO2021116820A1 - An improved process for the preparation of benoxaprofen - Google Patents
An improved process for the preparation of benoxaprofen Download PDFInfo
- Publication number
- WO2021116820A1 WO2021116820A1 PCT/IB2020/061304 IB2020061304W WO2021116820A1 WO 2021116820 A1 WO2021116820 A1 WO 2021116820A1 IB 2020061304 W IB2020061304 W IB 2020061304W WO 2021116820 A1 WO2021116820 A1 WO 2021116820A1
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- WIPO (PCT)
- Prior art keywords
- formula
- give
- acid
- benoxaprofen
- sodium
- Prior art date
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- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 229960005430 benoxaprofen Drugs 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- -1 aldehyde compound Chemical class 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 239000004593 Epoxy Substances 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 150000004703 alkoxides Chemical class 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 230000020477 pH reduction Effects 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- NMFLSBMOTSULJS-UHFFFAOYSA-N N-(5-acetyl-2-hydroxyphenyl)-4-chlorobenzamide Chemical compound CC(=O)C1=CC=C(O)C(NC(=O)C=2C=CC(Cl)=CC=2)=C1 NMFLSBMOTSULJS-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- VODRWDBLLGYRJT-UHFFFAOYSA-N propan-2-yl 2-chloroacetate Chemical compound CC(C)OC(=O)CCl VODRWDBLLGYRJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 3
- 229960002218 sodium chlorite Drugs 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- 239000003810 Jones reagent Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 claims description 2
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940093499 ethyl acetate Drugs 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- FIISKTXZUZBTRC-UHFFFAOYSA-N 2-phenyl-1,3-benzoxazole Chemical compound C1=CC=CC=C1C1=NC2=CC=CC=C2O1 FIISKTXZUZBTRC-UHFFFAOYSA-N 0.000 description 2
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 2
- 0 CC(c(cc1)cc(*C(c2ccc(C)cc2)=O)c1O)=O Chemical compound CC(c(cc1)cc(*C(c2ccc(C)cc2)=O)c1O)=O 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- YOCRMABISPGUSN-UHFFFAOYSA-N 2-(3-amino-4-hydroxyphenyl)propanenitrile Chemical compound N#CC(C)C1=CC=C(O)C(N)=C1 YOCRMABISPGUSN-UHFFFAOYSA-N 0.000 description 1
- RZSVLKAIDMAXLB-UHFFFAOYSA-N 2-(4-aminophenyl)propanenitrile Chemical compound N#CC(C)C1=CC=C(N)C=C1 RZSVLKAIDMAXLB-UHFFFAOYSA-N 0.000 description 1
- YLOVYLOYLHRGAG-UHFFFAOYSA-N 2-(4-hydroxy-3-nitrophenyl)propanenitrile Chemical compound N#CC(C)C1=CC=C(O)C([N+]([O-])=O)=C1 YLOVYLOYLHRGAG-UHFFFAOYSA-N 0.000 description 1
- BTNSSVRIZUUYGM-UHFFFAOYSA-N 2-(4-hydroxyphenyl)propanenitrile Chemical compound N#CC(C)C1=CC=C(O)C=C1 BTNSSVRIZUUYGM-UHFFFAOYSA-N 0.000 description 1
- RBGOLZYAUJDSGL-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propanenitrile Chemical compound N=1C2=CC(C(C#N)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 RBGOLZYAUJDSGL-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YIXZPTACROPVQY-UHFFFAOYSA-N ClC1(C(C=C(C=C1)C(C#N)C)NC(C1=CC=CC=C1)=O)O Chemical compound ClC1(C(C=C(C=C1)C(C#N)C)NC(C1=CC=CC=C1)=O)O YIXZPTACROPVQY-UHFFFAOYSA-N 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- SPWBTGHLRNYHPA-UHFFFAOYSA-N acetic acid;nitric acid;hydrochloride Chemical compound Cl.CC(O)=O.O[N+]([O-])=O SPWBTGHLRNYHPA-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- XUPYJHCZDLZNFP-UHFFFAOYSA-N butyl butanoate Chemical compound CCCCOC(=O)CCC XUPYJHCZDLZNFP-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
Definitions
- the present invention relates to an improved process for the preparation of Benoxaprofen having formula (I) and its intermediate thereof.
- Benoxaprofen (I) is chemically known as 2-(4-chlorophenyl)-a-methyl-5- benzoxazoleacetic acid. Benoxaprofen (I) is a non-steroidal anti-inflammatory drug (NSAID).
- NSAID non-steroidal anti-inflammatory drugs
- Non-steroidal anti-inflammatory drugs are a class of medications that possess analgesic and anti-pyretic activities. They are used for reducing body pains, cold, fever and inflammation in a large variety of musculoskeletal disorders, menstrual cramps.
- NSAIDS are perhaps most popular new group of medications in the market today. Generally, these drugs are used to treat all kinds of pain including rheumatoid arthritis, pain caused by autoimmune disease and physical trauma.
- the US Patent RE ‘608 described a process for the preparation of Benoxaprofen of formula (I) comprising: a Sandmeyer reaction, by diazotization of 2-(4-aminophenyl)propanenitrile of formula (a) with sodium nitrite followed by acid hydrolysis to give 2-(4-hydroxyphenyl)propionitrile of formula (b), which further undergoes nitration with nitric acid in presence of acetic acid to give 2-(3- nitro-4-hydroxyphenyl)propionitrile of formula (c) followed by reduction with stannous chloride dihydrate or with 10% palladium carbon to give 2-(3-amino-4- hydroxyphenyl)propionitrile of formula (d).
- ES 8302676 A1 of Ferrer International S.A described a process for the preparation of Benoxaprofen of formula (I), by acylation of compound of formula (k) with p-chlorobenzoyl chloride of formula (e) which is further heated to dehydration to give corresponding 2-phenyl benzoxazole (1) which further undergoes Grignard reaction to give Benoxaprofen (I).
- the process is schematically represented in Scheme-Ill.
- the disadvantage of the above said process is that it leads to the formation of a dimethyl impurity in methylation step which is difficult to eliminate in purification. Further, it is very difficult to remove unreacted intermediate (q) in the purification and also involves low temperature reaction (-78°C) in final stage.
- the primary objective of the present invention is to provide an improved process for the preparation of Benoxaprofen of formula (I).
- Another objective of the present invention is to provide a simple, cost effective & industrially viable process for the preparation of Benoxaprofen of formula (I) having good yield and purity.
- the present invention provides an improved and cost effective process for the preparation of Benoxaprofen of formula (I). which comprises: i) Reaction of N-(5-acetyl-2-hydroxyphenyl)-4-chlorobenzamide of formula (VI): with a base and in the presence of a catalyst to give l-(2-(4-chlorophenyl)benzo[d] oxazol-5-yl)-ethanone of formula (V); ii) Reaction of compound of formula (V) with isopropyl chloroacetate in the presence of metal alkoxides to give epoxy ester intermediate of formula (IV); iii) Hydrolysis of compound of formula (IV) to give salt of epoxy acid compound of formula (III)
- the present invention provides an improved process for the preparation of Benoxaprofen of formula (I); which comprises : i) reaction of N-(5-acetyl-2-hydroxyphenyl)-4-chlorobenzamide of formula (VI): with a base and in the presence of a catalyst to give l-(2-(4-chlorophenyl)benzo[d] oxazol-5-yl)-ethanone of formula (V); which may be optionally isolated or carried forward as such to the next step without isolation.
- M is Na, Kor Li followed by acidification using inorganic acid to give an aldehyde compound of formula (II); iv) Oxidation of aldehyde compound of formula (II) using a suitable oxidising agent to give Benoxaprofen crude compound of formula (I) which is optionally purified to give pure Benoxaprofen.
- the process for preparation of Benoxaprofen as described in the present invention is schematically represented as shown below.
- the base used in the intramolecular cyclisation of compound of formula VI comprises, triethylamine, pyridine or DIPEA (N,N-Diisopropylethylamine).
- the catalyst comprises, methane sulfonic acid, para toluene sulfonic acid or pyridinium para-toluene sulfonate.
- the solvent comprises, aprotic solvents toluene, hexane, dichloromethane, acetone, tetrahydrofuran, dimethyl sulfoxide and dimethyl formamide or mixtures thereof.
- the base used in the epoxidation step comprises, alkali alkoxides selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tertiary butoxide, potassium methoxide, potassium i-butoxide or potassium tertiary butoxide.
- the solvent comprises, polar aprotic solvents selected from tetrahydrofuran, dimethyl sulfoxide and dimethyl formamide or mixture thereof.
- alkali metal hydroxide comprises sodium, potassium or lithium hydroxides or mixtures thereof, preferably sodium hydroxide.
- Acidification of salt of acid is carried out in presence of mineral acids comprises hydrochloric acid, sulphuric acid or nitric acid.
- Oxidation of aldehyde intermediate is carried out in the presence of oxidising agents comprises potassium permanganate, peroxy acids, hydrogen peroxide, sodium chlorite, oxone, Jones reagent or a mixture thereof to provide the desired acid compound.
- Purification of crude Benoxaprofen is further carried out in solvents comprises water, methanol, ethanol, propanol, isopropanol, butanol ethylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof.
- Step-I N-(5-Acetyl-2-hydroxyphenyl)-4-chlorobenzamide of formula (VI) (185 g) was suspended in toluene (2000 ml) at 20-30°C. Triethylamine (74.16 g) was added to the reaction mixture. Methane sulfonic acid (104.2g) was added to the reaction mass at 20-45°C over a period of 55 to 65 min. The reaction was heated to 110-115°C with removal of water azeotropically. The reaction was monitored by HPLC, after completion of reaction, reaction mixture was concentrated under reduced pressure at 60-65°C. Isopropyl alcohol was added to the concentrated mass at 40-50°C.
- reaction mixture was heated to 65-70°C with continuous stirring and cooled to 10-15°C, stirred at this temperature for 40 to 50 minutes. Filtered the product and washed with precooled isopropyl alcohol, dried the product under reduced pressure at 60-65°C to get title compound of formula V.
- Step-II l-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)ethanone compound of formula (V) (25. Og) was suspended in tetrahydrofuran (250.0 mL) under nitrogen atmosphere. Isopropyl chloroacetate (25. Og) was added to this mixture at 20-30°C and the reaction mass was cooled to 10-15°C. Sodium ethoxide solution (58.4g) was added over a period of 30 minutes and continued stirring at this temperature for 2 hours ⁇ 15 min. The reaction was monitored by HPLC, after completion of reaction, DM water (25 mL) was added to the reaction mass at 10-20°C. The reaction mass was proceeded to the next step without isolation of epoxy ester intermediate.
- Step-III Sodium hydroxide (50% w/w, 7.35g) solution was added to the reaction mass obtained in step-II and stirred at 10-15°C. The reaction was monitored by HPLC. After completion of reaction, DM water (lOmL) was added to the reaction mass at 20-30°C. The reaction mass was concentrated under reduced pressure at 10-50°C till the reaction mass volume was reduced to ⁇ 75mL. The ⁇ reaction mass was cooled to 20-30°C and DM water was added (75mL). This reaction mass was proceeded to next step without isolation.
- Step-IV The pH of the reaction mass obtained from step -III was adjusted to 4.0 - 4.2 with cone. Hydrochloric acid ( ⁇ 10mL) at 20-30°C. The reaction mass was heated to reflux (65- 75°C) and maintained at this temperature for completion of epoxy acid intermediate. The reaction was monitored by HPLC. After completion of epoxy acid intermediate, the reaction mass was cooled to 50-60°C and toluene (150mL) and DM water (125mL) were added at 50-60°C. It was allowed to stir at 50-60°C for 20-25 min. The organic layer was separated and washed with water, the organic layer was further concentrated under reduced pressure at 10-50°C till reaction mass volume was about ⁇ 130mL.
- Step-V Acetonitrile (25mL) was charged into a solution of benzoxazole aldehyde solution obtained in previous stage at 20-30°C and cooled to 5-15°C. Hydrogen peroxide (12.5g) was added to the reaction mass at 5-15°C and later the pH was adjusted to 3.2 ⁇ 0.5 with aqueous sodium dihydrogen phosphate solution (lOOmL) at 5-15°C followed by addition of Potassium bromide (0.25g). 80% (w/w) Sodium chlorite solution ( ⁇ 95mL) was added to this reaction mixture at 5-15°C for a period of 1 hour ⁇ 5 min. The reaction mixture was stirred at 5-15°C until the completion of reaction which was monitored by HPLC.
- Step- VI The crude Benoxaprofen compound (16g) was suspended in methyl isobutyl ketone (MIBK) (288mL) at 25-30°C. The reaction mass was then heated to 110-115°C. To this reaction mass carbon enoanticromos (0.8g) was added and continued to stir at this temperature for 15-20 min.
- MIBK methyl isobutyl ketone
- reaction mass was then passed through celite bed and washed with MIBK (32mL) at 110-115°C.
- MIBK 32mL
- the fdtrate was concentrated under reduced pressure at 50-60°C to obtain a reaction mass volume ⁇ 130mL, cooled the slurry mass to 20-25°C and stirred for lhour ⁇ 1 Omin.
- the resulting product was filtered, washed and dried to get pure Benoxaprofen
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Citations (3)
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EP0000276B1 (en) * | 1977-06-28 | 1982-09-01 | Lilly Industries Limited | A novel crystalline form of benoxaprofen, methods of preparation thereof and pharmaceutical formulations containing said novel form |
WO2004046122A2 (en) * | 2002-11-16 | 2004-06-03 | Oxford Glycosciences (Uk) Ltd | Benzoxazole, benzthiazole and benzimidazole acid derivatives and their use as heparanase inhibitors |
EP1688413A1 (en) * | 2005-02-03 | 2006-08-09 | Hikma Pharmaceuticals Co. Ltd. | Benzoxazole derivatives for the prophylaxis and treatment of inflammatory bowel diseases |
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EP0000276B1 (en) * | 1977-06-28 | 1982-09-01 | Lilly Industries Limited | A novel crystalline form of benoxaprofen, methods of preparation thereof and pharmaceutical formulations containing said novel form |
WO2004046122A2 (en) * | 2002-11-16 | 2004-06-03 | Oxford Glycosciences (Uk) Ltd | Benzoxazole, benzthiazole and benzimidazole acid derivatives and their use as heparanase inhibitors |
EP1688413A1 (en) * | 2005-02-03 | 2006-08-09 | Hikma Pharmaceuticals Co. Ltd. | Benzoxazole derivatives for the prophylaxis and treatment of inflammatory bowel diseases |
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