CN106496015B - A kind of preparation method of Flurbiprofen - Google Patents
A kind of preparation method of Flurbiprofen Download PDFInfo
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- CN106496015B CN106496015B CN201610934843.8A CN201610934843A CN106496015B CN 106496015 B CN106496015 B CN 106496015B CN 201610934843 A CN201610934843 A CN 201610934843A CN 106496015 B CN106496015 B CN 106496015B
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- Prior art keywords
- fluoro
- flurbiprofen
- preparation
- acid
- chlorphenyl
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- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960002390 flurbiprofen Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 60
- 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 claims abstract description 38
- -1 fluoro- 4- chlorphenyl Chemical group 0.000 claims abstract description 34
- 235000019260 propionic acid Nutrition 0.000 claims abstract description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 10
- BZBAYMUKLAYQEO-UHFFFAOYSA-N phenylborane Chemical compound BC1=CC=CC=C1 BZBAYMUKLAYQEO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- FPNVMCMDWZNTEU-UHFFFAOYSA-N 1-bromo-4-chloro-2-fluorobenzene Chemical compound FC1=CC(Cl)=CC=C1Br FPNVMCMDWZNTEU-UHFFFAOYSA-N 0.000 claims description 12
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 239000007818 Grignard reagent Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 150000004795 grignard reagents Chemical class 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- CYMXTKNOROVINH-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.C1(=CC=CC=C1)OB(O)O Chemical compound OC(C)(C)C(C)(C)O.C1(=CC=CC=C1)OB(O)O CYMXTKNOROVINH-UHFFFAOYSA-N 0.000 claims description 5
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- DHXNZYCXMFBMHE-UHFFFAOYSA-N 3-bromopropanoic acid Chemical compound OC(=O)CCBr DHXNZYCXMFBMHE-UHFFFAOYSA-N 0.000 claims description 3
- FCHOBGNNICMPQI-UHFFFAOYSA-N B([O-])([O-])[O-].[K+].FC(S(=O)(=O)OC1=CC=CC=C1)(F)F.[K+].[K+] Chemical compound B([O-])([O-])[O-].[K+].FC(S(=O)(=O)OC1=CC=CC=C1)(F)F.[K+].[K+] FCHOBGNNICMPQI-UHFFFAOYSA-N 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- DWOZNANUEDYIOF-UHFFFAOYSA-L 4-ditert-butylphosphanyl-n,n-dimethylaniline;dichloropalladium Chemical compound Cl[Pd]Cl.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 DWOZNANUEDYIOF-UHFFFAOYSA-L 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- RJCGZNCCVKIBHO-UHFFFAOYSA-N 1-chloro-4-fluorobenzene Chemical compound FC1=CC=C(Cl)C=C1 RJCGZNCCVKIBHO-UHFFFAOYSA-N 0.000 claims 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 claims 1
- LXDRHVXMGDKBEK-UHFFFAOYSA-N [B].C1=CC=CC=C1 Chemical group [B].C1=CC=CC=C1 LXDRHVXMGDKBEK-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000008065 acid anhydrides Chemical class 0.000 claims 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 235000011056 potassium acetate Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 description 26
- 229940095574 propionic acid Drugs 0.000 description 22
- 239000007787 solid Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- ZIQCCIAIROIHHR-UHFFFAOYSA-N benzene;boric acid Chemical compound OB(O)O.C1=CC=CC=C1 ZIQCCIAIROIHHR-UHFFFAOYSA-N 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- KLECYOQFQXJYBC-UHFFFAOYSA-N 1-fluoro-2-phenylbenzene Chemical group FC1=CC=CC=C1C1=CC=CC=C1 KLECYOQFQXJYBC-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101150003085 Pdcl gene Proteins 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- VOXXGUAZBWSUSS-UHFFFAOYSA-N 2,4,6-triphenyl-1,3,5,2,4,6-trioxatriborinane Chemical compound O1B(C=2C=CC=CC=2)OB(C=2C=CC=CC=2)OB1C1=CC=CC=C1 VOXXGUAZBWSUSS-UHFFFAOYSA-N 0.000 description 2
- AGYWDGVTLKNTBS-UHFFFAOYSA-N 4-bromo-1-chloro-2-fluorobenzene Chemical compound FC1=CC(Br)=CC=C1Cl AGYWDGVTLKNTBS-UHFFFAOYSA-N 0.000 description 2
- XRMZKCQCINEBEI-UHFFFAOYSA-N 4-bromo-2-fluoro-1-iodobenzene Chemical compound FC1=CC(Br)=CC=C1I XRMZKCQCINEBEI-UHFFFAOYSA-N 0.000 description 2
- HTRNHWBOBYFTQF-UHFFFAOYSA-N 4-bromo-2-fluoro-1-phenylbenzene Chemical group FC1=CC(Br)=CC=C1C1=CC=CC=C1 HTRNHWBOBYFTQF-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- SYTBZMRGLBWNTM-JTQLQIEISA-N (S)-flurbiprofen Chemical compound FC1=CC([C@@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-JTQLQIEISA-N 0.000 description 1
- ZXRLXIQQNRFCNA-UHFFFAOYSA-N 2-bromopropanoic acid;sodium Chemical compound [Na].CC(Br)C(O)=O ZXRLXIQQNRFCNA-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- ADYWBFBXUJFLII-UHFFFAOYSA-N 4-bromo-n-fluoroaniline Chemical compound FNC1=CC=C(Br)C=C1 ADYWBFBXUJFLII-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- ALIVXCSEERJYHU-UHFFFAOYSA-N Flurbiprofen axetil Chemical compound FC1=CC(C(C)C(=O)OC(OC(C)=O)C)=CC=C1C1=CC=CC=C1 ALIVXCSEERJYHU-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 229950006887 esflurbiprofen Drugs 0.000 description 1
- 229950005941 flurbiprofen axetil Drugs 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A kind of preparation method of Flurbiprofen, belong to the technical field of medicine preparation, using Suzuki coupling reaction, in the presence of a base by 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid and phenyl borane reagent, in organic solvent, by the Suzuki coupling reaction of palladium chtalyst, Flurbiprofen is obtained, wherein the molar ratio of 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid and phenyl borane reagent is 1:(0.9-1.1).Preparation method of the present invention is simple, and gained Flurbiprofen yield is high, with high purity.
Description
Technical field
The invention belongs to the technical fields of medicine preparation, are related to the preparation of Non-steroidanalgetic drug, and in particular to one
The preparation method of kind Flurbiprofen, preparation method of the present invention is simple, and gained Flurbiprofen yield is high, with high purity.
Background technique
Flurbiprofen 1 (Flurbiprofen), entitled 2- (the 2- fluorine biphenyl -4- base) propionic acid of chemistry, the entitled 2- (2- of English
fluoro-4-biphenylyl)propionicacid.Its structure is as shown below:
Flurbiprofen is a kind of non-steroidal anti-inflammatory analgesics of Bu Zi company, Britain exploitation.The medicine is in 1976 in Britain
City is a kind of potent phenylpropionic acid antipyretic and anti-inflammatory antalgesic, prostaglandin can be inhibited to prepare cyclooxygenase and rise analgesic, it is anti-inflammatory and
Refrigeration function.Its anti-inflammatory and analgesic activity are respectively 250 times and 50 times of aspirin (also known as acetylsalicylic acid).It is mainly used for
Rheumatic arthritis, rheumatoid arthritis, ankylosing spondylitis, degenerative arthritis.After can also preventing surgical lens removal
The mottled oedema of aphacia capsule sample occurs, after inhibiting pupil contraction in operation, cataract and trabeculoplasty argon laser to perform the operation
The treatment of ocular inflamation.Apply also for some other reason pain as caused by wound, strain, operation etc..
Flurbiprofen axetil is developed jointly by Japanese Kaken Pharmaceufical Co., Ltd. and green cross Pharmaceutical Co., Ltd, 1992
Year lists in Japan, and 2004 in Discussion on Chinese Listed.It is separated and is studied according to the chiral structure in Flurbiprofen and developed
Drug Esflurbiprofen, i.e. (S)+Flurbiprofen.The further exploitation that they are carried out using Flurbiprofen as raw material.
Flurbiprofen itself is that drug and some prodrugs and improved basis, tool play a very important role.Existing system
The method of standby Flurbiprofen mainly has following approach:
1. the fluoro- 4- bromaniline of 2- passes through diazo-reaction, then is coupled under alkalinity with benzene and obtains the fluoro- 4- bromo biphenyl of 2-, so
It reacts to obtain Flurbiprofen, gross production rate about 48% again with 2 bromopropionic acid sodium by Grignard Reagent preparation afterwards；
2. the fluoro- 4- bromo-iodobenzene of 2- is by Suzuki coupling reaction with phenyl boric acid, using Grignard Reagent preparation again with 2-
Bromo-propionic acid sodium reacts to obtain Flurbiprofen, gross production rate about 55%；
3. diazonium salt is made by diazo-reaction in 2- (the fluoro- 4- aminophenyl of 3-) propionic acid, alkalinity is lower to be coupled to obtain with benzene
Flurbiprofen, gross production rate about 50%.
Wherein, method 1,3 uses the biggish diazo-reaction of wastewater flow rate, and much excessive and severe toxicity benzene, to ring
Border and operator's harm are huge；Method 2 uses efficient Suzuki coupling reaction, but the sequence of constructing arranged causes to need
Using the expensive fluoro- 4- bromo-iodobenzene of 2-, and before the Suzuki for using noble metal catalyst reaction is arranged in, cost mistake is caused
Height, and low yield.
Summary of the invention
The present invention is to solve the drawbacks described above of the prior art, provides a kind of preparation route of Flurbiprofen, environmentally protective,
Healthy and safe, yield is high, consumes low, Flurbiprofen purity is high.
The present invention be realize its purpose the technical solution adopted is that:
A kind of preparation method of Flurbiprofen, using Suzuki coupling reaction, by 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid and benzene
Base borane reagent in the presence of a base, in organic solvent, by the Suzuki coupling reaction of palladium chtalyst, obtains fluorine and compares Lip river
Sweet smell, wherein the molar ratio of 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid and phenyl borane reagent is 1:(0.9-1.1).
The preparation of 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid is the following steps are included: using the fluoro- 4- chloro-bromobenzene of 3- as raw material, first by 3-
Fluoro- 4- chloro-bromobenzene is prepared into Grignard Reagent, then carries out coupling reaction with 2 bromopropionic acid sodium, then acidified obtain 2- (the fluoro- 4- of 3-
Chlorphenyl) propionic acid, wherein the molar ratio of the fluoro- 4- chloro-bromobenzene of 3- and 2 bromopropionic acid sodium is 1:(1-2).It is added in coupling reaction process
Magnesium chips, 3- fluoro- 4- chloro-bromobenzene, magnesium chips, 2 bromopropionic acid sodium molar ratio be 1:(1-2): (1-2).
The temperature of Grignard Reagent and 2 bromopropionic acid sodium coupling reaction is -10~70 DEG C.
The solvent of coupling reaction is tetrahydrofuran, ether, cyclopentyl methyl ether, glycol dimethyl ether, methyl tertiary butyl ether(MTBE), just
Butyl ether, toluene, combination one or more of in dimethylbenzene.
Phenyl borane reagent is phenyl boric acid, phenyl boric acid glycol ester, phenyl boric acid -1,3- propylene glycol ester, phenyl boric acid neopentyl glycol
Ester, phenyl boric acid pinacol ester, triphenylboroxin, combination one or more of in phenyl trifluoromethanesulfonate potassium borate.
Organic solvent is ethyl alcohol, toluene, tetrahydrofuran, dimethylformamide, dioxane, a kind of in glycol dimethyl ether
Or several combination.
Palladium catalyst is used in the Suzuki coupling reaction of palladium chtalyst, is PdCl2(dtbpf)、PdCl2(Amphos)2、Pd
(Pt-Bu3)2、Pd(Amphos)2One or more of combination.
The molar ratio of 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid and palladium catalyst is 1:(0.00005-0.005).
The alkali is selected from potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, potassium fluoride, triethylamine, sodium acetate, acetic acid
The combination of one or more of potassium, lithium hydroxide, cesium carbonate.
The molar ratio of 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid and alkali is 1:(1-3).
The beneficial effects of the present invention are:
Safety and environment are caused using a large amount of benzene 1. avoiding conventional method and preparing in the fluoro- 4- bromo biphenyl of intermediate 2-
The problem of pollution；
2. preparation route is succinct, every step yield is higher, pass through creative arrangement reaction sequence, and the strictly handle to details
Control, palladium catalyst dosage substantially reduce, catalyst cost are reduced to the level also lower than solvent expense, can sufficiently control life
Cost is produced, and the high conversion rate realized, wastage in bulk or weight are low；
3. raw material is easy to get, acquisition can be commercialized；
4. process route is environmentally protective, easy to operate, yield is high, and atom utilization is high, and solvent usage is small, and the three wastes are few, produces
It can be big.
5, Flurbiprofen gross production rate prepared by the present invention is greater than 99.5% up to 73% or more, HPLC purity.
Specific embodiment
The present invention, which uses for the Grignard Reagent of the fluoro- 4- chloro-bromobenzene of 3- and 2 bromopropionic acid sodium to be coupled, is acidified to obtain 2- again that (3- is fluoro-
4- chlorphenyl) propionic acid；2- (the fluoro- 4- chlorphenyl of 3-) propionic acid compares Lip river using reacting to obtain fluorine with the Suzuki of phenyl borane reagent
It is fragrant.This method raw material is easy to get and simply, efficiently, is suitble to industrialized production.Preparation route is as follows: wherein phenyl borane reagent 5
For phenyl boric acid, phenyl boric acid glycol ester, phenyl boric acid -1,3- propylene glycol ester, phenyl boric acid neopentyl glycol ester, phenyl boric acid pinacol ester,
One or more of combination in triphenylboroxin, phenyl trifluoromethanesulfonate potassium borate；
The present invention is further illustrated combined with specific embodiments below.
Embodiment 1
A, 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid (4) is prepared
In 1000ml dry four-hole bottle, 14.4g (0.6mol) magnesium chips, 50mlTHF, two iodine grains, nitrogen atmosphere is added
50 DEG C are heated with stirring in enclosing.The solution that the fluoro- 4- chloro-bromobenzene (2) of 105g (0.5mol) 3- is dissolved in 370mlTHF is instilled into 20ml,
After initiation to be confirmed and reacting balance, maintains 50~60 DEG C to instill remaining solution, drip off rear insulated and stirred 1h.
Reaction solution is cooled to 0 DEG C, no more than 10 DEG C at a temperature of, be added 96.3g (0.55mol) 2 bromopropionic acid sodium
(3), back flow reaction 1h is gradually heated up after adding, reaction terminates.
Reaction solution is cooled to 0 DEG C, is slowly added into 5mol/L hydrochloric acid 400ml, temperature is no more than 20 DEG C, stirs naturally after adding
30min is mixed, 50 DEG C of stirring 1h are again heated to.
Liquid separation, organic phase retain, and water phase is extracted twice, and use ethyl acetate 200ml every time.Merge organic phase and extract liquor,
Water-bath decompression is lower to steam solvent, steams to there is solid appearance, 300ml toluene is added, and stirring is cooled to -10 DEG C, and resulting white is solid
Body filters drying, obtains product 85g, yield 84%, and HPLC measures purity and is greater than 99.5%.
B, 2- (the fluoro- biphenyl -4- base of 2-) propionic acid --- Flurbiprofen (1) is prepared
In 1000ml there-necked flask, product 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid (4) is walked in addition) 85g (0.42mol), benzene
Boric acid (5) 53.7g (0.44mol), ethyl alcohol 200ml, toluene 300ml, potassium carbonate 121g (0.88mol) are dissolved in the molten of 200ml water
Liquid.PdCl is added under nitrogen protection after mixing evenly2(Amphos)294mg (0.03mol%).It is heated to back flow reaction 4h,
TLC is displayed without raw material (4) residue, and reaction terminates.
Solvent is steamed, is cooled to 0 DEG C, is filtered.The solid of generation is washed with 200ml cold water.Then solid is dissolved in
In hot water, hydrochloric acid is added dropwise to pH value less than 3, a large amount of solids are precipitated, filter drying at room temperature, obtains the flurbiprofen product of white
89.2g, yield 87%, HPLC measure purity 99.57%.
Flurbiprofen gross production rate 73.1%.
Embodiment 2
Prepare 2- (the fluoro- biphenyl -4- base of 2-) propionic acid --- Flurbiprofen (1)
In 1000ml there-necked flask, A step operation product 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid (4) 85g in embodiment 1 is added
(0.42mol), phenyl boric acid pinacol ester (5) 89.7g (0.44mol), ethyl alcohol 200ml, toluene 300ml, potassium carbonate 121g
(0.88mol) is dissolved in the solution of 200ml water.PdCl is added under nitrogen protection after mixing evenly2(Amphos)2155mg (dosage
0.05mol%).It is heated to back flow reaction 4h, TLC shows no raw material (4), and reaction terminates.
Solvent is steamed, is cooled to 0 DEG C, is filtered.The solid of generation is washed with 200ml cold water.Then solid is dissolved in
In hot water, hydrochloric acid is added dropwise to pH value less than 3, a large amount of solids are precipitated, filter drying at room temperature, obtains the Flurbiprofen (1) of white
95.5g, yield 89%, HPLC measure purity 99.58%.
Flurbiprofen gross production rate 74.8%.
Embodiment 3
A, 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid (4) is prepared
In 1000ml dry four-hole bottle, 14.4g (0.6mol) magnesium chips, 50mlTHF, two iodine grains, nitrogen atmosphere is added
50 DEG C are heated with stirring in enclosing.The solution that the fluoro- 4- chloro-bromobenzene (2) of 105g (0.5mol) 3- is dissolved in 370mlTHF is instilled into 20ml,
After initiation to be confirmed and reacting balance, maintains 50~60 DEG C to instill remaining solution, drip off rear insulated and stirred 1h.
Reaction solution is cooled to 0 DEG C, no more than 10 DEG C at a temperature of, be added 105g (0.6mol) 2 bromopropionic acid sodium (3),
50~60 DEG C of reaction 2h of maintenance are gradually heated up after adding, reaction terminates.
Reaction solution is cooled to 0 DEG C, is slowly added into 5mol/L hydrochloric acid 400ml, temperature is no more than 20 DEG C, stirs naturally after adding
30min is mixed, 50 DEG C of stirring 1h are again heated to.
Liquid separation, organic phase retain, and water phase is extracted twice, and use ethyl acetate 200ml every time.Merge organic phase and extract liquor,
Water-bath decompression is lower to steam solvent, steams to there is solid appearance, 300ml toluene is added, and stirring is cooled to -10 DEG C, and resulting white is solid
Body filters drying, obtains product 87g, yield 86%.
B, 2- (the fluoro- biphenyl -4- base of 2-) propionic acid --- Flurbiprofen (1) is prepared
In 1000ml there-necked flask, product 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid (4) 85g that step A is obtained is added
(0.42mol), phenyl boric acid pinacol ester (5) 89.7g (0.44mol), ethyl alcohol 200ml, toluene 300ml, potassium carbonate 121g
(0.88mol) is dissolved in the solution of 200ml water.PdCl is added under nitrogen protection after mixing evenly2(Amphos)2155mg (dosage
0.05mol%).It is heated to back flow reaction 4h, TLC shows no raw material (4), and reaction terminates.
Solvent is steamed, is cooled to 0 DEG C, is filtered.The solid of generation is washed with 200ml cold water.Then solid is dissolved in
In hot water, hydrochloric acid is added dropwise to pH value less than 3, a large amount of solids are precipitated, filter drying at room temperature, obtains the Flurbiprofen (1) of white
95.5g yield 89%, HPLC measures purity 99.53%.
Flurbiprofen gross production rate 76.5%.
Embodiment 4:
A, 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid (4) is prepared
In 1000ml dry four-hole bottle, 14.4g (0.6mol) magnesium chips, 50mlTHF, two iodine grains, nitrogen atmosphere is added
50 DEG C are heated with stirring in enclosing.The solution that the fluoro- 4- chloro-bromobenzene (2) of 105g (0.5mol) 3- is dissolved in 370mlTHF is instilled into 20ml,
After initiation to be confirmed and reacting balance, maintains 50~60 DEG C to instill remaining solution, drip off rear insulated and stirred 1h.
Reaction solution is cooled to 0 DEG C, no more than 10 DEG C at a temperature of, be added 105g (0.6mol) 2 bromopropionic acid sodium (3),
Back flow reaction 1h is gradually heated up after adding, reaction terminates.
Reaction solution is cooled to 0 DEG C, is slowly added into 5mol/L hydrochloric acid 400ml, temperature is no more than 20 DEG C, stirs naturally after adding
30min is mixed, 50 DEG C of stirring 1h are again heated to.
Liquid separation, organic phase retain, and water phase is extracted twice, and use ethyl acetate 200ml every time.Merge organic phase and extract liquor,
Water-bath decompression is lower to steam solvent, steams to there is solid appearance, 300ml toluene is added, and stirring is cooled to -10 DEG C, and resulting white is solid
Body filters drying, obtains product 89g, yield 88%.
B, 2- (the fluoro- biphenyl -4- base of 2-) propionic acid --- Flurbiprofen (1) is prepared
In 1000ml there-necked flask, 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid (4) 85g (0.42mol), phenyl boric acid (5) is added
53.7g (0.44mol), ethyl alcohol 200ml, toluene 300ml, potassium carbonate 121g (0.88mol) are dissolved in the solution of 200ml water.Stirring
Pd (Pt-Bu is added under nitrogen protection after uniformly3)290mg (dosage 0.04mol%).It is heated to back flow reaction 4h, TLC is shown
Without raw material (4), reaction terminates.
Solvent is steamed, is cooled to 0 DEG C, is filtered.The solid of generation is washed with 200ml cold water.Then solid is dissolved in
In hot water, hydrochloric acid is added dropwise to pH value less than 3, a large amount of solids are precipitated, filter drying at room temperature, obtains the Flurbiprofen (1) of white
96.6g, yield 90%, HPLC measure purity 99.6%.
Flurbiprofen gross production rate 79.2%.
Claims (7)
1. a kind of preparation method of Flurbiprofen, using Suzuki coupling reaction, it is characterised in that: by 2- (the fluoro- 4- chlorobenzene of 3-
Base) propionic acid and phenyl borane reagent in the presence of a base, in organic solvent, by the Suzuki coupling reaction of palladium chtalyst,
Flurbiprofen is obtained, wherein the molar ratio of 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid and phenyl borane reagent is 1:(0.9-1.1), palladium is urged
Palladium catalyst is used in the Suzuki coupling reaction of change, is PdCl2(dtbpf)、PdCl2(Amphos)2、Pd(Pt-Bu3)2、Pd
(Amphos)2One or more of combination, the molar ratio of 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid and palladium catalyst is 1:
(0.00005-0.0004)；The preparation of 2- (the fluoro- 4- chlorphenyl of 3-) propionic acid is the following steps are included: be original with the fluoro- 4- chloro-bromobenzene of 3-
Material, is first prepared into Grignard Reagent for the fluoro- 4- chloro-bromobenzene of 3-, then carries out coupling reaction with 2 bromopropionic acid sodium, then acidified obtain
2- (the fluoro- 4- chlorphenyl of 3-) propionic acid, wherein the molar ratio of the fluoro- 4- chloro-bromobenzene of 3- and 2 bromopropionic acid sodium is 1:(1-2).
2. a kind of preparation method of Flurbiprofen according to claim 1, it is characterised in that: Grignard Reagent and 2 bromopropionic acid
The temperature of sodium coupling reaction is -10~70 DEG C.
3. a kind of preparation method of Flurbiprofen according to claim 1, it is characterised in that: the solvent of coupling reaction is four
It is hydrogen furans, ether, cyclopentyl methyl ether, glycol dimethyl ether, methyl tertiary butyl ether(MTBE), n-butyl ether, toluene, a kind of or several in dimethylbenzene
The combination of kind.
4. a kind of preparation method of Flurbiprofen according to claim 1, it is characterised in that: phenyl borane reagent is benzene boron
Acid, phenyl boric acid glycol ester, phenyl boric acid -1,3- propylene glycol ester, phenyl boric acid neopentyl glycol ester, phenyl boric acid pinacol ester, phenyl boric acid
One or more of combination in acid anhydride, phenyl trifluoromethanesulfonate potassium borate.
5. a kind of preparation method of Flurbiprofen according to claim 1, it is characterised in that: organic solvent is ethyl alcohol, first
Benzene, tetrahydrofuran, dimethylformamide, dioxane, combination one or more of in glycol dimethyl ether.
6. a kind of preparation method of Flurbiprofen according to claim 1, it is characterised in that: the alkali is selected from carbonic acid
Potassium, saleratus, sodium carbonate, sodium bicarbonate, potassium fluoride, triethylamine, sodium acetate, potassium acetate, lithium hydroxide, one in cesium carbonate
Kind or several combinations.
7. a kind of preparation method of Flurbiprofen according to claim 1, it is characterised in that: 2- (the fluoro- 4- chlorphenyl of 3-)
The molar ratio of propionic acid and alkali is 1:(1-3).
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| CN104649906A (en) * | 2015-01-10 | 2015-05-27 | 山东威高药业股份有限公司 | Preparation method of flurbiprofen axetil |
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| CN104649906A (en) * | 2015-01-10 | 2015-05-27 | 山东威高药业股份有限公司 | Preparation method of flurbiprofen axetil |
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