CN104649906A - Preparation method of flurbiprofen axetil - Google Patents
Preparation method of flurbiprofen axetil Download PDFInfo
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- CN104649906A CN104649906A CN201510023365.0A CN201510023365A CN104649906A CN 104649906 A CN104649906 A CN 104649906A CN 201510023365 A CN201510023365 A CN 201510023365A CN 104649906 A CN104649906 A CN 104649906A
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- flurbiprofen axetil
- acid
- fluorophenyl
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- flurbiprofen
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- 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 title claims abstract description 47
- 229950005941 flurbiprofen axetil Drugs 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 20
- -1 1-acetoxyl ethyl Chemical group 0.000 claims abstract description 17
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 22
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 235000019439 ethyl acetate Nutrition 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 229960001866 silicon dioxide Drugs 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000004327 boric acid Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- 229960004839 potassium iodide Drugs 0.000 claims description 5
- 235000007715 potassium iodide Nutrition 0.000 claims description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- GALSVFOXBFKMEG-UHFFFAOYSA-N 2-(3-fluoro-4-nitrophenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C([N+]([O-])=O)C(F)=C1 GALSVFOXBFKMEG-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 11
- 238000010898 silica gel chromatography Methods 0.000 abstract description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 238000006193 diazotization reaction Methods 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 abstract 5
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 abstract 2
- CGKKDGMMKSOGLM-UHFFFAOYSA-N 1-chloroethyl acetate Chemical compound CC(Cl)OC(C)=O CGKKDGMMKSOGLM-UHFFFAOYSA-N 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 230000026045 iodination Effects 0.000 abstract 1
- 238000006192 iodination reaction Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 12
- 229960002390 flurbiprofen Drugs 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 5
- 238000000199 molecular distillation Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 208000014540 Functional gastrointestinal disease Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940111134 coxibs Drugs 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
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of flurbiprofen axetil. The method comprises the following steps: condensing 2-(4-nitro-3-fluorophenyl) propionic and 1-chloroethyl acetate so as to generate 1-acetoxyl ethyl 2-(4-nitro-3-fluorophenyl) propionate, carrying out hydrogenation reduction on 1-acetoxyl ethyl 2-(4-nitro-3-fluorophenyl) propionate under the catalysis of palladium-carbon so as to generate 1-acetoxyl ethyl 2-(4-amino-3-fluorophenyl) propionate, carrying out diazotization and iodination on 1-acetoxyl ethyl 2-(4-amino-3-fluorophenyl) propionate so as to obtain 1-acetoxyl ethyl 2-(3-fluoro-4-iodophenyl) propionate, carrying out Suzuki coupling reaction on the intermediate and a phenylboronic acid in water by taking palladium-carbon as a catalyst so as to obtain a target product flurbiprofen axetil crude product, carrying out silica gel column chromatography on the crude product so as to obtain a flurbiprofen axetil finished product. The method disclosed by the invention enriches the synthesis methods of flurbiprofen axetil, a synthetic process is simple in operation, environment-friendly and low in cost, and the purity of obtained flurbiprofen axetil is over 99.3%, therefore, the method has a good industrial application prospect.
Description
Art
The present invention relates to pharmaceutical technology sectors, in particular to the preparation method of flurbiprofen axetil.
Background technology
Flurbiprofen axetil (Flurbiprofen Axetil) chemistry is by name: (±) 2-(the fluoro-4-xenyl of 2-) propionic acid-1-acetoxyethyl, molecular formula: C
19h
19fO
4, molecular weight: 330.4.
Flurbiprofen axetil is a kind of novel nonsteroidal anti-inflammatory analgetic, is the prodrug of flurbiprofen, is first nonsteroidal targeted analgesics thing of SFDA approval.Flurbiprofen axetil has certain lipotropy, its targeting and fat-soluble feature make it be easy to cross over cell, operative incision and inflammation part can be gathered in by target after entering human body, under Procaine esterase effect, hydrolysis generates flurbiprofen rapidly, by suppressing cyclooxygenase (COX) to reduce prostaglandin(PG) synthesis at spinal cord and periphery, reducing Sensory nerve fibre simultaneously and threshold of pain raised to the susceptibility of noxious stimulation thus plays preemptive analgesia effect.Research finds, the advanced use of cox-2 inhibitors can eliminate the latent period before onset, and make it the ideal medicament becoming preemptive analgesia, flurbiprofen axetil also can reduce the elevated levels of immune response medium bradykinin in tissue.Be widely used in the treatment of clinical inflammatory pain, pain caused by cancer and post-operative pain in recent years.
Flurbiprofen axetil is developed jointly by Japanese Kaken Pharmaceufical Co., Ltd. and the Green Cross Corporation, and within 1992, in day listing, 2004 in Discussion on Chinese Listed.Compared with flurbiprofen this medicine not only can avoid because of oral cause the untoward reaction such as functional gastrointestinal disorder, also have shorten onset time, strengthen drug effect, the advantage such as make duration of efficacy longer.Good market outlook cause the concern of a lot of enterprise to this kind, strengthen the dynamics to this research and development of products.
Current flurbiprofen axetil mainly synthesizes preparation by flurbiprofen and 1-bromoethylacetic ester or 1-chloroethyl acetic ester by a step esterification.Such as, Chinese invention patent CN201310079429.X reports a kind of method of being synthesized flurbiprofen axetil by flurbiprofen and 1-ethyl bromoacetate.Chinese invention patent CN201210574448.5 reports one and prepares flurbiprofen, and rear flurbiprofen and the condensation of 1-chloroethyl acetic ester generate the method for target compound flurbiprofen axetil.
Because raw material flurbiprofen is a kind of bulk drug, so synthesis cost is higher.And with flurbiprofen not being raw material, the method directly preparing flurbiprofen axetil by the intermediate of preparation flurbiprofen through condensation, reduction, diazotization halo, Suzuki linked reaction has no domestic and international data of literatures and patent report at present.
Because the proterties of flurbiprofen axetil is liquid in purifying, purifying cannot be carried out by the method for recrystallization.The method of the purifying of current report is mainly by silica gel column chromatography, underpressure distillation and molecular distillation method, but in actually operating, the temperature of underpressure distillation is too high, and heat transfer efficiency is low, and sample exposes for a long time and flurbiprofen axetil at high temperature can be caused to decompose.Molecular distillation equipment is expensive, and molecular distillation apparatus must the condition of high vacuum degree that reaches of guarantee system pressure, requires higher to material seal, and distance between generating surface and condensing surface is moderate, and apparatus processing difficulty is large, and cost is high, and general enterprises is difficult to build.Column chromatography remains a good purification process, and silica gel can realize recycle through excessive polar solvent purification process, the good method of a kind of purification of liquid oily matter of also can yet be regarded as.
Summary of the invention
The present invention supplements the one of existing synthesis flurbiprofen axetil method, solve synthesis flurbiprofen axetil mainly rely on flurbiprofen be raw material drawback, synthetic route is short, and the reaction of final step synthesis flurbiprofen axetil take water as solvent, relative environmental protection is green, and simple to operate, directly using palladium carbon as catalyzer, without the need to adding other part, optimize and enriched Suzuki reaction reaction conditions.Finished product flurbiprofen axetil purity >=99.3% prepared.
The invention provides a kind of synthetic method of new flurbiprofen axetil, synthesis path is as follows:
(1) 2-(4-nitro-3-fluorophenyl) propionic acid and the condensation of 1-chloroethyl acetic ester generate 2-(4-nitro-3-fluorophenyl) propionic acid-1-acetoxyethyl (intermediate compound I).
The mixed solvent of the one or more than one in the preferred DMF of solvent of this reaction, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone, acetonitrile, tetrahydrofuran (THF), more preferably acetonitrile.Temperature of reaction is 20 DEG C ~ 70 DEG C, preferably 35 ~ 40 DEG C.2-(4-nitro-3-fluorophenyl) propionic acid: Anhydrous potassium carbonate: the material ratio of 1-chloroethyl acetic ester is 1: 2: 2.
(2) intermediate compound I is reduced and is generated 2-(4-amino-3-fluorophenyl) propionic acid-1-acetoxyethyl (intermediate II) under catalyst action.
The catalyzer of this reaction is wet palladium carbon, dry palladium carbon, Raney's nickel preferably, more preferably wet palladium carbon, the charging capacity of catalyzer preferably 8 ~ 20%, and more preferably 9%.One or more than one mixed solvent in the solvent system preferred alcohol of this reaction, methyl alcohol, Virahol, more preferably ethanol.This temperature of reaction preferably 30 ~ 70 DEG C, more preferably 50 ~ 60 DEG C; Reduction reaction hydrogen pressure used is 0.3 ~ 0.4MPa.
(3) intermediate II is under the effect of catalyzer and Sodium Nitrite, carries out iodo generate 2-(the iodo-3-fluorophenyl of 4-) propionic acid-1-acetoxyethyl (intermediate III) with potassiumiodide.
The acid added in this reaction is selected from: the one in phenylformic acid, dichloro acetic acid, trichoroacetic acid(TCA), methylsulfonic acid, Glacial acetic acid, trifluoroacetic acid, hydrochloric acid, Hydrogen bromide, more preferably Hydrogen bromide.2-(4-amino-3-fluorophenyl) propionic acid-1-acetoxyethyl in this reaction: Sodium Nitrite: potassiumiodide ratio is 1: 1.1: 2.
(4) intermediate III generates target compound flurbiprofen axetil with boric acid derivatives coupling under the effect of catalyzer and alkali.
Catalyzer used in this reaction is selected from: the one in 10% wet palladium carbon, tetra-triphenylphosphine palladium, two (triphenylphosphine) palladium chloride, preferably 10% wet palladium carbon.Solvent is one or more mixed solvents in water, ethanol, 95% ethanol, methyl alcohol, Virahol.Temperature of reaction should control at 20 ~ 80 DEG C to reacting end, preferably 30 ~ 50 DEG C, and more preferably temperature of reaction is 35 ~ 40 DEG C.Boric acid derivatives is phenylo boric acid, Tetraphenyl sodium borate, boric acid gneissic suite ester.
(5) flurbiprofen axetil crude product obtains flurbiprofen axetil finished product through column chromatography, and silica gel weight is 3-5 times of crude product, and moving phase is normal hexane and isopropyl ether.
Compare below by way of experiment and further illustrate beneficial effect of the present invention.
The selection of process for refining:
The purification process of liquid starting material medicine is mainly by the method for underpressure distillation, but under in the process of distillation, medicine needs to be in the condition of high temperature for a long time, a large amount of degradeds can be produced, not only can reduce productive rate, also likely cause the off quality of product.Molecular distillation equipment is expensive, and molecular distillation apparatus must the condition of high vacuum degree that reaches of guarantee system pressure, requires higher to material seal, and distance between generating surface and condensing surface is moderate, and apparatus processing difficulty is large, and cost is high.Silica gel column chromatography remains a good purification process.
Get with a collection of flurbiprofen axetil synthesis crude product equivalent, use underpressure distillation and silica gel column chromatography to refine respectively.Underpressure distillation is carried out according to the method in patent FP0103265, and underpressure distillation pressure is 1.500 ~ 2.000mbar, collects 173.0 ~ 175.0 DEG C of cuts.Draw through repeatedly parallel laboratory test, productive rate, between 15.00 ~ 17.00%, obtains product purity between 95.50 ~ 97.10%.The general productive rate of silica gel column chromatography is between 24.10 ~ 27.10%, and product purity is between 99.50 ~ 99.90%.
Contrast and experiment shows, relative to underpressure distillation, silica gel column chromatography by flurbiprofen axetil and magazins' layout, and can better can not cause product degraded loss.
Beneficial effect:
The present invention passes through technical optimization, explore a kind of synthetic route of new flurbiprofen axetil, this route steps is shorter, easy to operate, environmental friendliness, that the one of existing synthesis flurbiprofen axetil method is supplemented, solve synthesis flurbiprofen axetil mainly rely on flurbiprofen be raw material drawback, enriched the synthesis technique of flurbiprofen axetil.Experiment obtains product content more than 99.3%, higher than the requirement of import quality standard.
Embodiment
Below in conjunction with specific examples, the present invention is further described.
Embodiment 1 prepares 2-(4-nitro-3-fluorophenyl) propionic acid-1-acetoxyethyl (intermediate compound I)
2-(4-nitro-3-fluorophenyl) propionic acid (213.0g is added in reactor, 1.000mol), anhydrous acetonitrile (2000ml), with nitrogen replacement air three times, slowly be warming up to 35 ~ 40 DEG C, add Anhydrous potassium carbonate (276.4g, 2.000mol) again.1-chloroethyl acetic ester (245.1g, 2.000mol) is dropped in system.After, control temperature in reaction system and react 5.0h at 35 ~ 40 DEG C.Reaction solution is evaporated to absence of liquid to flow out, after being cooled to 15 ~ 25 DEG C, add ethyl acetate (2000ml) and water (2000ml), stratification, organic phase concentrating under reduced pressure obtains pale yellow oil 242.4g, productive rate 81.00%.
Embodiment 2 prepares 2-(4-amino-3-fluorophenyl) propionic acid-1-acetoxyethyl (intermediate II)
By 2-(the fluoro-4-nitro of 2-) propionic acid-1-acetoxyethyl (149.6g, 0.500mol) with after dehydrated alcohol (900.0ml) dilution, add 10% wet palladium carbon (15.00g), passing into pressure after nitrogen replacement three times is that the hydrogen of 0.3 ~ 0.4MPa carries out reduction reaction, stirs filtering palladium carbon after 16h at 50 ~ 60 DEG C.Organic phase concentrating under reduced pressure obtains brown oil 128.0g, and productive rate is 95.10%.
Embodiment 3 prepares 2-(the fluoro-4-iodophenyl of 3-) propionic acid-1-acetoxyethyl (intermediate III)
By 2-(4-amino-3-fluorophenyl) propionic acid-1-acetoxyethyl (107.7,0.400mol), 40% Hydrogen bromide (0.440mol) and water (200ml) add in reactor, being cooled to 0 ~ 5 DEG C, is be system I; Sodium Nitrite (0.440mol) aqueous solution, at 0 ~ 5 DEG C, drops in system I by control temperature; Being cooled to 0 ~ 5 DEG C after potassiumiodide (0.800mol) and water are made solution, is be system II; The mixing solutions of system I, at 0 ~ 10 DEG C, is added dropwise in system II by control temperature, dropwises slowly to be warming up to 60 ~ 70 DEG C afterwards, reaction 2-3h.Use dichloromethane extraction 2 times after being cooled to 20 ~ 30 DEG C, aqueous phase discards, and merge organic phase, the organic phase hypo solution of 10% washes twice, aqueous phase discarded, and organic phase is concentrated to obtain brown oil 109.5g, and productive rate is 72.00%.
Embodiment 4 prepares flurbiprofen axetil
By 2-(the fluoro-4-iodophenyl of 3-) propionic acid-1-acetoxyethyl (76.00g, 0.200mol), phenylo boric acid (24.90g, 0.200mol), salt of wormwood (82.90g, 0.600mol), water (700.0ml) adds in reactor successively, after nitrogen replacement three times, add 10% wet palladium carbon (7.600g), 7-8h is reacted at 35 ~ 40 DEG C after nitrogen replacement twice, filtering palladium carbon, ethyl acetate is added in mother liquor, extraction, aqueous phase ethyl acetate washes twice, merge organic phase and be concentrated into and dryly obtain yellow oil 44.20g, productive rate is 90.60%.
Embodiment 5 refines flurbiprofen axetil
In 1000ml single port bottle, flurbiprofen axetil crude product (44.20g, 0.180mol) is even with n-hexane dissolution dilution, add and mix sample silica gel (44.00g), after mixing, be concentrated into dry, make crude product uniform adsorption on silica gel; Pour in silicagel column and carry out column chromatography.Wash-out: with normal hexane: isopropyl ether=8: the moving phase of 1 starts the wash-out that pressurizes, collect the flow point of detected result inclusion-free spot, vacuum concentration obtains pale yellow transparent oily matter.Vacuumize at 40 ~ 50 DEG C except molten residual 12h, obtain pale yellow transparent oily matter 10.80g, productive rate 24.40%, product purity is 99.30%.
Claims (6)
1. a synthetic method for flurbiprofen axetil, is characterized in that the method comprises the following steps:
(1) 2-(4-nitro-3-fluorophenyl) propionic acid and Anhydrous potassium carbonate, 1-chloroethyl acetic ester are joined in solvent, temperature control reaction 5h, add ethyl acetate and water, collect organic phase, concentrating under reduced pressure obtains 2-(4-nitro-3-fluorophenyl) propionic acid-1-acetoxyethyl (intermediate compound I)
(2) by after intermediate compound I solvent cut, add 10% wet palladium carbon, pass into hydrogen reducing, filtering palladium carbon after temperature control stirring 16h, concentrating under reduced pressure obtains 2-(4-amino-3-fluorophenyl) propionic acid-1-acetoxyethyl (intermediate II),
(3) in reactor, intermediate II, water and acid is added, Sodium Nitrite is dripped after being cooled to 0 ~ 5 DEG C, temperature control 0 ~ 10 DEG C, be added dropwise in the mixing solutions of potassiumiodide and water, be warming up to 60 ~ 70 DEG C, reaction 2-3h, rear methylene dichloride of lowering the temperature, 10% Sulfothiorine extract, obtain 2-(the fluoro-4-iodophenyl of 3-) propionic acid-1-acetoxyethyl (intermediate III)
(4) intermediate III, phenylo boric acid, salt of wormwood, water are added successively in reactor, add catalyzer, temperature control reaction 7-8h, is extracted with ethyl acetate after filtration, obtains flurbiprofen axetil crude product,
(5) flurbiprofen axetil crude product is even with n-hexane dissolution dilution, pour in silicagel column and carry out column chromatography, collect flow point, vacuumize at 40 ~ 50 DEG C except molten residual 12h, obtain flurbiprofen axetil.
2. the synthetic method of flurbiprofen axetil according to claim 1, is characterized in that: adopt 2-(4-nitro-3-fluorophenyl) propionic acid and Anhydrous potassium carbonate in step (1), the material ratio of 1-chloroethyl acetic ester is 1: 2: 2; In step (1), reaction solvent is selected from: the one or more than one mixed solvent in DMF, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone, acetonitrile, tetrahydrofuran (THF); In step (1), temperature of reaction is 20 ~ 70 DEG C.
3. the synthetic method of flurbiprofen axetil according to claim 1, is characterized in that: the charging capacity adopting the wet palladium carbon of 10% in step (2) is 8 ~ 20%; In step (2), reaction solvent is selected from: the one or more than one mixed solvent in ethanol, methyl alcohol, Virahol; In step (2), temperature of reaction is 30 ~ 70 DEG C; In step (2), pressure is 0.3 ~ 0.4MPa.
4. the synthetic method of flurbiprofen axetil according to claim 1, is characterized in that: the acid added in step (3) is selected from: the one in phenylformic acid, dichloro acetic acid, trichoroacetic acid(TCA), methylsulfonic acid, Glacial acetic acid, trifluoroacetic acid, hydrochloric acid, Hydrogen bromide; 2-(4-amino-3-fluorophenyl) propionic acid-1-acetoxyethyl in step (3): Sodium Nitrite: potassiumiodide ratio is 1: 1.1: 2.
5. flurbiprofen axetil preparation method according to claim 1, is characterized in that: in step (4), catalyzer used is selected from: the one in 10% wet palladium carbon, tetra-triphenylphosphine palladium, two (triphenylphosphine) palladium chloride; Solvent is water, methyl alcohol, ethanol, one or more mixed solvent of Virahol in step (4); In step (4), temperature of reaction is 30 ~ 50 DEG C; Step (4) mesoboric acid derivative is phenylo boric acid, Tetraphenyl sodium borate, boric acid gneissic suite ester.
6. flurbiprofen axetil process for purification according to claim 1, is characterized in that: silica gel weight is 3-5 times of flurbiprofen axetil crude product; Moving phase is normal hexane and isopropyl ether.
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| CN106496015A (en) * | 2016-11-01 | 2017-03-15 | 河北美星化工有限公司 | A kind of preparation method of flurbiprofen |
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| CN106496016B (en) * | 2016-11-01 | 2019-07-26 | 河北美星化工有限公司 | A kind of synthetic method of Flurbiprofen |
| CN106496015B (en) * | 2016-11-01 | 2019-07-26 | 河北美星化工有限公司 | A kind of preparation method of Flurbiprofen |
| CN107982248A (en) * | 2017-12-01 | 2018-05-04 | 山西普德药业有限公司 | A kind of preparation method of florfenicol residues |
| CN108218667A (en) * | 2017-12-29 | 2018-06-29 | 河北品制药股份有限公司 | A kind of synthetic method of Flurbiprofen |
| CN113636933A (en) * | 2020-05-11 | 2021-11-12 | 北京泰德制药股份有限公司 | Method for purifying flurbiprofen axetil |
| CN114075109A (en) * | 2020-08-21 | 2022-02-22 | 北京泰德制药股份有限公司 | Preparation method of flurbiprofen axetil and prepared crystal form |
| CN114075109B (en) * | 2020-08-21 | 2024-05-03 | 北京泰德制药股份有限公司 | Preparation method of flurbiprofen axetil and prepared crystal form |
| CN114195642A (en) * | 2020-09-17 | 2022-03-18 | 武汉华谱生物科技有限公司 | Refining method of high-content flurbiprofen axetil |
| CN113527098A (en) * | 2021-07-06 | 2021-10-22 | 山东威高药业股份有限公司 | Flurbiprofen axetil crystal form and preparation method thereof |
| CN113527098B (en) * | 2021-07-06 | 2024-03-29 | 山东威高药业股份有限公司 | Flurbiprofen axetil crystal form and preparation method thereof |
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