CN116102397A - 一种氟比洛芬的制备方法 - Google Patents
一种氟比洛芬的制备方法 Download PDFInfo
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- 229960002390 flurbiprofen Drugs 0.000 title claims abstract description 37
- 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 33
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 21
- HTRNHWBOBYFTQF-UHFFFAOYSA-N 4-bromo-2-fluoro-1-phenylbenzene Chemical group FC1=CC(Br)=CC=C1C1=CC=CC=C1 HTRNHWBOBYFTQF-UHFFFAOYSA-N 0.000 claims abstract description 14
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 nitrous acid amine Chemical class 0.000 claims abstract description 14
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 12
- 239000000654 additive Substances 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 229910052751 metal Inorganic materials 0.000 claims abstract description 10
- 239000002184 metal Substances 0.000 claims abstract description 10
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000000996 additive effect Effects 0.000 claims abstract description 9
- JLEJCNOTNLZCHQ-UHFFFAOYSA-N methyl 2-chloropropanoate Chemical compound COC(=O)C(C)Cl JLEJCNOTNLZCHQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims abstract description 6
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims abstract description 6
- 229940045803 cuprous chloride Drugs 0.000 claims abstract description 6
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims abstract description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 229950005941 flurbiprofen axetil Drugs 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 5
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims description 5
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 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
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 claims description 3
- VHSVJTYBTJCDFL-UHFFFAOYSA-L 1,2-dimethoxyethane;nickel(2+);dibromide Chemical compound Br[Ni]Br.COCCOC VHSVJTYBTJCDFL-UHFFFAOYSA-L 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- OCMNCWNTDDVHFK-UHFFFAOYSA-L dichloronickel;1,2-dimethoxyethane Chemical compound Cl[Ni]Cl.COCCOC OCMNCWNTDDVHFK-UHFFFAOYSA-L 0.000 claims description 2
- 229940078487 nickel acetate tetrahydrate Drugs 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- OINIXPNQKAZCRL-UHFFFAOYSA-L nickel(2+);diacetate;tetrahydrate Chemical compound O.O.O.O.[Ni+2].CC([O-])=O.CC([O-])=O OINIXPNQKAZCRL-UHFFFAOYSA-L 0.000 claims description 2
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-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
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000005265 energy consumption Methods 0.000 abstract 1
- 238000006482 condensation reaction Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 150000002815 nickel Chemical class 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YFVOFFKNHQTQQE-UHFFFAOYSA-N 1-(4-bromo-3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C([N+]([O-])=O)=C1 YFVOFFKNHQTQQE-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- CAMXVZOXBADHNJ-UHFFFAOYSA-N ammonium nitrite Chemical compound [NH4+].[O-]N=O CAMXVZOXBADHNJ-UHFFFAOYSA-N 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 239000003480 eluent Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/16—Reducing
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- 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
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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Abstract
一种氟比洛芬的制备方法，属于非甾体抗炎药制备方法技术领域。该方法包括将4‑溴‑2‑氟苯胺在三氯乙酸、氯化亚铜、原甲酸三乙酯和亚硝酸胺作用下与苯缩合成4‑溴‑2‑氟联苯，4‑溴‑2‑氟联苯在镍催化剂、配体、金属还原剂、添加物和三乙胺盐酸盐的作用下，与2‑氯丙酸甲酯发生偶联反应生成氟比洛芬酯，氟比洛芬酯经碱性条件下的水解反应制得氟比洛芬终产物。本方法条件温和，收率高，无缩合副产物，能耗低，操作简便。
Description
技术领域
本发明属于非甾体抗炎药制备方法技术领域，具体涉及一种氟比洛芬的制备方法。
背景技术
氟比洛芬，化学名为2-(3-氟-4-联苯基)-丙酸，其化学结构式如下：
氟比洛芬在1976年由英国补兹公司首先研制上市，是一种强效的芳基丙酸类解热镇痛抗炎药，目前已在七十多个国家销售。主要用于风湿性、类风湿性关节炎、强直性脊柱炎、变性关节炎，还适用于其他一些原因如外伤、扭伤、手术等引起的疼痛。氟比洛芬通过抑制前列腺素环氧合酶的作用起到镇痛抗炎的作用，目前市场上销售使用的为其消旋体，但现有的氟比洛芬的制备方法有以溴苯、4-溴-3-硝基苯乙酮为原料，或苯乙腈为原料，经多步反应制得，该方法步骤繁琐，后处理麻烦且产率低；郑州大学的郑庚修等设计以苯乙腈为反应原料经11步反应制得氟比洛芬，步骤冗长，总收率仅为7.2％；王立生等设计以N-乙酰苯胺为起始原料，原料不易制备，且反应步数较多，成本较高。。
发明内容
本发明解决的问题在于提供一种氟比洛芬的制备方法，相比于现有技术，能够避免使用贵金属催化剂、剧毒原料、试剂，条件温和且易于操作。
为了实现上述目的，本发明采用的技术方案如下：
本发明的一种氟比洛芬的制备方法，包括缩合反应、偶联反应和水解反应，其合成路线如下：
所述的氟比洛芬的制备方法，包括以下步骤：
(1)缩合反应
将4-溴-2-氟苯胺在三氯乙酸、氯化亚铜、原甲酸三乙酯和亚硝酸胺作用下与苯缩合得到4-溴-2-氟联苯；
其中，按摩尔比，4-溴-2-氟苯胺：三氯乙酸：氯化亚铜：原甲酸三乙酯：亚硝酸胺为1:1.7:0.5:2:1.4，其中，苯作为溶剂，也参与缩合反应，4-溴-2-氟苯胺在苯中的摩尔浓度为：1mol/L～2mol/L，反应温度为50～60℃。
(2)偶联反应
4-溴-2-氟联苯在镍催化剂、配体、金属还原剂、添加物和三乙胺盐酸盐作用下，与2-氯丙酸甲酯发生偶联反应生成氟比洛芬酯。
其中，按摩尔比，4-溴-2-氟联苯：2-氯丙酸甲酯：镍催化剂：配体：金属还原剂：添加物：三乙胺盐酸盐为1：1.5：0.1：0.12：(2～3)：(0.5～1)：0.5。
进一步的，反应的镍催化剂优选氯化镍、氯化镍六水合物、醋酸镍四水合物、碘化镍、溴化镍乙二醇二甲醚络合物或氯化镍乙二醇二甲醚络合物，更优选氯化镍六水合物。
进一步的，配体优选2,2'-联吡啶、4,4'-二叔丁基-2,2'-联吡啶或三苯基膦，更优选2,2'-联吡啶。
进一步的，金属还原剂优选锌粉或锰粉，更优选锰粉。
进一步的，添加物优选四氟硼酸钠、氯化钠、溴化钠、碘化钠、氟化钾或氯化锂中的一种，更优选氯化钠。
进一步的，偶联反应采用的溶剂优选：四氢呋喃、乙酸乙酯、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，更优选四氢呋喃。
作为优选，加料过程为先加入镍催化剂、配体、金属还原剂、添加物和三乙胺盐酸盐，40～50℃搅拌20min，加入4-溴-2-氟联苯和2-氯丙酸甲酯，氮气氛围下，40～50℃反应12h。
(3)水解反应
将氟比洛芬酯经碱性条件下的水解反应制得终产物氟比洛芬。
水解反应的碱性条件采用有机碱，有机碱优选氢氧化锂或氢氧化钠，更优选氢氧化钠，按摩尔比，氟比洛芬酯与有机碱为1:1.2。
进一步的，水解反应采用的溶剂优选四氢呋喃或甲醇，更优选甲醇。反应温度为25～40℃。
采用本发明的氟比洛芬的制备方法，制备得到的氟比洛芬为S-异构体。
相比于现有技术，本发明的有益效果在于：
本发明采取三步反应实现了氟比洛芬的制备，简化了传统繁琐的合成步骤，本发明采用更为廉价易得4-溴-2-氟苯胺为底物经一步反应制备联苯底物，无需生成格氏试剂，反应安全且易于操作。不同于以往采用钯等贵金属催化体系，使用二价镍盐作为催化剂，同时采用金属还原剂原位生成零价镍，使得反应在氮气氛围下即可进行，克服了零价镍催化剂易失活需再手套箱氩气氛围中反应、操作过程繁琐的不足。在添加物的选择上，不同于其他方法使用当量的四氟硼酸钠，本方法使用0.5当量的氯化钠，更加节省成本。
具体实施方式
下面结合实施例对本发明作进一步的详细说明。
氟比洛芬的合成
(1)4-溴-2-氟联苯的制备：
将4-溴-2-氟苯胺19g(0.1mol)、三氯乙酸27.7g(0.17mol)、氯化亚铜4.95g(0.05mol)、原甲酸三乙酯30g(0.2mol)以及苯50mL，氮气氛围下，60℃搅拌加入亚硝酸胺9.66g(0.14mol)，继续搅拌16h。反应完成后，缓慢加入稀盐酸，再加入300mL二氯甲烷，萃取分层，用100mL氯化钠饱和水溶液洗涤一次。无水硫酸钠干燥，真空浓缩，得到产物20g，产率80％。
(2)氟比洛芬酯的制备：
将氯化镍六水合物1.9g(0.008mol)、2,2'-联吡啶1.5g(0.096mol)、氯化钠2.3g(0.04mol)、锰粉13g(0.24mol)和三乙胺盐酸盐5.5g(0.04mol)溶于250mL四氢呋喃中，氮气氛围下，40℃搅拌20min。加入4-溴-2-氟联苯20g(0.08mol)、2-氯丙酸甲酯14.7g(0.12mol)和250mL无水四氢呋喃，氮气氛围下，40℃搅拌12h。反应完成后，以石油醚/乙酸乙酯按体积比20:1混合作为洗脱剂，过硅胶柱分离，得到偶联产物氟比洛芬18.7g，产率91％。
(3)氟比洛芬的制备：
将氟比洛芬酯18.7g(0.072mol)溶于70mL甲醇中，加入氢氧化钠水溶液135mL(0.088mol)，40℃搅拌3h。反应完成后，加入乙酸乙酯300mL，用1mol/L盐酸水溶液调节pH值1～2，萃取分层，有机相用100mL氯化钠饱和水溶液洗涤一次，用无水硫酸钠干燥，真空浓缩，得终产物氟比洛芬17.2g，产率97％，纯度98％。
上述过程用反应式表示为：
产物为白色固体：1H NMR(400MHz,CDCl3)δ7.53(dt,J＝8.1,1.5Hz,2H),7.48–7.33(m,4H),7.22–7.12(m,2H),3.79(q,J＝7.1Hz,1H),1.57(d,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ179.88,161.09,158.62,141.14,141.06,135.57,131.06,131.02,129.12,129.09,128.60,128.38,128.25,127.86,123.84,123.80,115.65,115.41,44.94,18.17.EI-MS(m/z)：267.0[M+Na]+。
对比例1
同实施例1，不同之处在于，步骤(1)中，缩合反应温度为为40℃，则收率下降，因此，缩合反应温度为50～60℃，有利于反应进行。
对比例2
同实施例1，不同之处在于，加料顺序是：将氯化镍六水合物、2,2'-联吡啶、氯化钠、锰粉、三乙胺盐酸盐、4-溴-2-氟联苯、2-氯丙酸甲酯置于无水四氢呋喃，氮气氛围下，40℃搅拌12h，无预先搅拌，出现4-溴-2-氟联苯自偶联副产物以及其他杂质，收率较低。因此，需要将镍催化剂、配体、还原剂和添加物预先搅拌，使二价镍盐与还原剂原位生成零价镍，再加入底物，反应即可顺利进行。
Claims (10)
1.一种氟比洛芬的制备方法，其特征在于，包括下列步骤：
(1)将4-溴-2-氟苯胺在三氯乙酸、氯化亚铜、原甲酸三乙酯和亚硝酸胺作用下与苯缩合得到4-溴-2-氟联苯；
(2)4-溴-2-氟联苯在溴催化剂、配体、金属还原剂、添加物和三乙胺盐酸盐作用下，与2-氯丙酸甲酯发生偶联反应生成氟比洛芬酯；
(3)氟比洛芬酯经碱性条件下的水解反应制得氟比洛芬。
2.根据权利要求1所述的氟比洛芬制备方法，其特征在于：步骤(1)中，按摩尔比，4-溴-2-氟苯胺：三氯乙酸：氯化亚铜：原甲酸三乙酯：亚硝酸胺为1:1.7:0.5:2:1.4；4-溴-2-氟苯胺在苯中的摩尔浓度为：1mol/L～2mol/L。
3.根据权利要求1所述的氟比洛芬制备方法，其特征在于：步骤(1)中，反应温度为50～60℃。
4.根据权利要求1所述的氟比洛芬制备方法，其特征在于：步骤(2)中，按摩尔比，4-溴-2-氟联苯：2-氯丙酸甲酯：镍催化剂：配体：金属还原剂：添加物：三乙胺盐酸盐为1：1.5：0.1：0.12：(2～3)：(0.5～1)：0.5。
5.根据权利要求1所述的氟比洛芬制备方法，其特征在于：步骤(2)中，镍催化剂选自：氯化镍、氯化镍六水合物、醋酸镍四水合物、碘化镍、溴化镍乙二醇二甲醚络合物或氯化镍乙二醇二甲醚络合物；
和/或，配体选自：2,2'-联吡啶、4,4'-二叔丁基-2,2'-联吡啶或三苯基膦；
和/或，金属还原剂选自：锌粉或锰粉；
和/或，添加物选自：四氟硼酸钠、氯化钠、溴化钠、碘化钠、氟化钾或氯化锂中的一种。
6.根据权利要求1所述的氟比洛芬制备方法，其特征在于：步骤(2)中，偶联反应采用的溶剂选自：四氢呋喃、乙酸乙酯、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
7.根据权利要求1所述的氟比洛芬制备方法，其特征在于：加料过程为先加入镍催化剂、配体、金属还原剂、添加物和三乙胺盐酸盐，40～50℃搅拌20min，加入4-溴-2-氟联苯和2-氯丙酸甲酯，氮气氛围下，40～50℃反应12h。
8.根据权利要求1所述的氟比洛芬制备方法，其特征在于：步骤(3)中，水解反应的碱性条件采用有机碱，有机碱为氢氧化锂或氢氧化钠，按摩尔比，氟比洛芬酯与有机碱为1:1.2。
9.根据权利要求1所述的氟比洛芬制备方法，其特征在于：水解反应采用的溶剂选自四氢呋喃或甲醇，反应温度为25～40℃。
10.根据权利要求1～9任意一项所述的氟比洛芬制备方法，其特征在于：制备得到的氟比洛芬为S-异构体。
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Non-Patent Citations (1)
| Title |
|---|
| EYAL TZUR, ET AL: "Homodinuclear Ruthenium Catalysts for Dimer Ring-Closing Metathesis", 《ANGEW. CHEM. INT. ED.》, vol. 47, 10 July 2018 (2018-07-10), pages 6422 - 6425 * |
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