CN112341352A - Preparation method of flurbiprofen - Google Patents
Preparation method of flurbiprofen Download PDFInfo
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- CN112341352A CN112341352A CN202011268683.0A CN202011268683A CN112341352A CN 112341352 A CN112341352 A CN 112341352A CN 202011268683 A CN202011268683 A CN 202011268683A CN 112341352 A CN112341352 A CN 112341352A
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- 229960002390 flurbiprofen Drugs 0.000 title claims abstract description 47
- 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 44
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 112
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 239000003054 catalyst Substances 0.000 claims abstract description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 29
- -1 N-substituted o-fluoroaniline Chemical class 0.000 claims abstract description 27
- 230000009471 action Effects 0.000 claims abstract description 24
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 21
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 19
- 239000002841 Lewis acid Substances 0.000 claims abstract description 17
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 17
- 230000002378 acidificating effect Effects 0.000 claims abstract description 15
- 238000005917 acylation reaction Methods 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 10
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims description 62
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 56
- 238000003756 stirring Methods 0.000 claims description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 239000012074 organic phase Substances 0.000 claims description 32
- 238000010438 heat treatment Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 22
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 18
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 18
- JEQDSBVHLKBEIZ-REOHCLBHSA-N (2s)-2-chloropropanoyl chloride Chemical compound C[C@H](Cl)C(Cl)=O JEQDSBVHLKBEIZ-REOHCLBHSA-N 0.000 claims description 14
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- AUZPZBPZWHEIDY-UHFFFAOYSA-N n-(2-fluorophenyl)acetamide Chemical group CC(=O)NC1=CC=CC=C1F AUZPZBPZWHEIDY-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000011592 zinc chloride Substances 0.000 claims description 9
- 235000005074 zinc chloride Nutrition 0.000 claims description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical group O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000003223 protective agent Substances 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229910052901 montmorillonite Inorganic materials 0.000 claims description 4
- 229940113115 polyethylene glycol 200 Drugs 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003021 water soluble solvent Substances 0.000 claims description 4
- ILLHORFDXDLILE-UHFFFAOYSA-N 2-bromopropanoyl bromide Chemical compound CC(Br)C(Br)=O ILLHORFDXDLILE-UHFFFAOYSA-N 0.000 claims description 3
- OZGMODDEIHYPRY-UHFFFAOYSA-N 2-bromopropanoyl chloride Chemical compound CC(Br)C(Cl)=O OZGMODDEIHYPRY-UHFFFAOYSA-N 0.000 claims description 3
- YWCOMVPBAMLMBY-UHFFFAOYSA-N 2-chloropropanoyl bromide Chemical compound CC(Cl)C(Br)=O YWCOMVPBAMLMBY-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- YUMWSAITHMEJKR-UHFFFAOYSA-N n-(2-fluorophenyl)propanamide Chemical compound CCC(=O)NC1=CC=CC=C1F YUMWSAITHMEJKR-UHFFFAOYSA-N 0.000 claims description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- AUHNQFOFWVWFTH-UHFFFAOYSA-N tert-butyl n-(2-fluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC=C1F AUHNQFOFWVWFTH-UHFFFAOYSA-N 0.000 claims description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical group CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 3
- 229940102001 zinc bromide Drugs 0.000 claims description 3
- 229910021595 Copper(I) iodide Chemical group 0.000 claims description 2
- MEMUCXUKCBNISQ-UHFFFAOYSA-N acetonitrile;trifluoroborane Chemical compound CC#N.FB(F)F MEMUCXUKCBNISQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 34
- 239000002994 raw material Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 26
- 238000001816 cooling Methods 0.000 description 25
- 239000007787 solid Substances 0.000 description 21
- 238000001035 drying Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 239000013067 intermediate product Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
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- 239000012065 filter cake Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
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- 238000004821 distillation Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 230000008707 rearrangement Effects 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
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- 235000010288 sodium nitrite Nutrition 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
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- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- 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
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Abstract
The invention relates to a preparation method of flurbiprofen, and belongs to the technical field of drug synthesis. In order to solve the problems of poor safety and low yield of the existing route, the preparation method of flurbiprofen is provided, which comprises the step of carrying out acylation reaction on o-fluoroaniline or N-substituted o-fluoroaniline and 2-halogenated propionyl halide under the action of Lewis acid to obtain an intermediate compound shown as a formula II; under the action of a ketal catalyst, performing ketal reaction on a compound shown in a formula II and a carbonyl protection reagent to obtain a ketal; carrying out rearrangement reaction on the ketal compound in the presence of an acidic catalyst to obtain a compound shown in the formula IV; carrying out hydrolysis reaction under acidic or alkaline conditions to obtain a compound shown in the formula V; under the action of a diazotization catalyst and a phase transfer catalyst, the compound of the formula V, benzene and nitrite are mixed under the acid condition for diazotization reaction, and after the diazotization reaction is finished, hydrolysis reaction is carried out to obtain the corresponding product, namely the compound flurbiprofen of the formula I. Has the effects of high reaction safety and high yield.
Description
Technical Field
The invention relates to a preparation method of flurbiprofen, and belongs to the technical field of drug synthesis.
Background
Flurbiprofen (flurbiprofen) belongs to propionic acid nonsteroidal anti-inflammatory drugs, and has a chemical name of (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid, and a structural formula shown as follows:
flurbiprofen is the best curative effect of the currently known propionic acid nonsteroidal anti-inflammatory drugs, and is mainly used for treating rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and the like clinically. The flurbiprofen has high antipyretic, anti-inflammatory and analgesic effects, low toxicity and small side effect, is an excellent variety of non-steroidal anti-inflammatory analgesics, and has wide market competitiveness and development prospect.
Flurbiprofen reported at home and abroad is mainly represented by biphenyls of starting materials 2-fluoro-4-bromobiphenyl, and is synthesized by the above route as reported in the prior documents of Chinese patent publication Nos. CN108218667A and CN103012144A, through Grignard reaction, reaction with halogenated isopropanoate or salt, and acidification. However, the main problems with this route are: 1) although the starting material for producing the 2-fluoro-4-bromobiphenyl is the o-fluoroaniline, the starting material uses expensive raw materials such as a metal palladium catalyst, a bromization reagent, an organic boron reagent and the like, and generates a large amount of byproducts and heavy metal residues and increases the treatment cost of three wastes, so that the starting material is relatively expensive comprehensively; 2) the anhydrous and anaerobic reaction conditions of the Grignard reaction are strict, the stability is poor, hydrolysis and self coupling are easy to occur, and the effective content of the Grignard reaction is difficult to accurately measure. The reaction route has low yield and high production cost, and finally, the price of flurbiprofen is high.
The other type of flurbiprofen is synthesized by using phenyl derivatives as raw materials and benzyl cyanide as raw materials through 10 reactions such as nitration, diazotization and reduction, wherein the total yield is only 7%, as reported in the existing literature data. Also for example, the research on the synthetic process of flurbiprofen [ D ], university of celand science and technology, 2012 reports that o-fluoroaniline is used as a raw material, and the bromo-reaction is carried out through 7 steps of bromination, diazotization, coupling, Grignard reaction and the like, and bromine or N-bromosuccinimide (NBS) is used as the bromo-reaction, so that the selectivity is poor, more byproducts are generated, and great pressure is brought to separation and purification and three-waste treatment; on the other hand, when 1, 5-dibromo-3, 3-dimethylhydantoin (DBDMH) is used, although the selectivity is high, the operation is complicated, and the raw material price is expensive. In conclusion, the synthetic methods of the routes reported in the existing documents generally have the problems of long routes, harsh reaction conditions, more byproducts, difficult separation and purification and the like, so that the total yield of the final product is very low, cannot meet the amplified requirement, and is not suitable for industrial production.
Disclosure of Invention
The invention provides a preparation method of flurbiprofen, aiming at the defects in the prior art, and solving the problem of providing a new route, having high safety and high yield.
The invention aims to realize the preparation method of flurbiprofen by the following technical scheme, and is characterized by comprising the following steps:
A. under the action of Lewis acid, performing acylation reaction on o-fluoroaniline or N-substituted o-fluoroaniline and 2-halogenated propionyl halide to obtain a corresponding intermediate compound shown as a formula II;
the N-substituted o-fluoroaniline is selected from o-fluoroacetanilide, o-fluoroaniline, o-fluoronitrobenzene, Boc-o-fluoroaniline or o-fluoropropionanilide;
in the above formula II, R1Selected from acetyl, propionyl, H or Boc group; x is the corresponding halogen in 2-halogen propionyl halide;
B. under the action of a ketal catalyst, performing ketal reaction on a compound shown in a formula II and a carbonyl protection reagent to obtain a ketal compound shown in a formula III;
r in the compound of the formula III is selected from methyl, ethyl or NPG;
C. carrying out rearrangement reaction on a ketal compound shown as a formula III under the heating condition in the presence of an acidic catalyst to obtain a corresponding compound shown as a formula IV;
D. carrying out hydrolysis reaction on the compound shown in the formula IV under acidic or alkaline conditions to obtain a compound shown in the formula V;
E. under the action of a diazotization catalyst and a phase transfer catalyst, mixing a compound shown in a formula V, benzene and nitrite in the presence of acid to carry out diazotization reaction, and after the diazotization reaction is finished, carrying out hydrolysis reaction to obtain a corresponding product, namely a compound flurbiprofen shown in a formula I;
the method has the advantages that by re-screening the initial raw materials, adopting the o-fluoroaniline or N-substituted o-fluoroaniline as the raw material and reacting the o-fluoroaniline or N-substituted o-fluoroaniline with 2-halogeno-propionyl halide, the high-efficiency conversion of the raw material can be realized under the action of Lewis acid, no obvious side reaction or impurity formation exists, the method has the effects of high yield and purity of intermediate products, more importantly, by adopting the raw material as the initial raw material, the raw material with high risk of using liquid bromine and expensive bromization reagent can be effectively avoided, and the requirements of safe production and the complicated separation and purification effects are improved; then, a corresponding intermediate is formed through ketal, the reaction can be carried out only under the action of a ketal catalyst, the adoption of expensive palladium catalysts, which are equivalent to palladium, is avoided, the cost is favorably controlled, the effects of easy control of the specific reaction and high conversion rate are achieved, the defects of high dangerousness, such as the adoption of Grignard reagents, in the reaction are avoided, and the overall operation safety of the reaction is improved; meanwhile, after the intermediate is formed by adopting the initial raw material, each reaction can be effectively carried out through the subsequent Friedel-crafts acylation reaction, ketal reaction, rearrangement, hydrolysis and coupling reaction, and after the intermediate is formed through the ketal reaction, the carbonyl ketone can be effectively protected, the reaction conditions are milder, and the process operation is simple; in addition, the whole reaction process effectively avoids the severe conditions of adopting a format reagent for reaction, and has unstable factors of easy hydrolysis and low total yield.
In the above-mentioned method for producing flurbiprofen, the halopropionyl halide in step A is preferably selected from 2-chloropropionyl chloride, 2-bromopropionyl bromide, 2-bromopropionyl chloride or 2-chloropropionyl bromide. By adopting the raw materials, the genes can be better introduced into corresponding positions of the initial raw materials for acylation, and the raw materials have low cost and are easier for industrial production. As a further preferred, 2-chloropropionyl chloride is used as the halopropionyl halide. On the other hand, the above-mentioned raw material o-fluoroaniline or N-substituted o-fluoroaniline and halogeno-propionic acid halide may be used in a ratio of molar equivalents to each other, and it is preferable that the molar ratio of the o-fluoroaniline or N-substituted o-fluoroaniline to halogeno-propionic acid halide is 1: 1 to 1.2.
In the above method for preparing flurbiprofen, the lewis acid in step a is preferably one or more selected from the group consisting of aluminum trichloride, zinc chloride, ferric trichloride, boron trifluoride acetonitrile and boron trifluoride diethyl etherate; under the action of the Lewis acid, the Lewis acid can be coordinated with halogenated propionyl halide to form an intermediate state, which is equivalent to better playing a role in activating, so that the acylation reaction can be better carried out to introduce the group in the corresponding halogenated propionyl halide into the corresponding substitution position on the benzene ring in the o-fluoroaniline or N-substituted o-fluoroaniline, the reaction efficiency and the conversion rate are improved, the reaction raw materials can be more fully converted, and the Lewis acid has the advantages of high selectivity, less byproducts and high purity of intermediate products. The temperature of the acylation reaction is preferably 50 ℃ to 60 ℃. Has the advantage of mild reaction conditions. Preferably, the molar ratio of the halopropanoyl halide to lewis acid is 1: 2.0 to 2.2.
In order to allow the reaction to proceed more efficiently, it is preferable to allow the acylation reaction in step A to proceed in a water-insoluble organic solvent, and these solvents allow the starting materials to proceed efficiently and also allow the reaction to proceed more gently. Still more preferably, the water-insoluble organic solvent in step A is selected from one or more of cyclohexane, petroleum ether, n-heptane, dichloromethane and dichloroethane. One or more of methylene chloride and ethylene dichloride are preferably used. The amount of the solvent to be used may be in accordance with the ordinary requirements in the art, and is preferably 8 to 10 mass% of the amount of the water-insoluble organic solvent based on the mass of the starting o-fluoroaniline or N-substituted o-fluoroaniline.
In the preparation method of flurbiprofen, the carbonyl protecting reagent is preferably trialkyl orthoformate or a dihydric alcohol protecting reagent, so that a corresponding group can be well formed, a subsequent rearrangement reaction can be better carried out, and the conversion rate of a corresponding intermediate product is high. Preferably, the carbonyl protecting agent in step B is selected from trimethyl orthoformate, triethyl orthoformate, neopentyl glycol or ethylene glycol. Can effectively carry out selective protection on ketone carbonyl in the halogenated propionyl group, better convert the ketone carbonyl into corresponding intermediate products, and have the effects of mild reaction conditions and high intermediate conversion rate. Preferably, the molar ratio of the intermediate compound of formula II to the carbonyl protecting agent is 1: 1.0 to 5.5. As a further preference, the ketal catalyst in step B is selected from p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate. The conversion rate of ketal is improved, so that the reaction is more effectively carried out. Preferably, the molar ratio of the intermediate compound of formula II to the ketal catalyst is 1: 2.0 to 3.0.
Further, it is preferable to carry out the ketal reaction in the above step B in an alcohol solvent, xylene or toluene solvent, so that the reaction proceeds more gently. Further, the alcohol solvent is selected from methanol, ethanol or isopropanol and the like.
In the above method for preparing flurbiprofen, preferably, the phase transfer catalyst in step E is one or more selected from tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 200 and polyethylene glycol 400. The reaction can be more efficiently carried out by the action of the phase transfer catalyst, and the reaction conversion rate is high, and the amount of the phase transfer catalyst is generally 0.01 to 2.0% of the molar equivalent of the intermediate compound of formula V, because the reaction can be carried out in the forward direction by the action of a catalytic amount.
In the above method for producing flurbiprofen, preferably, the diazotization catalyst in the step E is selected from cuprous chloride, cuprous bromide or cuprous iodide; the acid is selected from one or more of acetic acid, trifluoroacetic acid, trichloroacetic acid, hydrobromic acid and hydrochloric acid; the temperature of the diazotization reaction is preferably 20-80 ℃. The amount of the diazotization catalyst is added according to a catalytic amount, and is preferably 0.01 to 2.0 percent, more preferably 0.05 to 0.11 percent of the mass of the intermediate compound of formula V. The diazotization reaction in step E above is preferably carried out in an aqueous and/or alcoholic solvent.
In the above method for preparing flurbiprofen, preferably, the acidic catalyst in step C is one or more selected from zinc bromide, zinc chloride, ferric chloride and montmorillonite, the rearrangement reaction is performed in a toluene solvent, and the temperature of the rearrangement reaction is 100 ℃ to 110 ℃.
In the above method for preparing flurbiprofen, preferably, the acidic conditions in step D are specifically in the presence of one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid; the alkaline condition is specifically in Na2CO3、K2CO3NaOH and KOH in the presence of one or more of the following components.
In the above method for producing flurbiprofen, the method is preferably specifically:
A. under the action of Lewis acid, carrying out acylation reaction on o-fluoroacetanilide and 2-chloropropionyl chloride in a water-insoluble organic solvent under the condition of reflux, adding a hydrochloric acid solution after the reaction is finished, stirring, standing for layering, and distilling the collected organic phase to remove the solvent to obtain a corresponding intermediate compound shown in the formula II-1;
B. under the action of a ketal catalyst p-toluenesulfonic acid or mono-water p-toluenesulfonic acid, performing ketal reaction on a compound shown in a formula II and trimethyl orthoformate in an alcohol solvent at 50-60 ℃, adding a water-insoluble organic solvent and water after the reaction is finished, stirring, standing for layering, and distilling a collected organic layer to remove the solvent to obtain a ketal compound shown in a formula III-1;
r in the compound of the formula III is selected from methyl, ethyl or NPG;
C. in the presence of an acid catalyst, enabling a ketal compound III-1 to perform rearrangement reaction in a toluene solvent at the temperature of 100 ℃ and 110 ℃, adding water for stirring, standing for layering, and distilling a collected organic layer to remove the solvent to obtain a corresponding compound IV-1;
D. in the presence of concentrated hydrochloric acid, carrying out hydrolysis reaction on a compound shown in the formula IV in a mixed solvent of alcohol and water at the temperature of 70-80 ℃, adding an alkaline reagent to adjust the pH value of a reaction solution to 7-8 after the reaction is finished, distilling to remove an alcohol solvent, adding a non-water-soluble solvent, stirring, standing for layering, and distilling a collected organic phase to remove the solvent to obtain a compound shown in the formula V-1;
E. under the action of diazotization catalyst and phase transfer catalyst, mixing the compound of formula V-1, benzene and nitrite, heating to 50-60 ℃, adding acetic acid, preserving heat for diazotization reaction, after the reaction is finished, adding hydrochloric acid for hydrolysis reaction, adding water-insoluble solvent for stirring, standing for layering, collecting organic phase, removing solvent, and obtaining the corresponding product flurbiprofen compound of formula I.
In the preparation method of flurbiprofen, the chemical reaction equation of the specific process route when the o-fluoroacetanilide and the 2-chloropropionyl chloride are used as the starting raw materials is as follows:
in summary, compared with the prior art, the invention has the following advantages:
1. the method has the advantages that the initial raw materials are screened again, the o-fluoroaniline or the N-substituted o-fluoroaniline is used as the raw material and is reacted with the 2-halogeno-propionyl halide, the high-efficiency conversion of the raw material can be realized under the action of Lewis acid, no obvious side reaction and impurity formation exist, the yield and the purity of the intermediate product are high, the formed intermediate product only needs to form a corresponding intermediate through ketal reaction, high-risk Grignard reagent and other reactions are not needed, the safety is high, the high-risk raw materials using liquid bromine and expensive bromination reagents can be effectively avoided, and the requirements on safe production and the complicated separation and purification effects are improved.
2. After the initial raw materials are adopted to form the intermediate, the subsequent Friedel-crafts acylation reaction, ketal reaction, rearrangement, hydrolysis and coupling reaction are carried out, so that each reaction can be effectively carried out, after the intermediate is formed through the ketal reaction, the carbonyl ketone can be effectively protected, the reaction conditions are milder, and the process operation is simple.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
The preparation method of the flurbiprofen comprises the following steps:
under the action of Lewis acid, carrying out acylation reaction on o-fluoroaniline or N-substituted o-fluoroaniline and 2-halopropionyl halide in a non-water-soluble organic solvent to obtain a corresponding intermediate compound shown as a formula II;
in the above formula II, R1Selected from acetyl, propionyl, H or Boc group; x is the corresponding halogen in 2-halogen propionyl halide; the halogen may be chlorine, bromine or iodine, and the two halogen substituents at the corresponding halogen substitution positions may be the same or different, preferably both are chlorine, preferably chloropropionyl chloride. The water-insoluble organic solvent is preferably one or more selected from cyclohexane, petroleum ether, N-heptane, dichloromethane and dichloroethane, and the molar ratio of o-fluoroaniline or N-substituted o-fluoroaniline and 2-halopropanoyl halide is preferably 1: 1-1.2, more effective conversion of raw materials, reduction of waste and residue of raw materials, and optimal control of the temperature of acylation reaction at 50-60 ℃, preferablyPreferably 53 to 55 ℃. The N-substituted o-fluoroaniline is selected from o-fluoroacetanilide, o-fluoroaniline, o-fluoronitrobenzene, Boc-o-fluoroaniline or o-fluoropropionanilide, and the o-fluoroacetanilide is optimally adopted, wherein the o-fluoroaniline can be obtained by carrying out reduction reaction by adopting o-fluoronitrobenzene as a raw material, and the like, and can also complete the reaction.
The method further comprises post-treatment after the acylation reaction, wherein the post-treatment specifically comprises the following steps: and after the acylation reaction is finished, adding acid for treatment, wherein the acid is preferably diluted hydrochloric acid, standing and layering the mixture after fully stirring the mixture, collecting an organic phase, and distilling the organic phase to remove the solvent to obtain a corresponding residue, namely the intermediate compound shown as the formula II. The treatment by adding acid can better play a role in impurity removal, so that a small amount of unreacted o-fluoroaniline in the reaction liquid can form a salt-forming product, namely o-fluoroaniline hydrochloride, with acid, preferably hydrochloric acid, and the water solubility of the o-fluoroaniline hydrochloride is good, so that salts are remained in a water phase and cannot be brought into an organic phase in the subsequent extraction process, and the purity of the acylate is further improved. In order to better improve the purity and quality of the intermediate product, an inert solvent can be added for recrystallization, the inert solvent is preferably selected from one or more of n-heptane, n-hexane, cyclohexane, petroleum ether, methyl tert-butyl ether and isopropyl ether, during the recrystallization, the temperature can be raised to clear solution, then the solution is stirred for 30-60 minutes, then the temperature is slowly reduced to 0-10 ℃, the solution is stirred and fully crystallized, the solution is filtered, and the obtained filter cake is dried to obtain a dry product of the compound shown in the formula II for the next reaction.
After the reaction of the first step is completed, the reaction of the second step can be directly carried out, specifically: under the action of a ketal catalyst, performing ketal reaction on a compound shown in a formula II and a carbonyl protection reagent to obtain a ketal compound shown in a formula III;
r in the compound shown in the formula III is selected from methyl, ethyl, ethylene glycol group or NPG; when R is NPG, a cyclic ring structure is formed; when R is NPG, the corresponding compound of formula III has the following formula:
x in the above formula may specifically be chlorine or bromine. When R is ethylene glycol group, the corresponding compound of formula III also forms corresponding cyclic structure, that is, when dihydric alcohol is used as the raw material in R group, corresponding cyclic structure is formed, such as that formed when R is NPG.
The ketal reaction is preferably carried out in an alcohol solvent selected from lower alcohol solvents such as methanol, ethanol, isopropanol, etc., or in toluene or xylene. The amount of the alcohol solvent, toluene or xylene used in the ketal reaction can be any of those conventionally used, but it is preferable to use the solvent in an amount of about 10 to 12 times the amount of the intermediate compound of formula II. In the ketal reaction, when trimethyl orthoformate or triethyl orthoformate is used, it is preferable to use an alcohol solvent such as methanol or ethanol as a solvent, and the reaction can be preferably carried out; when neopentyl glycol (NPG) is used, it is preferable to use a high boiling point solvent such as toluene or xylene to allow the reaction to proceed more favorably, and the amount of the above-mentioned carbonyl protecting agent is preferably controlled to 1 to 5.5eq, and further, the amount of the carbonyl protecting agent is preferably 2 to 3eq, based on the molar equivalent of the compound of the formula II, corresponding to a molar ratio of the compound of the formula II to the carbonyl protecting agent of 1: 2-3, the yield of the obtained intermediate product is higher, and the purity of the product reaches more than 99%. The ketal catalyst is preferably prepared by catalyzing p-toluenesulfonic acid monohydrate or p-toluenesulfonic acid, and the amount of the ketal catalyst is preferably that the molar ratio of the compound shown in the formula II to the ketal catalyst is 1: 0.05-0.2.
After the second step of reaction, performing a third step of reaction, specifically: carrying out rearrangement reaction on a ketal compound shown as a formula III under the heating condition in the presence of an acidic catalyst to obtain a corresponding compound shown as a formula IV;
the rearrangement reaction is preferably carried out in a high-boiling water-insoluble solvent such as toluene, chlorobenzene, xylene, or the like at a relatively high temperature, so that the rearrangement reaction can be carried out more sufficiently, and the amount of the solvent is preferably 10 times or more, which is more favorable for the mild reaction and more effective for avoiding the influence of impurities. The acidic catalyst is preferably carried out by using zinc bromide, zinc chloride, ferric chloride or montmorillonite as the catalyst, the rearrangement reaction is carried out efficiently, the rearrangement conversion rate is high, and the generation of byproducts is avoided. Preferably, the molar ratio of the compound of formula III to the acidic catalyst is 1: 0.05 to 0.2, preferably 1: 0.06-0.1. The rearrangement reaction is further preferably carried out by heating at a temperature of 100 ℃ or higher, after the reaction is completed, cooling to 50 ℃ or lower, adding water, stirring thoroughly, standing for layering, collecting the organic layer, distilling to remove the solvent to obtain the corresponding white solid product, or further, after removing the solvent, adding a halogenated methane solvent such as dichloromethane and the like to the residue, heating to a temperature of 0 to-10 ℃ for recrystallization to obtain the corresponding white solid product intermediate.
And then carrying out a fourth step of reaction, which specifically comprises the following steps: under the acidic or alkaline condition, the compound of the formula IV is subjected to hydrolysis reaction in an alcohol or/and water solution at the temperature of 70-80 ℃, the temperature is reduced after the reaction is finished, the pH value of the system is adjusted to 7-8, further the pressure can be reduced to remove an alcohol solvent, a non-water-soluble solvent such as dichloromethane is added for stirring fully, standing and layering are carried out, and the collected organic phase is distilled to remove the solvent, so that the compound of the formula V is obtained;
the acidic conditions of this step may be those in the presence of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid, provided that the hydrolysis reaction proceeds efficiently; the alkaline condition is preferably an alkaline condition in the presence of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, and can be effectively performed;
after the rearrangement reaction is finished, performing a fourth reaction step, specifically: under the action of a diazotization catalyst and a phase transfer catalyst, mixing a compound shown in a formula V, benzene and nitrite in the presence of acid to carry out diazotization reaction, and after the diazotization reaction is finished, reinforcing the acid to carry out hydrolysis reaction to obtain a corresponding product, namely a compound flurbiprofen shown in a formula I;
the diazotization reaction is preferably carried out in water and/or an alcohol solvent, most preferably directly carried out by using water, the acid selected in the diazotization reaction is preferably one or more of acetic acid, trifluoroacetic acid, trichloroacetic acid, hydrobromic acid and hydrochloric acid, most preferably acetic acid, and the organic weak acid is adopted, so that the reaction can be effectively carried out, and other byproducts generated due to over-strong acidity can be avoided, and the purity and yield effect of the product can be better ensured. The temperature of the diazotization reaction is preferably controlled to be 20-80 ℃, preferably 50-70 ℃, and the nitrite is preferably sodium nitrite. Further, in the above diazotization step, a compound of formula V: the molar ratio of sodium nitrite is 1: 1.1 to 2.2, preferably in a molar ratio of 1: 1.2-1.3, preferably, the dosage of the diazotization catalyst is 0.01-1.0 percent of the dosage of the compound of the formula V, and more preferably 0.05-0.06 percent; further, the molar ratio of the compound of the formula V to the benzene is 1: 0.8 to 1.3, preferably 1: 1.0 to 1.02.
More specifically, in the acylation reaction in the first step, it is preferable to preliminarily react the Lewis acid and the halogenopropionyl halide. The reaction is more facilitated, and the detailed material ratio and the feeding mode of the 2-chloropropionyl chloride are further improved by adopting the reaction process parameters of aluminum trichloride for the Lewis acid as shown in the table 1.
Table 1: AlCl3Technological parameters of material proportioning and feeding mode
From the experimental data of table 1, it can be derived: when the aluminum trichloride and the 2-chloropropionyl chloride are subjected to coordination reaction, when the use equivalent is about 2.1eq, the HPLC (high performance liquid chromatography) controlled purity of the reaction liquid can reach more than 91.3 percent, and the molar yield of the intermediate compound II prepared by recrystallization can reach 78 percent; when the dosage of the aluminum trichloride is reduced, more raw materials cannot be converted into products; the use amount is increased, and the unknown impurities in HPLC are obviously increased, so that the central control purity is reduced. In addition, the feeding mode and the feeding sequence of the aluminum trichloride also have certain influence on the quality and the yield of the intermediate II: the multi-time feeding is better than one-time feeding, the multi-time feeding is preferably divided into more than two times, the purity is improved by about 5 percent, meanwhile, the reverse feeding effect of the experiment is better, and in sum, the dosage of the Lewis acid is preferably 2.0-3.0 eq.
Furthermore, the Lewis acid catalyst is preferably dissolved in a water-insoluble organic solvent, then the temperature is reduced, the halogenating reagent of the 2-halogen propionyl halide is dripped, the mixture is fully stirred, and then the temperature is increased to 50-60 ℃ for reaction. Furthermore, the addition of more than 10 times of water-insoluble organic solvent can reduce system impurities and improve the purity of the intermediate.
The following examples are further illustrated by more specific embodiments but are not intended to be limiting.
Example 1
First step preparation of intermediate Compound of formula II
Dispersing 168g of aluminum trichloride (1.26mol) in 400mL of dichloromethane solvent in a clean reactor, stirring until the aluminum trichloride is dissolved, cooling to 10-15 ℃ under the protection of nitrogen, dropwise adding 80g of 2-chloropropionyl chloride (0.63mol) into the reaction liquid, controlling the temperature, keeping the temperature, stirring for 1h, slowly dropwise adding 200mL of dichloromethane clear solution of 92g of o-fluoroacetanilide (0.6mol) prepared in advance into the reaction liquid of the reaction system, heating to reflux after the dropwise addition is finished, stirring for reacting for 18-20h, cooling the reaction system to 0-5 ℃ after the reaction is finished, dropwise adding 300mL of 5% dilute hydrochloric acid solution, fully stirring for 1h, standing for layering, collecting an organic phase, extracting the aqueous phase with dichloromethane once, combining the two collected organic phases, distilling the organic phase at normal pressure to recover the dichloromethane solvent, and after distillation till no liquid is discharged, adding 200mL of ethyl acetate into the residue, heating, dissolving, slowly cooling, crystallizing until solid is separated out, dropwise adding 800mL of n-heptane to fully crystallize, filtering to obtain a light yellow solid intermediate product, namely the compound of the formula II, drying a wet product in vacuum at 40 ℃ for 3-4h, drying, and discharging to obtain a powdery intermediate product, namely a dried product 114g (the yield is 78%) of the compound of the formula II (the intermediate 2), wherein the HPLC purity is more than 98%.
1H-NMR(400MHz，CDCl3)δ9.02(d,J＝7.2Hz，1H),7.79(d,J＝6.1Hz,1H),7.46(s,1H),7.19(t,J＝9.5Hz,1H),5.23(q,J＝6.6Hz,1H),2.26(s,3H),1.72(t,J＝10.3Hz,3H)。
Example 2:
98g (0.4mol) of the compound of the formula II (intermediate 2) obtained by the above-mentioned method was dissolved in 500mL of an anhydrous methanol solvent, and 53g of trimethyl orthoformate (0.5mol) and p-toluenesulfonic acid (0.02mol) were added thereto, followed by heating to 50 to 60 ℃ to carry out a reaction for 2 hours. After the reaction is finished, carrying out reduced pressure distillation to recover methanol and trimethyl orthoformate, distilling until no liquid flows out, adding 600mL of dichloromethane and 200mL of water into the solid concentrate, fully stirring, standing for layering, carrying out normal pressure distillation on the collected organic phase to recover the solvent, adding 200mL of isopropanol into the residue for fully pulping, filtering to obtain a filter cake, leaching the filter cake with a little isopropanol, and drying the obtained wet product at 50 ℃ under a vacuum condition for 5-6h to obtain 99g (the yield is 85%) of the intermediate compound III (the intermediate 3 a).
1H-NMR(400MHz,CDCl3)δ8.35(d,J＝7.4Hz,1H)，7.41(s,1H)，7.26(s,1H),7.07(t,J＝9.6Hz,1H)，4.36(q,J＝6.7Hz,1H)，3.34(s,3H)，3.20(s,3H)，2.21(s,3H)，1.33(d,J＝6.7Hz,3H)。
19F-NMR(376MHz，CDCl3)δF：-131.40ppm
Example 3:
dissolving 49g (0.2mol) of the compound of the formula II (the intermediate 2) in 600mL of toluene solvent, adding 31g of neopentyl glycol (0.3mol) and 1.9g of p-toluenesulfonic acid (0.01mol), slowly heating to 120 ℃, reacting for 10h by using a water separator, after the reaction is finished, cooling to below 50 ℃, adding 200mL of water, fully stirring, standing for layering, distilling the collected organic layer at normal pressure to recover the solvent, distilling until no liquid flows out, adding 200mL of isopropanol into the residue for fully pulping, draining the filter cake, and drying in vacuum at 50 ℃ for 5-6h to obtain the corresponding compound of the formula III (the intermediate 3b) with the yield of 57g (the yield of 87%).
1H-NMR(400MHz,CDCl3)δ8.31(d,J＝7.1Hz,1H),7.35(s,1H),7.19–7.07(m,2H),4.03(d,J＝6.7Hz,1H),3.46(s,4H),2.22(s,3H),1.58(s,3H),1.27(s,6H)。
Example 4:
dissolving 87g of the intermediate 3a (0.3mol) in 500mL of toluene solvent, stirring at room temperature until the intermediate is completely dissolved, adding 3g of zinc chloride (0.02mol), heating to 110 ℃, reacting for 0.5-1h, cooling to below 50 ℃, adding 200mL of deionized water, fully stirring, standing for layering, and distilling the toluene under reduced pressure to recover the solvent. Adding 400mL of dichloromethane for dissolution, distilling under normal pressure to remove about 320mL of solvent, separating out more white solid, cooling to-10 ℃ for crystallization for 1-2h, filtering to obtain pure white solid crystal, and drying in vacuum to obtain the compound (intermediate 4) of the formula IV with the yield of 58g and the yield of 81%.
1H-NMR(400MHz,DMSO)δ9.85(d,J＝56.2Hz,1H),8.56(d,J＝7.0Hz,1H),7.85(s,1H),7.43(t,J＝9.5Hz,1H),5.76–5.60(m,1H),3.33(s,3H)，2.11(s,3H),1.76(d,J＝6.3Hz,0.4H),1.60(d,J＝6.4Hz,2.6H)。
Example 5:
the rearrangement product intermediate 4(48g (0.2mol)) was dissolved in a mixed solvent of 200mL of ethanol and 100mL of water, 35g of concentrated hydrochloric acid (0.36mol) was added thereto at room temperature, and the mixture was reacted at 70 to 80 ℃ for 3 hours. Cooling to about 10 ℃, adjusting the pH value of a reaction system to 7-8 by using 10% NaOH aqueous solution, distilling an ethanol solvent out under reduced pressure, adding 300mL of dichloromethane, fully stirring, standing for layering, collecting an organic phase, extracting a water phase by using 100mL of dichloromethane, combining two organic phases, decoloring by using 6g of activated carbon, removing the solvent under reduced pressure, and concentrating to dryness to obtain a gray solid product, namely a compound (an intermediate 5) (35g, the yield is 88%).
1H-NMR(400MHz,DMSO)δ7.41(d,J＝8.8Hz,1H),7.25(s,1H),7.20–7.08(m,1H),5.61(d,J＝6.5Hz,1H),5.47(s,2H),1.57(d,J＝6.5Hz,3H)。
Example 6
The method for synthesizing flurbiprofen is as follows:
dispersing 30g of intermediate 5(0.15mol), 0.6g of cuprous chloride (0.006mol) and 12g of sodium nitrite (0.18mol) in 200g of water, stirring uniformly, adding 12.5g of benzene (0.16mol) and 2.5g of tetrabutylammonium chloride (0.009mol), heating in a water bath to 50-60 ℃, slowly dropwise adding 12g of acetic acid (0.2mol), keeping the temperature for reaction for 2-3h, and reacting after the reaction is finished. Adding 100mL of 5% diluted hydrochloric acid for hydrolysis, and stirring thoroughly for 30 min. Adding 200mL of toluene for extraction, standing for layering, extracting the water phase once with 100mL of toluene, combining the organic phases, and washing with water to be neutral. 150mL of water is added into the toluene layer at the upper layer, the pH value is adjusted to about 8 by 10% saturated sodium bicarbonate, 2g of medicinal activated carbon is added for decoloration for 1h, and the mixture is filtered to obtain a light yellow solution. And (3) adjusting the pH value to 2-3 by using 10% hydrochloric acid, precipitating a pure white solid, filtering, washing a filter cake by using pure water, draining, and drying in vacuum at 40-50 ℃ for 6 hours to obtain 28g of the flurbiprofen compound shown in the formula I, wherein the yield is 76%.
mp：110.4-112.6℃。
1H-NMR(400MHz,CDCl3)δ7.53(d,J＝7.2Hz,2H),7.40(ddd,J＝22.3,14.6,7.3Hz,4H),7.16(t,J＝9.7Hz,2H),3.79(q,J＝7.0Hz,1H),1.56(d,J＝7.1Hz,3H)。
13C-NMR(101MHz,CDCl3)δ179.50,160.90,158.43,140.98,135.39,130.85,128.92,128.42,128.11,127.68,123.64,115.46,115.22,44.78,18.02。
Example 7
Dispersing 168g of aluminum trichloride (1.26mol) in 400mL of n-heptane solvent, stirring until the aluminum trichloride is dissolved, cooling to 10-15 ℃ under the protection of nitrogen, dropwise adding 83.8g of 2-chloropropionyl chloride (0.66mol) into a reaction liquid, dropwise adding one third of the amount of the 2-chloropropionyl chloride in two times, reacting for 30 minutes, dropwise adding the rest, controlling the temperature to 10-15 ℃, keeping the temperature and stirring for 1.5 hours, slowly dropwise adding 200mL of n-heptane clear solution of 92g of o-fluoroacetanilide (0.6mol) into the reaction liquid of the reaction system, after dropwise adding, heating to 50-55 ℃ and keeping the temperature and stirring for reacting for 20 hours, after the reaction is finished, cooling the reaction system to 0-5 ℃, dropwise adding 300mL of 5% dilute hydrochloric acid solution, fully stirring for 0.5 hours, standing for layering, collecting an organic phase, extracting a water phase by using n-heptane once, and combining the organic phases collected twice, distilling the organic phase at normal pressure to recover an n-heptane solvent, distilling until no liquid is discharged, adding 200mL of ethyl acetate into the residue, heating to dissolve, slowly cooling to crystallize until solid is separated out, dropwise adding 600mL of n-heptane to fully crystallize, filtering to obtain a pale yellow solid intermediate product, namely the compound of the formula II, drying a wet product at 40 ℃ in vacuum for 4 hours, drying, and discharging to obtain a powdery intermediate product, namely the compound of the formula II (intermediate 2), namely 117.2g of a dry product (yield is 80.2%) with the HPLC purity of more than 98%.
Dissolving 98g (0.4mol) of the compound of formula II (intermediate 2) obtained by the method in 400mL of absolute ethanol solvent, adding 84.9g of trimethyl orthoformate (0.8mol) and p-toluenesulfonic acid (0.03mol), heating to about 55 ℃, keeping the temperature and reacting for 2h, after the reaction is finished, carrying out reduced pressure distillation to recover ethanol and trimethyl orthoformate, distilling until no liquid flows out, adding 500mL of dichloromethane and 200mL of water into a solid concentrate, fully stirring, standing for layering, carrying out atmospheric distillation on a collected organic phase to recover the solvent, adding 200mL of isopropanol into a residue, fully pulping, filtering to obtain a filter cake, leaching the filter cake with a little isopropanol, drying the obtained wet product at 50 ℃ for 5.5h, and obtaining 100.4g of the intermediate compound of formula III (intermediate 3a) with the yield of 85%.
Dissolving 87g (0.3mol) of the compound (intermediate 3a) of the corresponding formula III obtained in the previous step into 500mL of xylene solvent, stirring at room temperature until the compound is completely dissolved, adding 4.5g of zinc chloride (0.03mol), heating to a reflux state for reaction for 1h, cooling to below 50 ℃, adding 300mL of deionized water, fully stirring, standing for layering, carrying out reduced pressure distillation on a collected xylene layer to recover the solvent xylene until no liquid flows out, adding 400mL of dichloromethane into the residue for dissolving, distilling at normal pressure to remove about 320mL of the solvent, separating out more white solids, cooling to-10 ℃ for fully crystallizing for 2h, filtering to obtain pure white solid crystals, and drying in vacuum to obtain the rearrangement product, namely the compound (intermediate 4) of the formula IV, wherein the yield is 58.7g and the yield is 82%.
Dissolving the rearrangement product intermediate 4(48g (0.2mol)) in a mixed solvent of 300mL of ethanol and 100mL of water, adding 35g of concentrated hydrochloric acid (0.36mol) at room temperature, heating to reflux for reaction for 3h, cooling to about 10 ℃, adjusting the pH value of a reaction system by using a 10% NaOH aqueous solution to 7-8, distilling the ethanol solvent under reduced pressure, adding 300mL of dichloromethane, fully stirring, standing for layering, collecting an organic phase, extracting the aqueous phase once by using 100mL of dichloromethane, combining the two organic phases, adding 7g of activated carbon into the organic phase for decolorization for 30 minutes, filtering, removing the solvent under reduced pressure from the filtrate, and concentrating to obtain a gray solid product, namely the compound of the formula V (intermediate 5), wherein the yield is 36g and 90.5%.
30g of the intermediate 5(0.15mol), 0.3g of cuprous chloride (0.003mol) and 12g of sodium nitrite (0.18mol) are dispersed in 200g of water, and after the mixture is uniformly stirred, 12.5g (0.16mol) of benzene and 2.3g of benzyltriethylammonium chloride (0.01mol) are added, then the mixture is heated to 55 ℃ in a water bath, 12g (0.2mol) of acetic acid is slowly added dropwise, the mixture is subjected to heat preservation reaction for 3 hours, after the reaction is finished, 100mL of 5% diluted hydrochloric acid is added for hydrolysis, and the mixture is fully stirred for 30 minutes. Adding 200mL of toluene for extraction, standing for layering, extracting the water phase once with 100mL of toluene, combining the organic phases, and washing with water to be neutral. Adding 150mL of water into the toluene layer on the upper layer, adjusting the pH value to be about 8 by using 10% saturated sodium bicarbonate, adding 2g of medicinal grade activated carbon for decoloring for 1h, filtering to obtain a light yellow solution, adjusting the pH value to be 2-3 by using 10% hydrochloric acid, precipitating a pure white solid, filtering, washing a filter cake by using pure water, drying by pumping, and drying in vacuum at 40-50 ℃ for 6h to obtain 30g of flurbiprofen product, wherein the yield is 81.4%.
Example 8
Dispersing 176.8g of zinc chloride (1.3mol) in 400mL of dichloroethane solvent, stirring until dissolving, cooling to 10-12 ℃ under the protection of nitrogen, dropwise adding 91.5g of 2-chloropropionyl chloride (0.72mol) into the reaction liquid, controlling the temperature to 10-12 ℃, keeping the temperature and stirring for 2.0h, then slowly dropwise adding 200mL of dichloroethane solution of 92g of o-fluoroacetanilide (0.6mol) prepared in advance into the reaction liquid of the reaction system, after dropwise adding, heating to 55-60 ℃, keeping the temperature and stirring for reaction for 18h, after the reaction is finished, cooling the reaction system to 0-5 ℃, dropwise adding 300mL of 5% diluted hydrochloric acid solution, fully stirring for 0.5h, standing for layering, collecting an organic phase, extracting the aqueous phase once with dichloroethane, combining the two collected organic phases, distilling the organic phase at normal pressure to recover the n-heptane solvent, and after distillation till no liquid is discharged, adding 200mL of ethyl acetate into the residue, heating, dissolving, slowly cooling, crystallizing to separate out a solid, dropwise adding 600mL of n-heptane to fully crystallize, filtering to obtain a light yellow solid intermediate product, namely the compound of the formula II, drying a wet product at 40 ℃ in vacuum for 4 hours, drying, discharging to obtain a powdery intermediate product, namely 118.7g of the compound of the formula II (intermediate 2), namely a dry product (the yield is 80.2 percent), and the HPLC purity is more than 98 percent.
Dissolving 49g (0.2mol) of the compound of the formula II (intermediate 2) obtained in the above into 600mL of dimethylbenzene solvent, adding 41.3g of neopentyl glycol (0.4mol) and 3.8g of p-toluenesulfonic acid (0.02mol), slowly heating to 135 ℃, reacting for 11h by using a water separator, after the reaction is finished, cooling to below 50 ℃, adding 200mL of water, fully stirring, standing for layering, distilling the collected organic layer at normal pressure to recover the solvent, distilling until no liquid flows out, adding 200mL of isopropanol into the residue for fully pulping, draining the filter cake, and drying in vacuum at 50 ℃ for 5-6h to obtain the corresponding compound of the formula III (intermediate 3b) with the yield of 56.3g (the yield of 86%).
Dissolving 91.3g (0.3mol) of the corresponding intermediate 3b obtained in the previous step in 400mL of toluene solvent, stirring at room temperature until the intermediate is completely dissolved, adding 6.1g of zinc chloride (0.045mol), heating to a reflux state for reaction for 1h, cooling to below 50 ℃, adding 250mL of deionized water, fully stirring, standing for layering, carrying out reduced pressure distillation on the collected toluene layer to recover the solvent toluene until no liquid flows out, adding 400mL of dichloromethane into the residue for dissolution, distilling at normal pressure to remove about 320mL of the solvent, separating out more white solids, cooling to-10 ℃, fully crystallizing for 2h, filtering to obtain pure white solid crystals, and drying in vacuum to obtain the rearrangement product of the compound of formula IV (57.6g, yield 80.5%).
The hydrolysis after the following rearrangement reaction and the synthesis of the final flurbiprofen are identical to those of example 7 and will not be described here.
Example 9
Preparation of intermediate Compound (2a) of formula II in the first step
Dispersing 184.6g of boron trifluoride diethyl etherate (1.3mol) in 400mL of dichloromethane solvent in a clean reactor, stirring until the boron trifluoride diethyl etherate is dissolved, cooling to 10-13 ℃ under the protection of nitrogen, dropwise adding 82.6g of 2-chloropropionyl chloride (0.65mol) into the reaction liquid, controlling the temperature, stirring for 1h under heat preservation, slowly dropwise adding 200mL of dichloromethane clear solution of 103.8g of o-fluoropropionylaniline (0.6mol) prepared in advance into the reaction liquid of the reaction system, heating to reflux after the dropwise adding is finished, stirring for reaction for 20h, cooling the reaction system to 0-3 ℃ after the reaction is finished, dropwise adding 200mL of 10% diluted hydrochloric acid solution, fully stirring for 1h, standing for layering, collecting an organic phase, extracting the aqueous phase once with dichloromethane, combining the two collected organic phases, distilling the organic phase under normal pressure to recover the dichloromethane solvent, and after distillation till no liquid is discharged, adding 200mL of ethyl acetate into the residue, heating, dissolving, slowly cooling, crystallizing until solid is separated out, dropwise adding 800mL of n-heptane to fully crystallize, filtering to obtain a light yellow solid intermediate product, namely the compound of the formula II, drying the wet product in vacuum at 40 ℃ for 3-4h, drying, and discharging to obtain a powdery intermediate product, namely the compound of the formula II (the intermediate 2a), wherein the dry product is 114g (the yield is 78%) and the HPLC purity is more than 98.5%.
The following specific process is the same as that of example 7, and is not described herein again.
Example 10
The synthesis process of the intermediate 2a in this embodiment is substantially the same as that in embodiment 9, except that 2-chloropropionyl chloride is replaced by 2-bromopropionyl bromide, 2-bromopropionyl chloride or 2-chloropropionyl bromide, and the specific implementation is performed one by one to obtain the corresponding intermediate 2a, wherein the yield of the dried product of the intermediate 2a can reach 78% and the purity is more than 98.5%. Illustrating that the use of these halides allows substantially comparable levels to be achieved in the process of the present invention.
Example 11
Dissolving 87g of the intermediate 3a (0.3mol) in 900mL of xylene solvent, stirring at room temperature until the intermediate is completely dissolved, adding 4g of montmorillonite, heating to 130 ℃ for reaction for 1h, cooling to below 50 ℃, adding 200mL of deionized water, fully stirring, standing for layering, and distilling xylene under reduced pressure to recover the solvent. Adding 400mL of dichloromethane for dissolution, distilling under normal pressure to remove about 320mL of solvent, separating out more white solid, cooling to-10 ℃ for crystallization for 2h, filtering to obtain pure white solid crystal, and drying in vacuum to obtain the compound (intermediate 4) of the formula IV with the yield of 59.4g and the yield of 83%.
Example 12
The method for synthesizing flurbiprofen is as follows:
dispersing 30g of intermediate 5(0.15mol), 0.9g of cuprous bromide (0.006mol) and 12g of sodium nitrite (0.18mol) in 200g of water, stirring uniformly, adding 11.8g of benzene and 2.4g of polyethylene glycol 200(0.009mol), heating in a water bath to 55 ℃, slowly dropwise adding 20.3g of concentrated hydrochloric acid (0.2mol), preserving heat and reacting for 2 hours, and finishing the reaction. Adding 100mL of 5% diluted hydrochloric acid for hydrolysis, and stirring thoroughly for 30 min. Adding 200mL of toluene for extraction, standing for layering, extracting the water phase once with 100mL of toluene, combining the organic phases, and washing with water to be neutral. 150mL of water is added into the toluene layer at the upper layer, the pH value is adjusted to about 8 by 10% saturated sodium bicarbonate, 2g of medicinal activated carbon is added for decoloration for 1h, and the mixture is filtered to obtain a light yellow solution. And (3) adjusting the pH value to 2-3 by using 10% hydrochloric acid, precipitating a pure white solid, filtering, washing a filter cake by using pure water, draining, and drying in vacuum at 40-50 ℃ for 6 hours to obtain 28.7g of the flurbiprofen compound product shown in the formula I, wherein the yield is 76%.
The polyethylene glycol 200 can be replaced by polyethylene glycol 400 and then implemented specifically, and can meet the yield and quality requirements equivalent to those of the product in the embodiment.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (10)
1. A method for preparing flurbiprofen, comprising the steps of:
A. under the action of Lewis acid, performing acylation reaction on o-fluoroaniline or N-substituted o-fluoroaniline and 2-halogenated propionyl halide to obtain a corresponding intermediate compound shown as a formula II;
the N-substituted o-fluoroaniline is selected from o-fluoroacetanilide, o-fluoroaniline, o-fluoronitrobenzene, Boc-o-fluoroaniline or o-fluoropropionanilide;
in the above formula II, R1Selected from acetyl, propionyl, H or Boc group; x is the corresponding halogen in 2-halogen propionyl halide;
B. under the action of a ketal catalyst, performing ketal reaction on a compound shown in a formula II and a carbonyl protection reagent to obtain a ketal compound shown in a formula III;
r in the compound of the formula III is selected from methyl, ethyl or NPG;
C. carrying out rearrangement reaction on a ketal compound shown as a formula III under the heating condition in the presence of an acidic catalyst to obtain a corresponding compound shown as a formula IV;
D. carrying out hydrolysis reaction on the compound shown in the formula IV under acidic or alkaline conditions to obtain a compound shown in the formula V;
E. under the action of a diazotization catalyst and a phase transfer catalyst, mixing a compound shown in a formula V, benzene and nitrite in the presence of acid to carry out diazotization reaction, and after the diazotization reaction is finished, carrying out hydrolysis reaction to obtain a corresponding product, namely a compound flurbiprofen shown in a formula I;
2. the method for producing flurbiprofen according to claim 1, wherein the halopropionyl halide in the step A is selected from the group consisting of 2-chloropropionyl chloride, 2-bromopropionyl bromide, 2-bromopropionyl chloride and 2-chloropropionyl bromide.
3. The method for preparing flurbiprofen according to claim 1, wherein the lewis acid in step a is one or more selected from the group consisting of aluminum trichloride, zinc chloride, ferric trichloride, boron trifluoride acetonitrile and boron trifluoride diethyl etherate; the temperature of the acylation reaction is preferably 50 ℃ to 60 ℃.
4. The method for preparing flurbiprofen according to claim 1, wherein the carbonyl protecting agent in step B is selected from trimethyl orthoformate, triethyl orthoformate, neopentyl glycol or ethylene glycol.
5. The method for producing flurbiprofen according to claim 1, wherein the ketal catalyst in the step B is p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate.
6. The method for preparing flurbiprofen according to any one of claims 1 to 5, wherein the phase transfer catalyst in step E is one or more selected from tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, polyethylene glycol 200 and polyethylene glycol 400.
7. The method for producing flurbiprofen according to claim 6, wherein the diazotization catalyst in step E is selected from cuprous chloride, cuprous bromide or cuprous iodide; the acid is selected from one or more of acetic acid, trifluoroacetic acid, trichloroacetic acid, hydrobromic acid and hydrochloric acid; the temperature of the diazotization reaction is preferably 20-80 ℃.
8. The method for preparing flurbiprofen according to any one of claims 1 to 5, wherein the acidic catalyst in step C is selected from one or more of zinc bromide, zinc chloride, ferric chloride and montmorillonite, the rearrangement reaction is carried out in a toluene solvent, and the temperature of the rearrangement reaction is 100 to 110 ℃.
9. The method for preparing flurbiprofen according to any one of claims 1 to 5, wherein the acidic conditions in step D are specifically in the presence of one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid; the alkaline condition is specifically in Na2CO3、K2CO3NaOH and KOH in the presence of one or more of the following components.
10. The method for preparing flurbiprofen according to any one of claims 1 to 5, which comprises:
A. under the action of Lewis acid, carrying out acylation reaction on o-fluoroacetanilide and 2-chloropropionyl chloride in a water-insoluble organic solvent under the condition of reflux, adding a hydrochloric acid solution after the reaction is finished, stirring, standing for layering, and distilling the collected organic phase to remove the solvent to obtain a corresponding intermediate compound shown in the formula II-1;
B. under the action of a ketal catalyst p-toluenesulfonic acid or mono-water p-toluenesulfonic acid, performing ketal reaction on a compound shown in a formula II and trimethyl orthoformate in an alcohol solvent at 50-60 ℃, adding a water-insoluble organic solvent and water after the reaction is finished, stirring, standing for layering, and distilling a collected organic layer to remove the solvent to obtain a ketal compound shown in a formula III-1;
r in the compound of the formula III is selected from methyl, ethyl or NPG;
C. in the presence of an acid catalyst, enabling a ketal compound III-1 to perform rearrangement reaction in a toluene solvent at a controlled temperature of 100-110 ℃, adding water, stirring, standing for layering, and distilling a collected organic layer to remove the solvent to obtain a corresponding compound IV-1;
D. in the presence of concentrated hydrochloric acid, carrying out hydrolysis reaction on a compound shown in the formula IV in a mixed solvent of alcohol and water at the temperature of 70-80 ℃, adding an alkaline reagent to adjust the pH value of a reaction solution to 7-8 after the reaction is finished, distilling to remove an alcohol solvent, adding a non-water-soluble solvent, stirring, standing for layering, and distilling a collected organic phase to remove the solvent to obtain a compound shown in the formula V-1;
E. under the action of a diazotization catalyst and a phase transfer catalyst, mixing a compound shown in the formula V-1, benzene and nitrite, heating to 50-60 ℃, adding acetic acid, preserving heat for diazotization, adding hydrochloric acid for hydrolysis reaction after the reaction is finished, adding a non-water-soluble solvent for stirring, standing for layering, collecting an organic phase, and removing the solvent to obtain a corresponding product, namely a compound flurbiprofen shown in the formula I.
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| CN (1) | CN112341352A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01242537A (en) * | 1988-03-23 | 1989-09-27 | Morita Kagaku Kogyo Kk | Production of 2-fluorobiphenyl derivative |
| US20020001732A1 (en) * | 1997-10-23 | 2002-01-03 | Hermannus F.M. Schoo | Polymer electroluminescent device |
| CN105037059A (en) * | 2015-06-16 | 2015-11-11 | 青岛科技大学 | Preparation method of alpha-(4-substituted phenyl)isobutyric acid |
-
2020
- 2020-11-13 CN CN202011268683.0A patent/CN112341352A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01242537A (en) * | 1988-03-23 | 1989-09-27 | Morita Kagaku Kogyo Kk | Production of 2-fluorobiphenyl derivative |
| US20020001732A1 (en) * | 1997-10-23 | 2002-01-03 | Hermannus F.M. Schoo | Polymer electroluminescent device |
| CN105037059A (en) * | 2015-06-16 | 2015-11-11 | 青岛科技大学 | Preparation method of alpha-(4-substituted phenyl)isobutyric acid |
Non-Patent Citations (4)
| Title |
|---|
| GANG LU ET AL.: "Synthesis of flurbiprofen via suzuki reaction catalyzed by palladium charcoal in water", 《CHINESE CHEMICAL LETTERS》 * |
| ORESTE PICCOLO ET AL.: "Zinc salt catalyzed rearrangement of acetals of optically active aryl 1-chloroethyl ketones: synthesis of optically active 2-arylpropionic acids and esters", 《J.ORG.CHEM.》 * |
| 姜卓文: "布洛芬合成工艺改进研究", 《中国优秀博硕士学位论文全文数据库（硕士） 工程科技I辑》 * |
| 王尊元等: "氟比洛芬的新法合成", 《齐鲁药事》 * |
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