WO2022099439A1 - Procédé de préparation d'acide 2,4,5-trifluorophénylacétique - Google Patents
Procédé de préparation d'acide 2,4,5-trifluorophénylacétique Download PDFInfo
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- WO2022099439A1 WO2022099439A1 PCT/CN2020/127713 CN2020127713W WO2022099439A1 WO 2022099439 A1 WO2022099439 A1 WO 2022099439A1 CN 2020127713 W CN2020127713 W CN 2020127713W WO 2022099439 A1 WO2022099439 A1 WO 2022099439A1
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- WIPO (PCT)
- Prior art keywords
- reaction
- acid
- nitrotoluene
- preparation
- difluoro
- Prior art date
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- YSQLGGQUQDTBSL-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=C(F)C=C1F YSQLGGQUQDTBSL-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- 239000002994 raw material Substances 0.000 claims abstract description 45
- ZGEAYXBIJAYBKA-UHFFFAOYSA-N 1,2,4-trifluoro-5-methylbenzene Chemical compound CC1=CC(F)=C(F)C=C1F ZGEAYXBIJAYBKA-UHFFFAOYSA-N 0.000 claims abstract description 29
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims abstract description 28
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000007864 aqueous solution Substances 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 238000005336 cracking Methods 0.000 claims abstract description 14
- 235000003270 potassium fluoride Nutrition 0.000 claims abstract description 14
- 239000011698 potassium fluoride Substances 0.000 claims abstract description 14
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 14
- 239000012954 diazonium Substances 0.000 claims abstract description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 12
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 11
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 11
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 10
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 8
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 6
- 150000001989 diazonium salts Chemical class 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 76
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- JMXPOOVDUVHJRO-UHFFFAOYSA-N 1-(chloromethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CCl)C=C1F JMXPOOVDUVHJRO-UHFFFAOYSA-N 0.000 claims description 23
- JTYBTJVFXUKNKW-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetonitrile Chemical compound FC1=CC(F)=C(CC#N)C=C1F JTYBTJVFXUKNKW-UHFFFAOYSA-N 0.000 claims description 23
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical group N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 238000003682 fluorination reaction Methods 0.000 claims description 10
- AOTWCYSQDSKAQT-UHFFFAOYSA-N 1,2-dichloro-4-methyl-5-nitrobenzene Chemical compound CC1=CC(Cl)=C(Cl)C=C1[N+]([O-])=O AOTWCYSQDSKAQT-UHFFFAOYSA-N 0.000 claims description 9
- DJEBTFSOEQWELL-UHFFFAOYSA-N 1,2-difluoro-4-methyl-5-nitrobenzene Chemical compound CC1=CC(F)=C(F)C=C1[N+]([O-])=O DJEBTFSOEQWELL-UHFFFAOYSA-N 0.000 claims description 9
- PEQYJEJKUTUIFJ-UHFFFAOYSA-N 1,4-dichloro-2-methyl-5-nitrobenzene Chemical compound CC1=CC(Cl)=C([N+]([O-])=O)C=C1Cl PEQYJEJKUTUIFJ-UHFFFAOYSA-N 0.000 claims description 9
- ABWWQMGGJXKGBL-UHFFFAOYSA-N 1,4-difluoro-2-methyl-5-nitrobenzene Chemical compound CC1=CC(F)=C([N+]([O-])=O)C=C1F ABWWQMGGJXKGBL-UHFFFAOYSA-N 0.000 claims description 8
- OTHIQMSDVAQZQM-UHFFFAOYSA-N 1,5-dichloro-2-methyl-4-nitrobenzene Chemical compound CC1=CC([N+]([O-])=O)=C(Cl)C=C1Cl OTHIQMSDVAQZQM-UHFFFAOYSA-N 0.000 claims description 8
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 8
- BVVAZYONIKSNFT-UHFFFAOYSA-N 1,5-difluoro-2-methyl-4-nitrobenzene Chemical compound CC1=CC([N+]([O-])=O)=C(F)C=C1F BVVAZYONIKSNFT-UHFFFAOYSA-N 0.000 claims description 7
- HKAMTWLPOCYTMX-UHFFFAOYSA-N 4,5-difluoro-2-methylaniline Chemical compound CC1=CC(F)=C(F)C=C1N HKAMTWLPOCYTMX-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- CWBIWGJHOJZWBJ-UHFFFAOYSA-N 2,5-difluoro-4-methylaniline Chemical compound CC1=CC(F)=C(N)C=C1F CWBIWGJHOJZWBJ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- BXKWEKJPNHPFTM-UHFFFAOYSA-N 2,4-difluoro-5-methylaniline Chemical compound CC1=CC(N)=C(F)C=C1F BXKWEKJPNHPFTM-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- ATPPNMLQNZHDOG-UHFFFAOYSA-N 2-fluoro-2-phenylacetic acid Chemical compound OC(=O)C(F)C1=CC=CC=C1 ATPPNMLQNZHDOG-UHFFFAOYSA-N 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract description 9
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 238000010791 quenching Methods 0.000 abstract description 3
- 230000000171 quenching effect Effects 0.000 abstract description 3
- 230000026030 halogenation Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 63
- 239000000047 product Substances 0.000 description 22
- -1 2,4,5-trifluorophenylethyl Chemical group 0.000 description 10
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 8
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229910015900 BF3 Inorganic materials 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ROJNMGYMBLNTPK-UHFFFAOYSA-N 1,2,4-trifluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(F)C=C1F ROJNMGYMBLNTPK-UHFFFAOYSA-N 0.000 description 2
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000013475 authorization Methods 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 2
- 229940091173 hydantoin Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- RYKLMXMJFLRFEH-UHFFFAOYSA-N 2-(2,5-difluoro-4-nitrophenyl)propanedioic acid Chemical compound OC(=O)C(C(O)=O)C1=CC(F)=C([N+]([O-])=O)C=C1F RYKLMXMJFLRFEH-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010538 cationic polymerization reaction Methods 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000002685 polymerization catalyst Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004115 sitagliptin phosphate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004227 thermal cracking Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/02—Monocyclic aromatic halogenated hydrocarbons
- C07C25/13—Monocyclic aromatic halogenated hydrocarbons containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
Definitions
- the present application relates to the technical field of preparation of pharmaceutical intermediates, and more particularly, to a preparation method of 2,4,5-trifluorophenylacetic acid.
- 2,4,5-Trifluorophenylacetic acid is a key intermediate in the novel antidiabetic drug dipeptidyl peptidase-4 (DPP-4) inhibitor Sitagliptin phosphate.
- DPP-4 novel antidiabetic drug dipeptidyl peptidase-4
- Sitagliptin phosphate At present, a lot of preparation processes of 2,4,5-trifluorophenylethyl have been disclosed.
- 2,5-difluoro-4-nitrophenylmalonic acid is obtained by condensation of 2,4,5-trifluoronitrobenzene and diethyl malonate as raw materials first. Diethyl ester is then subjected to hydrolysis, acidification, decarboxylation, nitro reduction, and finally to diazotization and fluorination of amino groups.
- the price of the initial raw material 2,4,5-trifluoronitrobenzene used is relatively high, which may easily lead to a relatively high preparation cost of 2,4,5-trifluorophenylacetic acid.
- 1,2,4-trifluorobenzene is usually reacted with paraformaldehyde and chlorinating agent as raw materials to obtain 2,4,5-trifluorobenzyl chloride, which is then mixed with a solvent and a phase transfer catalyst.
- the cyanation reaction is carried out under the following conditions to obtain 2,4,5-trifluorobenzyl cyanide, which is then hydrolyzed under acidic or basic conditions to obtain 2,4,5-trifluorophenylacetic acid.
- the yields of 2,4,5-trifluorobenzyl chloride and 2,4,5-trifluorobenzyl cyanide obtained in the first two steps are all relatively low, not higher than 66%.
- the cost of the initial raw materials used is too high; on the other hand, the yield of the corresponding product obtained in each preparation step is relatively low, resulting in obtaining an equivalent amount of 2,4,5-tris Fluorophenylacetic acid needs to consume more raw materials, that is, the preparation cost of 2,4,5-trifluorophenylacetic acid is increased, which in turn affects its industrialized large-scale production and promotion and application in the market.
- the present application provides a kind of 2,4,5-trifluorophenylacetic acid. Preparation.
- a preparation method of 2,4,5-trifluorophenylacetic acid provided by the present application adopts the following technical scheme: a preparation method of 2,4,5-trifluorophenylacetic acid, comprising the following steps:
- Step 1 with raw material, quaternary ammonium salt catalyst, sulfolane, potassium fluoride, under the condition that reaction temperature is 150-230 °C, form sufficient reaction, obtain the first intermediate;
- step 2 the first intermediate obtained in step 1 is subjected to hydrogenation catalytic reaction to obtain the second intermediate;
- step 3 the second intermediate obtained in step 2 and the fluorinating reagent are subjected to a salt-forming reaction at a temperature of 25 ⁇ 5 °C, quenched, and then diazotized with an aqueous sodium nitrite solution to obtain diazonium. Salt;
- step 4 the diazonium salt in step 3 is subjected to high temperature cracking reaction to obtain 2,4,5-trifluorotoluene;
- step 5 the 2,4,5-trifluorotoluene obtained in step 4 is subjected to halogenation reaction to obtain 2,4,5-trifluorobenzyl chloride;
- step 6 the 2,4,5-trifluorobenzyl chloride obtained in step 5 is subjected to a cyanation reaction to obtain 2,4,5-trifluorobenzeneacetonitrile;
- step seven the 2,4,5-trifluorophenylacetonitrile obtained in step six is subjected to a hydrolysis reaction to obtain 2,4,5-trifluorophenylacetic acid;
- the raw material in step 1 is any one of 3,4-dichloro-6-nitrotoluene, 2,4-dichloro-5-nitrotoluene and 2,5-dichloro-4-nitrotoluene;
- the first intermediate in step 1 is one of 4,5-difluoro-2-nitrotoluene, 2,4-difluoro-5-nitrotoluene and 2,5-difluoro-4-nitrotoluene. kind;
- the second intermediate is one of 4,5-difluoro-2-methylaniline, 2,4-difluoro-5-methylaniline and 2,5-difluoro-4-methylaniline. kind;
- the fluorination reagent includes any one of fluoroboric acid aqueous solution and hydrogen fluoride pyridine solution.
- 3,4-dichloro-6-nitrotoluene, 2,4-dichloro-5-nitrotoluene, 2,5-dichloro-4-nitrotoluene are used in Any one of the three raw materials is used as a raw material, and the price of the three raw materials is low and easy to obtain, which reduces the cost of the raw materials to a certain extent, and is convenient for industrialized large-scale production.
- the raw materials are sequentially prepared to obtain the corresponding first intermediate, which is not easy to generate other impurities, which is conducive to the full reaction and improves the purity and yield of the first intermediate.
- step 2 a hydrogenation catalytic reaction is carried out to form a corresponding second intermediate corresponding to the first intermediate, which is not easy to generate other impurities, and is beneficial to improve the yield and purity of the second intermediate.
- Fluoroboric acid diazonium salt can be obtained by reacting with fluoroboric acid aqueous solution.
- 2,4,5-trifluorotoluene, boron trifluoride gas and nitrogen gas can be obtained.
- Organic solvents such as diethyl ether can be used
- tetrahydrofuran 1,4-dioxane
- methanol 1,4-dioxane
- methanol 1,4-dioxane
- acetic acid etc.
- the boron trifluoride organic solution can also be used as a cationic polymerization catalyst for commonly used drug synthesis, providing additional income for the recycling of by-products for enterprises, and further reducing the cost of producing 2,4,5-trifluorophenylacetic acid.
- step 3 usually add ice brine with a mass concentration of 20-30% for quenching, until the temperature of the reaction system at this time is kept below 0 ° C, in order to control the reaction, safety accidents are not easy to occur, and it can also make the salt-forming reaction relatively. proceed fully. If the quenching treatment is not carried out, it is easy to cause the phenomenon of incomplete salt formation, which is not conducive to the subsequent treatment.
- Step 4 is carried out under solvent-free conditions, and the high-temperature cracking reaction treatment reduces the use of solvents, which is beneficial to reduce the possibility of generating wastes in the cracking reaction. And through the treatment in step 4, 2,4,5-trifluorotoluene is finally obtained, and through the reaction in steps 5 to 7, 2,4,5-trifluorophenylacetic acid is finally formed.
- step 1 the weight ratio to sulfolane is 1:(2 ⁇ 5);
- the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene;
- the first intermediate is 4,5-difluoro-2-nitrotoluene or 2,5-difluoro-4-nitrotoluene.
- step 1 when the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene, the temperature is 120-180°C and 220°C successively.
- the reaction is carried out under the temperature condition of -230°C, which is favorable for the meta-position in the first intermediate to be fully fluorinated. If the latter reaction temperature is too low, other impurities are likely to be produced; if the latter reaction temperature is too high, the energy consumption is too large and the preparation cost is increased.
- step 1 the weight ratio of raw material to sulfolane is 1:(2 ⁇ 5), the molar ratio of potassium fluoride to raw material is (2.1 ⁇ 3.5):1, the reaction temperature is 180°C, and the heat preservation reaction is performed for 10h, obtain the first intermediate;
- the raw material is 2,4-dichloro-5-nitrotoluene
- the first intermediate is 2,4-difluoro-5-nitrotoluene.
- the yield of the obtained first intermediate (2,4-difluoro-5-nitrotoluene) is relatively high by adopting the above technical scheme.
- step 1 the weight ratio of raw material to sulfolane is 1:(2 ⁇ 5);
- the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene;
- the first intermediate is 4,5-difluoro-2-nitrotoluene or 2,5-difluoro-4-nitrotoluene.
- step 1 when the raw material is 3,4-dichloro-6-nitrotoluene or 2,5-dichloro-4-nitrotoluene, the above operation method is adopted, and the temperature is 120-180°C and 220- The reaction at 230°C is favorable for the meta-position in the first intermediate to be fully fluorinated, and the yield of the first intermediate is improved.
- step 2 the temperature of the hydrogenation catalytic reaction is 50-75 °C, the pressure of hydrogen is 0.1-1.0 MPa, and the time of the hydrogenation catalytic reaction is 2-5h;
- the catalyst used in the hydrogenation catalytic reaction is Raney Nickel catalyst or palladium carbon catalyst.
- Raney nickel catalyst or palladium carbon catalyst can be used but not limited to.
- step 3 the molar ratio of the second intermediate, the fluorinating reagent and the sodium nitrite is 1:(2.5 ⁇ 4):(1.05 ⁇ 1.1); the second intermediate and the fluorinating reagent undergo a salt-forming reaction After being quenched to -40 ⁇ 0°C, the diazotization reaction is carried out; the mass concentration of the fluorination reagent is 25-40%.
- the fluorinating reagent concentration is 25-40% and the excess is used, so that the reversible salt-forming reaction can be fully carried out.
- the diazotization reaction is a rapid exothermic process, that is, when the sodium nitrite aqueous solution is added dropwise, the system heats up, and after the salt-forming reaction, it is quenched to -40 ⁇ 0 ° C, and the drop rate of the sodium nitrite aqueous solution is controlled, which is beneficial to control the reaction. Vigorous intensity for increased safety.
- step 4 the temperature of the high-temperature cracking reaction is 90-300° C., and the time is 2-4 h.
- step 5 during the halogenation reaction, 2,4,5-trifluorotoluene and the catalyst are reacted in a weight ratio of 1:(0.005-0.02), the temperature is raised to 110-130 ° C, and the drying is continued. After 3-5 hours of chlorine gas, the chlorine gas is stopped, cooled, washed with water until neutral, dried, and distilled under reduced pressure to obtain 2,4,5-trifluorobenzyl chloride; the catalyst is azobisisobutyronitrile.
- the halogenation reaction of 2,4,5-trifluorotoluene can be fully carried out, and the yield of 2,4,5-trifluorobenzyl chloride can be improved.
- the halogenating agent can be any one of chlorine, phosphorus pentachloride, sulfonyl chloride, trichloroisocyanate, hydantoin, bromine, NBS, hydrogen bromide, and hydantoin.
- step 6 during the cyanation reaction, the molar ratio of 2,4,5-trifluorobenzyl chloride: sodium cyanide in the aqueous sodium cyanide solution is 1:(1-1.1), the phase transfer catalyst, 2 ,
- the weight ratio of 4,5-trifluorobenzyl chloride and dimethyl sulfoxide is (0.01-0.02): 1: (1-3) for mixing, and the temperature is 60-80 °C under the condition of keeping the cyanidation reaction 2 -5h, then extracted with ethanol, dried, distilled and then rectified to obtain 2,4,5-trifluorophenylacetonitrile
- the phase transfer catalyst is azobisisobutyronitrile.
- step 7 during the hydrolysis reaction, the acid is heated to a stable range of 100-110 °C, and 2,4,5-trifluorophenylacetonitrile is added dropwise, the temperature is kept at 120 °C for 6 hours, and then cooled to room temperature, 100 mL of water was added dropwise, cooled and suction filtered, the solid was recrystallized with methanol, purified and dried to obtain 2,4,5-trifluorophenylacetic acid;
- the acid includes at least one of sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, and acetic acid.
- the acid is formed by mixing sulfuric acid and acetic acid, the weight ratio of 2,4,5-trifluorophenylacetonitrile, sulfuric acid and acetic acid is 1:(1.5-3):0.1, and the mass concentration of sulfuric acid is 70%.
- step 1 to step 4 can be used to obtain 2,4,5-trifluorotoluene, and then halogenation, cyanation, and hydrolysis are carried out in turn, and 2,4,5-trifluorophenylacetic acid is finally obtained.
- the yields of the corresponding products obtained after each step are all high, and the by-products produced in the preparation process are less, which is beneficial to improve the purity and yield of the final product 2,4,5-trifluorophenylacetic acid formed, and the use of etc.
- a higher yield of the final product, 2,4,5-trifluorophenylacetic acid can be obtained with a higher amount of starting material.
- the cost of the initial raw materials involved in the reaction process is relatively low, and the preparation cost in the present application is reduced from the source, which is conducive to industrialized large-scale production.
- the 2,4,5-trifluorotoluene prepared in this application has a purity higher than 98%, stable quality, and meets the requirements for the use of pharmaceutical intermediates. It can be directly subjected to subsequent halogenation reactions without further purification operations. , cyanation reaction, hydrolysis reaction, easy to operate.
- the preparation method in the present application has low operational difficulty, which is beneficial to the industrialized large-scale production of 2,4,5-trifluorophenylacetic acid.
- Embodiment 1 a preparation method of 2,4,5-trifluorophenylacetic acid, comprising the steps:
- Step 1 the preparation of the first intermediate 4,5-difluoro-2-nitrotoluene:
- Step 2 the preparation of the second intermediate 4,5-difluoro-2-methylaniline, the reaction formula is as follows:
- Step 3 the preparation of 4,5-difluoro-2-methylaniline fluoroborate diazonium salt, the reaction formula is as follows:
- the filter cake is washed with 20 ml of frozen 40% fluoroboric acid aqueous solution, and then washed with 20 ml of alcohol aqueous solution with a freezing point temperature of -15 °C and a mass concentration of 30%. The operation was repeated twice, and the filter cake was subjected to vacuum distillation to remove the solvent to obtain 4,5-difluoro-2-methylaniline fluoroborate diazonium salt.
- the 4,5-difluoro-2-methylaniline fluoroborate diazonium salt in step 3 is subjected to a high temperature cracking reaction, that is, the temperature is slowly raised to 100 ° C, and kept for 1 h, and then slowly raised to 180 ° C and kept for 1 h to obtain 2,4,5-Trifluorotoluene.
- the reflux condenser is connected to an HCl absorption system, and a light source is installed near the flask.
- Embodiment 2 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 1, 2,5-dichloro-4-nitrotoluene is used as a raw material for the reaction , the reaction operation is the same as that in Example 1, and the first intermediate finally obtained is 2,5-difluoro-4-nitrotoluene which is a light red oily substance.
- the reaction formula is as follows:
- Embodiment 3 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 1, 2,4-dichloro-5-nitrotoluene is used as a raw material for the reaction , potassium fluoride is 62.0g, tetrabutylammonium bromide catalyst is 1g, tracked by GC, the content of raw materials is ⁇ 0.2% after 10h of reaction, cooled to 75 ⁇ 80°C, filtered, and the filtrate is rectified to separate sulfolane and light yellow oily substance the first intermediate.
- the reaction formula is as follows:
- Embodiment 4 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in the process of preparing the second intermediate in step 2, the first intermediate obtained in embodiment 3 is used 2,4-difluoro-5-nitrotoluene was reacted, and the reaction operation was the same as that of step 2 in Example 1, and finally the second intermediate 2,4-difluoro-5 with pale yellow oily texture was obtained -methylaniline, and the mass of the second intermediate is 81.2 g, the GC purity is 99.6%, and the yield is 98.2%.
- the reaction formula is as follows:
- Embodiment 5 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in the process of preparing the second intermediate in step 2, the first intermediate obtained in embodiment 2 is used 2,5-difluoro-4-nitrotoluene was reacted, and the reaction operation was the same as that of step 2 in Example 1, and finally the second intermediate 2,5-difluoro-4 with pale yellow oily texture was obtained -methylaniline, and the mass of the second intermediate 2,5-difluoro-4-methylaniline was 79.2 g, the GC purity was 99.5%, and the yield was 95.8%.
- the reaction formula is as follows:
- Example 6 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 4 is that in the process of preparing the third intermediate in step 3, the second intermediate prepared in Example 4 is used. 2,4-difluoro-5-methylaniline is reacted, and the reaction operation is the same as that in step 3 in Example 1, and finally the third intermediate 2,4-difluoro-5-methyl is obtained Aniline fluoroborate diazonium salt, and the mass is 63.2g.
- the reaction formula is as follows:
- Example 7 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 5 is that in the process of preparing the third intermediate in step 3, the second intermediate prepared in Example 5 is used. 2,5-difluoro-4-methylaniline is reacted, and the reaction operation is the same as that in step 3 in Example 1, and finally the third intermediate 2,5-difluoro-4-methyl is obtained Aniline fluoroborate diazonium salt, and the mass is 64.3g.
- the reaction formula is as follows:
- Embodiment 8 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that during the high temperature cracking in step 4, the temperature is slowly raised to 100 ° C, and kept for 1 h to obtain 2,4, 5-Trifluorotoluene.
- Embodiment 9 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that during the high temperature cracking in step 4, the temperature is slowly raised to 100 ° C, and kept for 2 h to obtain 2,4, 5-Trifluorotoluene.
- Example 10 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 100° C., kept for 1 hour, and then slowly raised to 150° C. °C, and kept for 1 h to obtain 2,4,5-trifluorotoluene.
- Example 11 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 9 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 100° C., and kept for 4 hours to obtain 2,4, 5-Trifluorotoluene.
- Example 12 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 9 is that during the high-temperature cracking in step 4, the temperature is slowly raised to 90° C., kept for 1 hour, and then slowly raised to 300° C. °C, and kept for 1 h to obtain 2,4,5-trifluorotoluene.
- Embodiment 13 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:2.5 : 15, and finally 2,4,5-trifluorotoluene was obtained.
- Embodiment 14 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:4 : 1.1, and finally obtain 2,4,5-trifluorotoluene.
- Embodiment 15 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step 3, the molar ratio of the second intermediate, fluoroboric acid, and sodium nitrite is 1:2.8 : 15, and finally 2,4,5-trifluorotoluene was obtained.
- Embodiment 16 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that the fluorination reagent in step 3 is a hydrogen fluoride pyridine solution.
- Embodiment 17 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Embodiment 1 is that in step five,
- Embodiment 18 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from embodiment 1 is that in step six, 2,4,5-trifluorobenzyl chloride: cyanide in sodium cyanide aqueous solution
- the molar ratio of sodium chloride is 1:1, and the weight ratio of tetrabutylammonium bromide, 2,4,5-trifluorobenzyl chloride and dimethyl sulfoxide is 0.01:1:3.
- Embodiment 19 a preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that in step seven, the weight ratio of 2,4,5-trifluorophenylacetonitrile, sulfuric acid, and acetic acid is: 1:3:0.1 to obtain 2,4,5-trifluorophenylacetic acid.
- Comparative Example 1 A preparation method of 2,4,5-trifluorophenylacetic acid, the difference from Example 1 is that it is a Chinese application with an authorization announcement number of CN100347142C and an authorization announcement date of November 7, 2007. Preparation:
- Test sample the corresponding product obtained in each step in Example 1; the corresponding product obtained in each step in Comparative Example 1.
- Test method The corresponding products obtained in each step in Example 1 are collected and the yield is calculated, recorded and analyzed; the corresponding products obtained in each step in Example 1 are collected and the yield is calculated. Calculate, record and analyze.
- Test results the specific conditions of the corresponding products obtained in each step in Example 1 are shown in Table 1; the specific conditions of the corresponding products obtained in each step in Comparative Example 1 are shown in Table 2.
- Step 2 4,5-Difluoro-2-methylaniline 96.8 99.4
- Step 3 4,5-Difluoro-2-methylaniline fluoroborate diazonium salt 76.2 / Step 4
- 2,4,5-Trifluorotoluene 73 99.3
- Step 6 2,4,5-Trifluorophenylacetonitrile 88.10 99.20 Step seven 2,4,5-Trifluorophenylacetic acid 99.00 99.50
- the yield and purity of the corresponding products obtained in each step are relatively high, especially the yields in steps 1 and 2, and the yield and purity of the final product obtained are also relatively high.
- Test object select the preparation method in Examples 2-19.
- Test method Calculate the yield of the 2,4,5-trifluorophenylacetic acid prepared in Examples 2-19, record and analyze.
- Table 3 adopts the yields of corresponding products obtained in different steps in the preparation methods in Examples 2-19
- Example 3 As can be seen from Table 1 and Table 3, compared with Example 1-3, the yield of the obtained first intermediate is different, the main reason is that the raw materials used in Example 2-3 are different, resulting in the obtained first intermediate. different and their yields are also different. But relatively speaking, it is easier to prepare the first intermediate 2,4-difluoro-5-nitrotoluene by using 2,4-dichloro-5-nitrotoluene as a raw material.
- Example 4-5 and Example 1 Compared with Example 4-5 and Example 1, the yields of the obtained second intermediates are different, the main reason is that the first intermediates obtained in Examples 3 and 4 are respectively used in Examples 4-5 as product, resulting in different obtained second intermediates and different yields.
- the 2,5-difluoro-4-nitrotoluene prepared by the method in Example 2 as the first intermediate it is easier to obtain a higher yield of the second intermediate 2,5-dinitrotoluene Fluoro-4-methylaniline.
- Example 6-7 Compared with Example 6-7 and Example 1, the yield of the obtained third intermediate is different, the main reason is that in Example 6-7, the second intermediate obtained in Examples 4 and 5 was used as product, resulting in different obtained third intermediates and different yields.
- Example 6-7 the second intermediate obtained in Examples 4 and 5 was used as product, resulting in different obtained third intermediates and different yields.
- using 4,5-difluoro-2-methylaniline as the second intermediate for thermal cracking is beneficial to improve the yield of the third intermediate obtained, which is also related to the purity of the second intermediate. close connection.
- Embodiments 17-19 are relative to embodiment 1, although steps five to seven are different respectively, but the product yield obtained in the corresponding steps is not much different from that in embodiment 1, indicating that the operations in steps five to seven are not easy to correspond to the steps. impact on the product yield.
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Abstract
La présente invention concerne un procédé de préparation d'acide 2,4,5-trifluorophénylacétique, comprenant : étape un, la réaction de matières premières, d'un catalyseur à base de sel d'ammonium quaternaire, de sulfolane et de fluorure de potassium pour obtenir un premier intermédiaire; étape deux, la soumission du premier intermédiaire à une réaction catalytique d'hydrogénation pour obtenir un deuxième intermédiaire; étape trois, la réaction du deuxième intermédiaire avec un réactif de fluoration pour former un sel, un refroidissement, puis la conduite d'une réaction de diazotation avec une solution aqueuse de nitrite de sodium pour obtenir un sel de diazonium; étape quatre, le craquage du sel de diazonium à une température élevée pour obtenir du 2,4,5-trifluorotoluène; et étapes cinq à sept, successivement la soumission du 2,4,5-trifluorotoluène à des réactions d'halogénation, de cyanation et d'hydrolyse de manière à obtenir l'acide 2,4,5-trifluorophénylacétique. Les matières premières du procédé sont faciles à obtenir et les coûts sont relativement faibles; de plus, le rendement de chaque étape est relativement élevé, ce qui est bénéfique pour la production à grande échelle d'acide 2,4,5-trifluorophénylacétique.
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