CN101823952A - Method for preparing 2,4,5-trifluorophenylacetic acid - Google Patents
Method for preparing 2,4,5-trifluorophenylacetic acid Download PDFInfo
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- CN101823952A CN101823952A CN 201010153098 CN201010153098A CN101823952A CN 101823952 A CN101823952 A CN 101823952A CN 201010153098 CN201010153098 CN 201010153098 CN 201010153098 A CN201010153098 A CN 201010153098A CN 101823952 A CN101823952 A CN 101823952A
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- CN
- China
- Prior art keywords
- trifluoro
- grignard reagent
- acetic acid
- benzyl
- benzene acetic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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 abstract description 15
- 238000000034 method Methods 0.000 title abstract description 11
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 45
- -1 2,4,5-trifluorobenzyl halide Chemical class 0.000 claims abstract description 35
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 239000003999 initiator Substances 0.000 claims abstract description 5
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 43
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 38
- 229960003424 phenylacetic acid Drugs 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 235000011089 carbon dioxide Nutrition 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- 229960001701 chloroform Drugs 0.000 claims description 5
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 5
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- CPHORTCGMDXMEI-UHFFFAOYSA-N C(C)(=O)O.FC1=CC=C(C(=C1)F)F Chemical compound C(C)(=O)O.FC1=CC=C(C(=C1)F)F CPHORTCGMDXMEI-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- ZUXSIERAZXKNSW-UHFFFAOYSA-N benzene;2-chloropropane Chemical compound CC(C)Cl.C1=CC=CC=C1 ZUXSIERAZXKNSW-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical group [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 claims description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims 3
- 230000020477 pH reduction Effects 0.000 claims 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- JMXPOOVDUVHJRO-UHFFFAOYSA-N 1-(chloromethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CCl)C=C1F JMXPOOVDUVHJRO-UHFFFAOYSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical class 0.000 claims 1
- 125000003118 aryl group Chemical class 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 230000000977 initiatory effect Effects 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 239000003495 polar organic solvent Substances 0.000 claims 1
- 239000011777 magnesium Substances 0.000 abstract description 5
- 229910052749 magnesium Inorganic materials 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052799 carbon Inorganic materials 0.000 abstract description 3
- 239000005431 greenhouse gas Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000012847 fine chemical Substances 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000007788 liquid Substances 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 229910001629 magnesium chloride Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910001623 magnesium bromide Inorganic materials 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- UDSFAEKRVUSQDD-UHFFFAOYSA-N Dimethyl adipate Chemical compound COC(=O)CCCCC(=O)OC UDSFAEKRVUSQDD-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- AVPMRIWGOGRNBF-UHFFFAOYSA-N [bromo(fluoro)methyl]benzene Chemical compound FC(Br)C1=CC=CC=C1 AVPMRIWGOGRNBF-UHFFFAOYSA-N 0.000 description 2
- SCSHFLIEEIYUPB-UHFFFAOYSA-N acetic acid;1,2,3-trifluorobenzene Chemical compound CC(O)=O.FC1=CC=CC(F)=C1F SCSHFLIEEIYUPB-UHFFFAOYSA-N 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000007265 chloromethylation reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 2
- 229960004034 sitagliptin Drugs 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 238000005659 Kindler reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 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 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于精细化工领域，涉及一种2，4，5-三氟苯乙酸的制备方法。其特征是以2，4，5-三氟苄卤为原料，在无水有机溶剂中与金属镁反应，制得2，4，5-三氟苄基格氏试剂，在格氏试剂的制备过程中使用或不使用引发剂均可。2，4，5-三氟苄基格氏试剂再与二氧化碳进行反应得到2，4，5-三氟苯乙酸盐。最后2，4，5-三氟苯乙酸盐经过酸化、提取后得到2，4，5-三氟苯乙酸粗品，重结晶即得2，4，5-三氟苯乙酸。该方法的合成路线短、条件温和、环境友好、易实现工业化，并且所得产品纯度高；该方法使用温室气体二氧化碳作为一个碳源，原料易得廉价。The invention belongs to the field of fine chemical industry and relates to a preparation method of 2,4,5-trifluorophenylacetic acid. It is characterized in that 2,4,5-trifluorobenzyl halide is used as raw material to react with metal magnesium in anhydrous organic solvent to prepare 2,4,5-trifluorobenzyl Grignard reagent, which is used in the preparation of Grignard reagent The process can be used with or without an initiator. 2,4,5-trifluorobenzyl Grignard reagent reacts with carbon dioxide to obtain 2,4,5-trifluorophenylacetate. Finally, the 2,4,5-trifluorophenylacetic acid salt is acidified and extracted to obtain crude 2,4,5-trifluorophenylacetic acid, which can be recrystallized to obtain 2,4,5-trifluorophenylacetic acid. The method has the advantages of short synthesis route, mild conditions, environmental friendliness, easy realization of industrialization, and high purity of the obtained product; the method uses carbon dioxide, a greenhouse gas, as a carbon source, and the raw materials are readily available and cheap.
Description
Technical field
The invention belongs to pharmaceutical-chemical intermediate and relevant technical field of chemistry, relate to a kind of known 2,4, the preparation method of 5-trifluoro benzene acetic acid (formula III).
Background technology
2,4, the 5-trifluoro benzene acetic acid is a kind of synthetic intermediate that is used for the treatment of the new drug sitagliptin of type ii diabetes, sitagliptin is the first DPP-IV inhibitor of the up-to-date listing of Merck company, little, the security of good effect, side effect and the better tolerance of its treatment type ii diabetes have vast market prospect.
U.S. Pat 20040068141 has reported that with 2,4 5-trifluorobromobenzene and diethyl malonate are raw material, be substituted the reaction of reaction, hydrolysis decarboxylation and obtain 2,4, the 5-trifluoro benzene acetic acid, but there is the shortcoming of severe reaction conditions in this method, is not suitable for suitability for industrialized production.United States Patent (USP) has reported with 2,4 in (US 20040077901) that the 5-trifluorobromobenzene is a raw material, make behind the Grignard reagent and the allyl bromide 98 reaction with MAGNESIUM METAL, reoxidize and obtain 2,4,5-trifluoro benzene acetic acid, this method cost height, impurity are difficult to control and are not suitable for suitability for industrialized production.
Chinese patent CN1749232 has reported that with 1,2 the 4-trifluoro-benzene is a raw material, obtains 2,4 through chloromethylation, cyaniding, hydrolysis, the 5-trifluoro benzene acetic acid, and this technology has been used hypertoxic sodium cyanide, has certain security hidden danger in suitability for industrialized production.Chinese patent has reported with 1,2 in (CN 101092345) that the 4-trifluoro-benzene is a raw material, obtains 2,4 through chloromethylation equally, and 5-trifluoro-benzene benzyl chlorine then, obtains 2,4 with reaction of carbon monoxide, the 5-trifluoro benzene acetic acid in the presence of catalyzer.This technology has been used hypertoxic carbon monoxide, has certain security hidden danger in industrial production, and has used expensive catalyzer.Chinese patent has reported with 1,2 in (CN 101244994) that the 4-trifluoro-benzene is a raw material, obtains 2,4, the 5-trifluoro benzene acetic acid through F-C acylations, Willegerodt-Kindler reaction, hydrolysis.This operational path length, complicated operation, a large amount of trade effluent of generation.
Summary of the invention
The invention provides a kind ofly 2,4, the preparation method of 5-trifluoro benzene acetic acid, easily realizes industrialization and products obtained therefrom purity height at the synthetic route weak point of this method, mild condition, environmental friendliness; This method uses greenhouse gases carbonic acid gas as a carbon source, the raw material cheapness that is easy to get.
The present invention is with 2,4, and 5-trifluoro benzyl halogen is raw material, obtains 2,4 with carbon dioxide reaction after making Grignard reagent, the 5-trifluoro benzene acetic acid, and synthetic route is as follows:
The technical scheme that this method adopts is as follows:
(1) 2,4, the preparation of 5-trifluoro-benzyl Grignard reagent: with 2,4,5-trifluoro benzyl halogen is raw material, with MAGNESIUM METAL reaction, makes 2,4 in anhydrous organic solvent, and 5-trifluoro-benzyl Grignard reagent uses in the preparation process of Grignard reagent or do not use initiator all can.
Halogen atom refers to chlorine, bromine atoms.
Solvent comprises: tetrahydrofuran (THF), methyl tertiary butyl ether, trichloromethane, methylene dichloride, ether, propyl ether, n-butyl ether, tetracol phenixin, sherwood oil, hexanaphthene, normal hexane, normal heptane etc., preferred tetrahydrofuran (THF), methyl tertiary butyl ether.
Range of reaction temperature is-50 ℃～120 ℃, preferred-5 ℃～60 ℃.
The form of MAGNESIUM METAL comprises various forms such as powder, bits shape, strip.
Used Grignard reagent initiator comprises following reagent: methyl chloride, monobromethane, methyl iodide, 1-monochloroethane, 1, the 2-ethylene dichloride, the 1-monobromethane, glycol dibromide, chlorobenzene, bromobenzene, benzyl chlorine, the benzyl bromine, paradibromobenzene, santochlor, styroyl chlorine, phenethyl bromide, the benzene isopropyl chloride, the benzene isopropyl bromide, the sec.-propyl Grignard reagent, the methyl Grignard reagent, the ethyl Grignard reagent, the propyl group Grignard reagent, the isobutyl-Grignard reagent, the butyl Grignard reagent, phenyl grignard reagent, the phenmethyl Grignard reagent, the styroyl Grignard reagent, benzene sec.-propyl Grignard reagent, benzene butyl Grignard reagent, phenyl isobutyl-Grignard reagent etc.
2,4, the mol ratio of 5-trifluoro benzyl halogen and MAGNESIUM METAL is 1: 1～1: 10.
2,4, the mol ratio of 5-trifluoro benzyl halogen and organic solvent is 1: 0.5～1: 100.
2,4,5-trifluoro benzyl halogen is 1: 0.0011: 100 with the mol ratio that causes reagent.
(2) 2,4, the preparation of 5-trifluoro benzene acetic acid salt: obtain in the operation steps (1) 2,4,5-trifluoro-benzyl Grignard reagent reacts with carbonic acid gas in organic solvent and obtains 2,4,5-trifluoro benzene acetic acid salt.
Temperature of reaction is-50 ℃～150 ℃ scopes.
The pressure of reaction is in 0.1MPa～50MPa scope.
The carbonic acid gas that participates in reaction comprises forms such as the gas of carbonic acid gas, liquid, solid; Comprise the mixed gas, the blended solid that contains carbonic acid gas that contain carbonic acid gas, contain the mixing liquid of carbonic acid gas etc.
Reaction solvent can be same with solvent phase in the described step (1), also can be different with solvent in the described step (1); Single solvent can be, also mixed solvent can be.Solvent is selected from trichloromethane, methylene dichloride, ether, propyl ether, n-butyl ether, tetracol phenixin, sherwood oil, methyl tertiary butyl ether, tetrahydrofuran (THF), hexanaphthene, normal hexane, normal heptane etc.
Carbonic acid gas and 2,4, the mol ratio of 5-trifluoro-benzyl Grignard reagent is greater than 0.01.
2,4, the mol ratio of 5-trifluoro-benzyl Grignard reagent and organic solvent is 1: 0.5～1: 100.
(3) 2,4, the preparation of 5-trifluoro benzene acetic acid: obtain in the reactions steps (2) 2,4,5-trifluoro benzene acetic acid salt, acidified, obtain 2,4 after extracting, 5-trifluoro benzene acetic acid crude product, recrystallization promptly gets 2,4, the 5-trifluoro benzene acetic acid.
Temperature of reaction is-50 ℃～150 ℃ scopes.
Be used for the alcoholic solution that acidifying acid comprises the aqueous solution of hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, acetate, butyric acid, Citric Acid, citric acid, phenylformic acid etc. or methyl alcohol, ethanol, Virahol, propyl carbinol, isopropylcarbinol etc.
The organic solvent that is used to extract comprises polar solvent and non-polar solvent.Solvent is selected from trichloromethane, methylene dichloride, ether, propyl ether, n-butyl ether, dithiocarbonic anhydride, tetracol phenixin, sherwood oil, methyl tertiary butyl ether, methyl iso-butyl ketone (MIBK), tetrahydrofuran (THF), N, dinethylformamide, N,N-dimethylacetamide, pyridine, hexanaphthene, normal hexane, normal heptane, ethyl acetate, dimethyl adipate, dimethyl sulfoxide (DMSO) etc.
The organic solvent that is used for the purifying crude product comprises polarity and non-polar solvent.Solvent is selected from trichloromethane, methylene dichloride, ether, propyl ether, n-butyl ether, dithiocarbonic anhydride, tetracol phenixin, sherwood oil, methyl tertiary butyl ether, methyl iso-butyl ketone (MIBK), tetrahydrofuran (THF), N, dinethylformamide, N,N-dimethylacetamide, pyridine, hexanaphthene, normal hexane, normal heptane, ethyl acetate, dimethyl adipate, dimethyl sulfoxide (DMSO) etc.
Be used for acidifying acid with 2,4, the mol ratio of 5-trifluoro benzene acetic acid salt is greater than 0.01.
In the organic solvent and 2,4 that is used to extract, the mol ratio of 5-trifluoro benzene acetic acid is greater than 0.01.
Be used for the organic solvent and 2,4 of purifying, the mol ratio of 5-trifluoro benzene acetic acid is greater than 0.01.
The invention has the beneficial effects as follows the synthetic route weak point, mild condition, environmental friendliness of this method, easily realize industrialization and products obtained therefrom purity height; This method uses greenhouse gases carbonic acid gas as a carbon source, has that raw material is easy to get, advantages of being cheap.
Embodiment
The preparation method of trifluoro benzene acetic acid of the present invention, reactions steps is few, and cost of material is cheap, reaction conditions gentleness, environmental friendliness, the major safety risks in having avoided producing; And products obtained therefrom yield height, purity height, steady quality meet the specification of quality as pharmaceutical intermediate fully, for the suitability for industrialized production of trifluoro benzene acetic acid provides favourable condition.
Below in conjunction with specific embodiment, further set forth the present invention.These embodiment only are used to the present invention is described and are not used in and limit the scope of the invention.Those skilled in the art to simple replacement that the present invention did or improve within the technical scheme that all belongs to the present invention and protected.
Embodiment 1:
Step 1:2,4, the preparation of 5-trifluoro-benzyl magnesium chloride
In the three-necked bottle of 250mL; add tetrahydrofuran (THF) 120mL, magnesium chips (7.2g under the nitrogen protection room temperature successively; 0.45mol); (0.56g 0.003mol) treats that temperature rises to 30 ℃ earlier slowly to be added dropwise to glycol dibromide under stirring; slowly drip 2; 4, (9g 0.05mol) treats to continue slowly to drip 2 after temperature rises to 60 ℃ 5-trifluoro benzyl chlorine again; 4; (45g 0.25mol) keeps that solution is little to boil to 5-trifluoro benzyl chlorine, dropwises back back flow reaction 5-6h; treat that magnesium chips disappears substantially; promptly make 2,4,5-trifluoro-benzyl magnesium chloride.
Step 2:2,4, the preparation of 5-trifluoro benzene acetic acid
Under the nitrogen protection, what obtain in embodiment 1 contains 2,4, adds solid dry ice 10g * 3 in the reaction solution of 5-trifluoro-benzyl magnesium chloride 61g in batches, adds once every 3 hours, and control reaction temperature is at 0 ℃-15 ℃.Treat that dry ice adds 0 ℃-28 ℃ reactions of back temperature control 3-4h fully, then, reaction solution slowly is added dropwise in the 2mol/L HCl solution of mixture of ice and water, extract water with ethyl acetate 30g * 3, merge organic layer saturated common salt water washing 40g * 2, organic phase anhydrous sodium sulfate drying after-filtration is considered the liquid evaporate to dryness and is got 2,4,5-trifluoro benzene acetic acid crude product 54g.2,4,5-trifluoro benzene acetic acid crude product obtains 2,4 with anhydrous methanol 140mL recrystallization, 5-trifluoro benzene acetic acid 50.7g.
Embodiment 2:
Step 1:2,4, the preparation of 5-trifluoro-benzyl magnesium bromide
In the three-necked bottle of 250mL, add successively under the nitrogen protection room temperature tetrahydrofuran (THF) 140mL, magnesium powder (7.2g, 0.45mol); stir down and earlier slowly be added dropwise to 2,4,5-three fluorobenzyl bromides (5g; 0.02mol) treat to continue again slowly to drip 2,4,5-three fluorobenzyl bromide (70g after temperature rises to 65 ℃; 0.31mol) keep that solution is little to boil; dropwise back back flow reaction 2-3h, treat that the magnesium powder disappears substantially, promptly makes 2; 4,5-trifluoro-benzyl magnesium bromide.
Step 2:2,4, the preparation of 5-trifluoro benzene acetic acid
Under the nitrogen protection, what obtain in embodiment 1 contains 2,4, adds solid dry ice 10g * 3 in the reaction solution of 5-trifluoro-benzyl magnesium chloride 61g in batches, adds once every 3 hours, and control reaction temperature is at 0 ℃-15 ℃.Treat that dry ice adds 0 ℃-28 ℃ reactions of back temperature control 3-4h fully, then, reaction solution slowly is added dropwise in the 2mol/L HCl solution of mixture of ice and water, extract water with ethyl acetate 30g * 3, merge organic layer saturated common salt water washing 40g * 2, organic phase anhydrous sodium sulfate drying after-filtration is considered the liquid evaporate to dryness and is got 2,4,5-trifluoro benzene acetic acid crude product 54g.2,4,5-trifluoro benzene acetic acid crude product obtains 2,4 with anhydrous methanol 140mL recrystallization, 5-trifluoro benzene acetic acid 50.7g.
Embodiment 3:
Step 1:2,4, the preparation of 5-trifluoro-benzyl magnesium chloride
In the three-necked bottle of 250mL; add methyl tertiary butyl ether 120mL, magnesium chips (7.2g under the nitrogen protection room temperature successively; 0.45mol); (0.56g 0.003m0l) treats that temperature rises to 30 ℃ earlier slowly to be added dropwise to glycol dibromide under stirring; slowly drip 2; 4, (9g 0.05mol) treats to continue slowly to drip 2 after temperature rises to 60 ℃ 5-trifluoro benzyl chlorine again; 4; (45g 0.25mol) keeps that solution is little to boil to 5-trifluoro benzyl chlorine, dropwises back back flow reaction 5-6h; treat that magnesium chips disappears substantially; promptly make 2,4,5-trifluoro-benzyl magnesium chloride.
Step 2:2,4, the preparation of 5-trifluoro benzene acetic acid
Under the nitrogen protection, what obtain in embodiment 1 contains 2,4, adds solid dry ice 10g * 3 in the reaction solution of 5-trifluoro-benzyl magnesium chloride 61g in batches, adds once every 3 hours, and control reaction temperature is at 0 ℃-15 ℃.Treat that dry ice adds 0 ℃-28 ℃ reactions of back temperature control 3-4h fully, then, reaction solution slowly is added dropwise in the 2mol/L HCl solution of mixture of ice and water, extract water with ethyl acetate 30g * 3, merge organic layer saturated common salt water washing 40g * 2, organic phase anhydrous sodium sulfate drying after-filtration is considered the liquid evaporate to dryness and is got 2,4,5-trifluoro benzene acetic acid crude product 54g.2,4,5-trifluoro benzene acetic acid crude product obtains 2,4 with anhydrous methanol 140mL recrystallization, 5-trifluoro benzene acetic acid 50.7g.
Embodiment 4:
Step 1:2,4, the preparation of 5-trifluoro-benzyl magnesium bromide
In the three-necked bottle of 250mL, add successively under the nitrogen protection room temperature methyl tertiary butyl ether 140mL, magnesium powder (7.2g, 0.45mol); stir down and earlier slowly be added dropwise to 2,4,5-three fluorobenzyl bromides (5g; 0.02mol) treat to continue again slowly to drip 2,4,5-three fluorobenzyl bromide (70g after temperature rises to 65 ℃; 0.31mol) keep that solution is little to boil; dropwise back back flow reaction 2-3h, treat that the magnesium powder disappears substantially, promptly makes 2; 4,5-trifluoro-benzyl magnesium bromide.
Step 2:2,4, the preparation of 5-trifluoro benzene acetic acid
Under the nitrogen protection, what obtain in embodiment 1 contains 2,4, adds solid dry ice 10g * 3 in the reaction solution of 5-trifluoro-benzyl magnesium chloride 61g in batches, adds once every 3 hours, and control reaction temperature is at 0 ℃-15 ℃.Treat that dry ice adds 0 ℃-28 ℃ reactions of back temperature control 3-4h fully, then, reaction solution slowly is added dropwise in the 2mol/L HCl solution of mixture of ice and water, extract water with ethyl acetate 30g * 3, merge organic layer saturated common salt water washing 40g * 2, organic phase anhydrous sodium sulfate drying after-filtration is considered the liquid evaporate to dryness and is got 2,4,5-trifluoro benzene acetic acid crude product 54g.2,4,5-trifluoro benzene acetic acid crude product obtains 2,4 with anhydrous methanol 140mL recrystallization, 5-trifluoro benzene acetic acid 50.7g.
Claims (9)
1. one kind 2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that with 2,4, and 5-trifluoro benzyl halogen is raw material, obtains 2,4 with carbon dioxide reaction after making Grignard reagent, the 5-trifluoro benzene acetic acid, and synthetic route is as follows:
May further comprise the steps:
(1) with 2,4,5-trifluoro benzyl halogen is having initiator or is not having under the situation of initiator in organic solvent, makes 2,4,5-trifluoro-benzyl Grignard reagent with the MAGNESIUM METAL reaction; 2,4,5-trifluoro benzyl halogen comprises 2,4,5-trifluoro benzyl chlorine and 2,4,5-three fluorobenzyl bromides; Temperature of reaction is controlled at-50 ℃～120 ℃ scopes;
(2) use that step (1) obtains 2,4,5-trifluoro-benzyl Grignard reagent and carbonic acid gas react under normal pressure or pressurized conditions and make 2,4,5-trifluoro benzene acetic acid salt; During pressurization, the pressure of reaction is in the 0.1MPa-50MPa scope; Temperature of reaction is controlled at-50 ℃ of-150 ℃ of scopes;
(3) with obtain in the step (2) 2,4,5-trifluoro benzene acetic acid salt carries out acidification reaction, obtains 2,4, the 5-trifluoro benzene acetic acid.
2. as claimed in claim 1 a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid, its feature are that also described step (1) is carried out in polarity or non-polar organic solvent, and solvent is identical or different in the reaction solvent of step (2) and the described step (1); Described organic solvent is single solvent or mixed solvent.
Described in claim 1 or 2 a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid, its feature is that also described organic solvent is selected from tetrahydrofuran (THF), methyl tertiary butyl ether, trichloromethane, methylene dichloride, ether, propyl ether, n-butyl ether, tetracol phenixin, sherwood oil, hexanaphthene, normal hexane or normal heptane.
Described in claim 1 a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid, its feature also is, the organism that is used for initiation reaction in the described step (1) is the Grignard reagent of halogen-containing alkane or halogen-containing aromatic hydrocarbons, alkane or aromatic hydrocarbons, halogen-containing alkane is selected from methyl chloride, monobromethane, methyl iodide, 1-monochloroethane, 1,2-ethylene dichloride, 1-monobromethane or glycol dibromide; Halogen-containing aromatic hydrocarbons is selected from chlorobenzene, bromobenzene, benzyl chlorine, benzyl bromine, paradibromobenzene, santochlor, styroyl chlorine, phenethyl bromide, benzene isopropyl chloride or benzene isopropyl bromide; The alkyl Grignard reagent is selected from sec.-propyl Grignard reagent, methyl Grignard reagent, ethyl Grignard reagent, propyl group Grignard reagent, isobutyl-Grignard reagent or butyl Grignard reagent; The aromatic hydrocarbons Grignard reagent is selected from phenyl grignard reagent, phenmethyl Grignard reagent, styroyl Grignard reagent, benzene sec.-propyl Grignard reagent, benzene butyl Grignard reagent or phenyl isobutyl-Grignard reagent; Described Grignard reagent is the halogen magnesium salts of alkyl or aryl; Described halogen atom is chlorine, bromine or iodine.
Described in claim 1 a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid, its feature also is, the acid that is used for acidification reaction in the described step (3) comprises hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, acetate, butyric acid, Citric Acid, citric acid or the benzoic aqueous solution, and the alcoholic solution of methyl alcohol, ethanol, Virahol, propyl carbinol or isopropylcarbinol; Be used for acidifying acid with 2,4, the mol ratio of 5-trifluoro benzene acetic acid salt is greater than 0.01.
6. a kind of 2,4 described in claim 1, the preparation method of 5-trifluoro benzene acetic acid, its feature also be, in the described step (1) 2,4, the mol ratio of 5-trifluoro benzyl halogen and MAGNESIUM METAL is 1: 1～1: 10; 2,4, the mol ratio of 5-trifluoro benzyl halogen and organic solvent is 1: 0.5～1: 100; 2,4,5-trifluoro benzyl halogen is 1: 0.001～1: 100 with the mol ratio that causes reagent.
7. a kind of 2,4 described in claim 1, the preparation method of 5-trifluoro benzene acetic acid, its feature also are, carbonic acid gas and 2,4 in the described step (2), the mol ratio of 5-trifluoro-benzyl Grignard reagent is greater than 0.01; 2,4, the mol ratio of 5-trifluoro-benzyl Grignard reagent and organic solvent is 1: 0.5～1: 100.
8. a kind of 2,4 described in claim 1, the preparation method of 5-trifluoro benzene acetic acid, its feature also are, the organic solvent and 2,4 that is used to extract in the described step (3), the mol ratio of 5-trifluoro benzene acetic acid is greater than 0.01.
9. a kind of 2,4 described in claim 1, the preparation method of 5-trifluoro benzene acetic acid, its feature also are, are used for the organic solvent and 2,4 of purifying in the described step (3), the mol ratio of 5-trifluoro benzene acetic acid is greater than 0.01.
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