CN100427454C - Method for producing difluoro-acetyl-acetic acid alkylesters - Google Patents
Method for producing difluoro-acetyl-acetic acid alkylesters Download PDFInfo
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- CN100427454C CN100427454C CNB2004800185125A CN200480018512A CN100427454C CN 100427454 C CN100427454 C CN 100427454C CN B2004800185125 A CNB2004800185125 A CN B2004800185125A CN 200480018512 A CN200480018512 A CN 200480018512A CN 100427454 C CN100427454 C CN 100427454C
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- CN
- China
- Prior art keywords
- alkyl
- structural formula
- difluoro
- acid
- butyl
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 150000002081 enamines Chemical class 0.000 claims abstract description 11
- 125000005600 alkyl phosphonate group Chemical group 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 52
- -1 alkyl acetate Chemical compound 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 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
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000009834 vaporization Methods 0.000 description 11
- 230000008016 vaporization Effects 0.000 description 11
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 125000004494 ethyl ester group Chemical group 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- MSNUFQLXHYSSRD-UHFFFAOYSA-N 2-fluoroethyl 3-oxobutanoate Chemical class CC(=O)CC(=O)OCCF MSNUFQLXHYSSRD-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 229940117389 dichlorobenzene Drugs 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 150000002085 enols Chemical group 0.000 description 2
- BUCVOFLZGVLNTN-UHFFFAOYSA-N ethyl 4-(difluoromethyl)-3-methyl-2h-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C1=C(C(F)F)N(C)CS1 BUCVOFLZGVLNTN-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 2
- 150000004715 keto acids Chemical class 0.000 description 2
- DGVNWNYQSOYWKZ-UHFFFAOYSA-N methyl dihydrogen phosphite Chemical compound COP(O)O DGVNWNYQSOYWKZ-UHFFFAOYSA-N 0.000 description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 2
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 description 2
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 1
- OAWAZQITIZDJRB-UHFFFAOYSA-N 2-chloro-2,2-difluoroacetic acid Chemical compound OC(=O)C(F)(F)Cl OAWAZQITIZDJRB-UHFFFAOYSA-N 0.000 description 1
- CTTXMUZEFPPHGD-UHFFFAOYSA-N 5-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical compound CN1N=CC(C(O)=O)=C1C(F)F CTTXMUZEFPPHGD-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical compound NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000531807 Psophiidae Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- UCWBKJOCRGQBNW-UHFFFAOYSA-M sodium;hydroxymethanesulfinate;dihydrate Chemical compound O.O.[Na+].OCS([O-])=O UCWBKJOCRGQBNW-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/113—Esters of phosphoric acids with unsaturated acyclic alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a method for producing 4,4-difluoro-acetyl-acetic acid alkylesters using three steps, thereinto, in the first step, the 4-chlorin-4,4-difluoro-acetyl-acetic acid alkylesters reacts with trialkyl phosphites of structure formula (III), P(OR<1>)3 (III), thereinto, R<1> represents C1-C4 alkyl, residues R<1> is same or different through fair and foul, so as to prepare structure formula (IV) alkylphosphonate. The structure formula (IV) compound reacts with the structure formula (V) amic, thereinto, R<2> and R<3> represent hydrogen or C1-C4 alkyl respectively, or -CH2-CH2-O-CH2-CH2-, so as to prepare structure formula (VI) enamine, thereinto, R<2> and R<3> have the meaning as above mentioned, the compound of structure formula (VI) hydrolyzes in the third steps under the state of acid existing.
Description
The present invention relates to a kind of by 4-chloro-4,4-difluoro-acetyl-acetic acid alkylesters preparation 4, the novel method of 4-difluoro-acetyl-acetic acid alkylesters (4,4-two fluoro-3-ketobutyric acid alkyl esters), and 4-chloro-4, the 4-difluoro-acetyl-acetic acid alkylesters is made by 2-chlorine difluoroacetic acid alkyl ester again.
Known 4, the reaction acquisition that 4-difluoro methyl aceto acetate can be by ethyl difluoro in the presence of sodium hydride and ethyl acetate is (with reference to Tetrahedron 2001,57,2689-2700).But the productive rate that is somebody's turn to do reaction 25% is also unsatisfactory.In addition, the by product methyl aceto acetate that obtains also is difficult to separate from desired product.
Equally, known 4, the reaction acquisition that 4-difluoro methyl aceto acetate can be by ethyl difluoro in the presence of zinc and ethyl bromoacetate is (with reference to Tetrahedron 1996,52,119-130).But the productive rate that should react and desirable also far apart.
And a common defective of above-mentioned two kinds of methods is that used ethyl difluoro price is very expensive, and is therefore not attractive for large-scale industrial production as educt (educt).
Also known chloro difluoro ethanoyl as the aromatic hydrocarbons substituting group can with sodium formaldehyde sulphoxylate dihydrate reduction (with reference to Tetrahedron Lett.2001,42,4811-4814).But this reaction can't change into 4-chloro-4,4-difluoro methyl aceto acetate.
Therefore, task of the present invention provides and a kind ofly can obtain high purity 4, the novel method of the economy of 4-difluoro-acetyl-acetic acid alkylesters with high overall yield.
Therefore, theme of the present invention is 4 of a kind of preparation structural formula (I), the method for 4-difluoro-acetyl-acetic acid alkylesters,
Wherein R represents alkyl,
It is characterized in that
A) exist
The first stepIn, the 4-chloro-4 of structural formula (II), the trialkyl phosphite reaction of 4-difluoro-acetyl-acetic acid alkylesters and structural formula (III),
Wherein R has aforesaid implication
P(OR
1)
3 (III)
R wherein
1Represent C
1-C
4Alkyl, and residue R
1Under any circumstance can be identical or different, the alkyl phosphonates of the structural formula that is obtained (IV) thus
Wherein R and R
1Has aforesaid implication
Second stepIn randomly in the presence of thinner with the reaction of the amine of structure formula V,
Wherein
R
2And R
3Represent hydrogen or C independently of one another
1-C
8Alkyl or common representative-CH
2-CH
2-O-CH
2-CH
2-,-CH
2-CH
2-S-CH
2-CH
2-or-CH
2-CH
2-N (R
4)-CH
2-CH
2-,
R
4Represent hydrogen or C
1-C
8Alkyl,
The enamine of the structural formula that is obtained (VI) thus
Wherein R, R
2And R
3Has aforesaid implication
The 3rd stepIn hydrolysis in the presence of acid.
Beat all is that the alkyl phosphonates of structural formula (IV) can not be converted into desirable final product by acid hydrolysis, but observes decomposition under the described conditions.Same beat allly be, in second step of the inventive method, desirable 4,4-difluoro-acetyl-acetic acid alkylesters and corresponding phosphonic amide can not obtain from the alkyl phosphonates of structural formula (IV) and the amine of structure formula V, but obtain the enamine and the phosphodiester ammonium salt of structural formula (VI).By acid hydrolysis, described enamine unexpectedly is easy to be converted into 4 of structural formula (I), 4-difluoro acetylacetic ester.For this reason, the separation of described enamine is unnecessary.
Therefore method of the present invention has overcome above-mentioned known preparation method's defective, has obtained high purity 4 with high yield, the 4-difluoro-acetyl-acetic acid alkylesters.In addition, the present invention be advantageous in that the ester class of the etheric acid that may exist with the impurity form in the 4-chloro-4-difluoro-acetyl-acetic acid alkylesters of structural formula (II) is easy to remove from reaction mixture.In the conversion process, the ester class of etheric acid not with the reaction of the trialkyl phosphite of structural formula (III), and can from the alkyl phosphonates of structural formula (IV), remove by distilling.
From 4-chloro-4,4-difluoro methyl aceto acetate, tricresyl phosphite methyl ester and di-isopropyl are amine-initiated, and method of the present invention can be expressed as following reaction scheme figure.
Can by method of the present invention obtain 4, the keto-acid that the 4-difluoro-acetyl-acetic acid alkylesters both can structural formula (I) also can enol form exist:
Keto-acid enol form
Remove 4, outside the 4-difluoro-acetyl-acetic acid alkylesters, also can obtain the hydrate of this compounds by method of the present invention:
Hydrate
Therefore, remove 4, outside the 4-difluoro-acetyl-acetic acid alkylesters (keto-acid and enol form), corresponding hydrate also is appreciated that the product of the inventive method.According to the difference of follow-up chemical treatment method, whole three kinds of forms of product, or some only independent form can further be reacted (with reference to hereinafter).
Be used as the 4-chloro-4 of the structural formula (II) of starting raw material in the first step of the present invention (a), the 4-difluoro-acetyl-acetic acid alkylesters is that known compound is (with reference to Journal of FluorineChemistry
1992,
56, 271-284; The chemistry journal
1983,
41, 729-729 and chemical abstracts
1984,
100, digest numbers 22308; EP-A 0 082 252).Described compound can be according to for example following method preparation
B) the chloro difluoroacetic acid alkyl ester of structural formula (VII) in the presence of alkali and thinner with the reaction of the alkyl acetate of structural formula (VIII),
Wherein R has aforesaid implication
Wherein R has aforesaid implication.
The enamine of the alkyl phosphonates of structural formula (IV) and structural formula (VI) is new compound.Described compound can prepare according to method of the present invention (a).
The chloro difluoroacetic acid alkyl ester of the trialkyl phosphite of structural formula (III), the amine of structure formula V, structural formula (VII) (feasible preparation method sees preparation embodiment) and the alkyl acetate of structural formula (VIII) are known synthesis of chemicals.
In the inventive method (a)
The first stepThe 4-chloro-4 of middle utilization structure formula (II), the 4-difluoro-acetyl-acetic acid alkylesters, wherein R preferably represents C
1-C
8Alkyl,
C
1-C
6Alkyl,
Methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl,
Methyl or ethyl.
In the inventive method (a)
The first stepThe trialkyl phosphite of middle utilization structure formula (III), wherein R
1Under any circumstance can be identical or different.R
1Preferred represent methylidene, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl,
Methyl or ethyl.
Preferred alkyl phosphonates is the described compound of structural formula (IV), and wherein R has above respectively as preferably, more preferably, most preferably reaching the most preferred given implication, and R wherein
1Under any circumstance can be identical or different, and have above respectively as preferred or more preferably given implication.
In the inventive method (a)
Second stepThe amine of middle utilization structure formula V, wherein R
2And R
3Preferably represent hydrogen, C independently of one another
1-C
6Alkyl or common representative-CH
2-CH
2-O-CH
2-CH
2-,-CH
2-CH
2-S-CH
2-CH
2-or-CH
2-CH
2-N (R
4)-CH
2-CH
2-,
Hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl or common representative-CH
2-CH
2-O-CH
2-CH
2-,
Represent sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl or common representative-CH independently of one another
2-CH
2-O-CH
2-CH
2-,
Under any circumstance represent sec.-propyl.R in the structure formula V
4Preferred hydrogen or the C of representing
1-C
6Alkyl,
Hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl or the tertiary butyl.
Preferred enamine is the described compound of structural formula (VI), and wherein R has above respectively as preferably, more preferably, most preferably reaching the most preferred given implication, R
2And R
3Have above respectively as preferably, more preferably reaching most preferably given implication.
The first step of the inventive method (a)
The inventive method (a)
The first stepUsually under the condition of not having other thinner, implement.Yet this step reaction also can be used thinner (for example methylene dichloride) in addition.
The inventive method (a)
The first stepCan in wide relatively temperature range, implement.Typical temperature is 10 ℃ to 50 ℃, preferred 20 ℃ to 40 ℃, and more preferably 20 ℃ to 30 ℃.Most preferably
The One stepIn being reflected at 25 ℃ to 30 ℃ and causing down of each reactive component.Further be reflected at 40 ℃ to 45 ℃ and carry out, be chilled to room temperature then.
Reaction times is not crucial, can how much selecting in the scope of broad according to production lot.Generally speaking, each reactant combines and reaches 150 minutes most, and preferably the longest is 120 minutes, and more preferably the longest is 90 minutes.Further the time of reaction is generally 3 hours and cool overnight (promptly about 16 hours).
Handle and carry out according to a conventional method.In the inventive method (a)
The first stepIn, at first, carry out reduction vaporization, and pass through the product in this step of fractionation by distillation.
Implementing the inventive method (a)
The first stepIn the process, for the 4-chloro-4 of the structural formula (II) of 1mol, 4-difluoro-acetyl-acetic acid alkylesters, the trialkyl phosphite of employed structural formula (III) is generally 0.5mol to 5mol, preferred 0.5mol to 3mol, more preferably 1mol to 2mol, most preferably 1.2mol to 1.7mol.
Second step of the inventive method (a)
The inventive method (a)
Second stepRandomly in the presence of thinner, implement.All be fit to for all conventional organic solvents of inert for this step reaction.What preferably use is optional halogenated aliphatic hydrocrbon, alicyclic hydrocarbon or aromatic hydrocarbon, for example sherwood oil, hexane, heptane, hexanaphthene, methylcyclohexane, benzene,toluene,xylene, naphthalane, chlorobenzene, dichlorobenzene or methylene dichloride; Ether, for example ether, isopropyl ether, methyl tertiary butyl ether, tert amyl methyl ether(TAME), diox, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1,2-diethoxyethane or methyl-phenoxide; Nitrile, for example acetonitrile, propionitrile, n-Butyronitrile, isopropyl cyanide or benzonitrile; Acid amides, N for example, dinethylformamide, N,N-dimethylacetamide, N-methyl formyl aniline, N-Methyl pyrrolidone or hexamethylphosphoramide; Sulfoxide, for example dimethyl sulfoxide (DMSO); Or sulfone, for example tetramethylene sulfone.
The inventive method (a)
Second stepCan in wideer temperature range, implement.The general temperature that adopts 10 ℃ to 100 ℃, preferably each reactive component is 20 ℃ to 30 ℃ mixing, then 30 ℃ to 100 ℃, preferred 50 ℃ to 75 ℃ reactions.
Reaction times is not crucial, can how much selecting in the scope of broad according to production lot.Generally speaking, reactant mixed in several minutes to 60 minutes, preferred 10 to 30 minutes, made its reaction several hours then, and preferably the longest is 24 hours, and more preferably the longest is 20 hours.
Handle and carry out according to a conventional method.
Second stepIn reaction mixture is chilled to room temperature, with sodium chloride solution and water washing, with thick product drying and reduction vaporization.Separate with other impurity by the enamine of distillation then structural formula (VI).
Implementing the inventive method (a)
Second stepIn the process, for the alkyl phosphonates of the structural formula (IV) of 1mol, the amine of employed structure formula V is generally 2.5mol to 5mol, preferred 3mol to 5mol, more preferably 2mol to 4mol.
The 3rd step of the inventive method (a)
The inventive method (a)
The 3rd stepIn hydrolysis in the presence of acid, implement preferred randomly sulfuric acid, phosphoric acid or the hydrochloric acid of dilute with water, more preferably hydrochloric acid, the most preferably mixture of hydrochloric acid and water.
The inventive method (a)
The 3rd stepCan in wideer temperature range, implement.Generally speaking, adopt 10 ℃ to 50 ℃ temperature, preferred 20 ℃ to 30 ℃.
Reaction times is not crucial, can be according to the scope of how much selecting broad of production lot.Generally speaking, each reactant mixed number minute is to the longest 60 minutes, preferred 10 to 30 minutes, and makes its reaction several hours, and preferably the longest is 24 hours, and more preferably the longest is 20 hours.
Handle and carry out according to a conventional method.
The 3rd stepMiddle reaction mixture washs with sodium chloride solution and sodium hydrogen carbonate solution, with thick product drying and reduction vaporization usually with the solvent extraction that is fit to.By distilling 4 of structural formula (I), the 4-difluoro-acetyl-acetic acid alkylesters separates with other impurity then.
Implementing the inventive method (a)
The 3rd stepIn the process, for the enamine of the structural formula (VI) of 1mol, employed acid is generally 0.5mol to 5mol, preferred 1mol to 5mol, more preferably 1mol to 2.5mol.
Method of the present invention (b)
In method of the present invention (b), the alkyl acetate of the chloro difluoroacetic acid alkyl ester of utilization structure formula (VII) and structural formula (VIII), wherein R preferably represents C
1-C
8Alkyl,
C
1-C
6Alkyl,
Methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl,
Methyl or ethyl.
Method of the present invention (b) is implemented in the presence of the alkali that is fit to.All conventional mineral alkali and organic basess all are fit to.Described alkali preferably includes alkaline-earth metal and alkali-metal hydride, amide, alcoholate, for example sodium hydride, sodium amide, lithium diisopropylamine (LDA), sodium methylate, sodium ethylate, potassium tert.-butoxide, more preferably lithium diisopropylamine (LDA) and sodium hydride.
Method of the present invention (b) is implemented in the presence of thinner.All be fit to for all conventional organic solvents of inert for this step reaction.What preferably use is optional halogenated aliphatic hydrocrbon, alicyclic hydrocarbon or aromatic hydrocarbon, for example sherwood oil, hexane, heptane, hexanaphthene, methylcyclohexane, benzene,toluene,xylene, naphthalane, chlorobenzene, dichlorobenzene or methylene dichloride; Ether, for example ether, isopropyl ether, methyl tertiary butyl ether, tert amyl methyl ether(TAME), diox, tetrahydrofuran (THF), 1,2-glycol dimethyl ether, 1,2-diethoxyethane or methyl-phenoxide; Nitrile, for example acetonitrile, propionitrile, n-Butyronitrile, isopropyl cyanide or benzonitrile; Acid amides, N for example, dinethylformamide, N,N-dimethylacetamide, N-methyl formyl aniline, N-Methyl pyrrolidone or hexamethylphosphoramide; Sulfoxide, for example dimethyl sulfoxide (DMSO); Or sulfone, for example tetramethylene sulfone.
Method of the present invention (b) can be implemented in wide temperature range.Generally speaking, adopt-80 ℃ to+100 ℃ temperature, preferred-70 ℃ to 0 ℃.
Reaction times is not crucial, can be according to the scope of how much selecting broad of production lot.Generally speaking, each reactant mixed number minute is to the longest 180 minutes, preferred 10 to 90 minutes, and makes its reaction several hours, and preferably the longest is 24 hours, and more preferably the longest is 16 hours.
Handle and carry out according to a conventional method.Usually with the reaction mixture neutralization, be separated, with the sodium chloride solution washing, with thick product drying and reduction vaporization.By the 4-chloro-4 of distillation with structural formula (II), the 4-difluoro-acetyl-acetic acid alkylesters separates with other impurity then.
In the process of implementing the inventive method (b), for the chloro difluoroacetic acid alkyl ester of the structural formula (VII) of 1mol, the alkyl acetate of employed structural formula (VIII) is generally 0.5mol to 5mol, preferred 1mol to 5mol, more preferably 1mol to 2.5mol.
The inventive method (a) and institute (b) implement under normal pressure in steps usually.But under also can or reducing pressure at high pressure-and being generally 0.1 to 50bar, a certain step that preferred 1bar to 10bar-enforcement is independent or institute are in steps.
Can be by 4 of method of the present invention (a) acquisition, the 4-difluoro-acetyl-acetic acid alkylesters is valuable intermediate for pyrazolyl carboxylic acid for preparing the difluoromethyl replacement and thiazolyl carboxylic acid derivative, and described derivative is the precursor (reference example such as WO 02/08197 and DE-A 102 15 292) with compound of anti-mycotic activity.
For example, 4, the 4-difluoro-acetyl-acetic acid alkylesters can be earlier and diacetyl oxide and alkyl orthoformate be converted into 2-(difluoro ethanoyl)-3-alkoxy propone acid alkyl ester (productive rate of ethyl ester is higher than 90%, with reference to preparation embodiment) with higher productive rate.Obtain 1-methyl-3-difluoromethyl-pyrazoles-4-carboxylic acid (productive rate is higher than 65% with regard to ethyl ester) with the methylhydrazine cyclisation.Unwanted isomer (1-methyl-5-difluoromethyl-pyrazoles-4-carboxylic acid) can pass through Crystallization Separation.Conversion process can be expressed as following reaction scheme figure:
Equally, 4, the 4-difluoro-acetyl-acetic acid alkylesters also can first chlorination, obtain monochloroization and dichloride product (2 this moment, 2-two chloro-4,4-two fluoro-3-ketobutyric acid alkyl ester and 2-chloro-4,4-two fluoro-3-ketobutyric acid alkyl esters), the two all can almost make 3-methyl-4-difluoromethyl thiazole-5-carboxylic acid alkyl ester (with reference to following route map) with the thioacetamide reaction quantitatively:
The further example of following examples is explained above explanation, wherein discuss of the present invention 4, the preparation method of 4-difluoro-acetyl-acetic acid alkylesters and be used to prepare the purposes of difluoromethyl substituted heterocycle.Yet described embodiment should not explain in the mode of restriction.
Preparation embodiment
Embodiment 1:
Step 1:
3-[(dimethoxy phosphoryl) oxygen base]-4, the system of 4-difluoro fourth-3-olefin(e) acid ethyl ester (IV-1)
Be equipped with
Under the condition of ice bath cooling and gas generation, in the time of 25 ℃ to 30 ℃ with the tricresyl phosphite methyl ester (232.0g 1.87mol) splashed into 4-chloro-4 in 90 minutes, 4-difluoro methyl aceto acetate (305.1g, content 77.0%, 1.17mol) in.30 ℃ are continued down to stir 1 hour, stirred 3 hours down at 40 ℃ to 45 ℃ then.During processing reaction mixture is chilled to room temperature (about 16 hours) and reduction vaporization.Thick product is further purified by distillation.
Obtain 302.0g (97%, theoretical value 91%) 3-[(dimethoxy phosphoryl) the oxygen base]-4,4-difluoro fourth-3-olefin(e) acid ethyl ester (92-95 ℃ of 0.4hPa boiling point).
Step 2:
3-(diisopropylaminoethyl)-4, the preparation of 4-difluoro fourth-3-olefin(e) acid ethyl ester (VI-1)
With diisopropylamine (15.2g 0.15mol) splashes into 3-[(dimethoxy phosphoryl) oxygen base]-4,4-difluoro fourth-3-olefin(e) acid ethyl ester (IV-1) (14.2g, 97%, 0.05mol) be dissolved in the solution of 100ml methyl tertiary butyl ether 10 minutes dropping time.Reflux was chilled to room temperature with reaction mixture after 19 hours, and the sodium chloride solution washed twice with 10%, each 10ml are with dried over sodium sulfate, filtration and reduction vaporization.Resistates is distilled to treat further use.
Obtain 8.8g (95%, theoretical value 67.4%) 3-(diisopropylaminoethyl)-4,4-difluoro fourth-3-olefin(e) acid ethyl ester (55-57 ℃ of 0.5hPa boiling point).
Step 2 and 3:
Do not separate 3-(diisopropylaminoethyl)-4,4 under the situation of 4-difluoro fourth-3-olefin(e) acid ethyl ester (VI-1), the preparation of 4-difluoro methyl aceto acetate (I)
20 ℃ with diisopropylamine (2811.6g; 27.8mol) splash into 3-[(dimethoxy phosphoryl) the oxygen base]-4,4-difluoro fourth-3-olefin(e) acid ethyl ester (VI-1) (2570g, 98.8%; 9.26mol) methyl tertiary butyl ether (18.5l) solution in, 10 minutes dropping time.(57 ℃) continue to stir 20 hours under the reflux conditions.In the time of 20 ℃ to 25 ℃, splash into the solution that the 2037g concentrated hydrochloric acid is dissolved in 4080ml water under the cooling conditions then, and continue to stir 20 hours.Two of formation is separated.Water methyl tertiary butyl ether extracting twice, each 2.3l.The organic phase that merges with the sodium chloride solution of 2.8l 10%, is used 10% sodium hydrogen carbonate solution earlier then, again with 10% sodium chloride solution washing.Use dried over sodium sulfate, filter then and reduction vaporization.Thick product is purified by distillation.
Obtain 4 of 1179g (92%, theoretical value 76.6%), 4-difluoro methyl aceto acetate.
Embodiment 2:
4-chloro-4, the preparation of 4-difluoro methyl aceto acetate (II)
312.6g (3.09mol) diisopropylamine is dissolved in the tetrahydrofuran (THF) of 1.55l and is chilled to-70 ℃.In the time of-60 ℃ 852.9g (3.08mol) n-Butyl Lithium (hexane solution of 2.5mol/L) is splashed in the above-mentioned solution, 80 minutes dropping time ,-70 ℃ are continued down to stir 45 minutes.Temperature is of short duration to be in-20 ℃, is cooled to-70 ℃ more immediately.In the time of-60 ℃, splash into 264.3g (3.0mol) ethyl acetate, 50 minutes dropping time then.Splash into 242.7g chloro ethyl difluoro under the uniform temp, 30 minutes dropping time ,-65 ℃ to-70 ℃ are continued down to stir 3 hours, make temperature rise to room temperature then.Add the 4N HCl of 1500ml when rising to-5 ℃ and made reaction mixture sat 16 hours.Water phase separated (pH 6-7), organic phase is washed with the 2N HCl of 750ml and the saturated nacl aqueous solution of 1200ml.The organic phase dried over sodium sulfate is filtered and reduction vaporization.Distill thick product with further purification.
Obtain the 4-chloro-4 of 282.9g (92%, theoretical value 86.3%), 4-difluoro methyl aceto acetate.
Embodiment 3:
The preparation of chloro ethyl difluoro (VII)
504.3g (3.87mol) chloro difluoroacetic acid and 5.0g tosic acid are dissolved in the 775ml methylene dichloride, and at room temperature use 311.6g (6.76mol) Ethanol Treatment 30 minutes (temperature rises to 33 ℃).Continuing under the condition that water trap exists refluxes stirred 38 hours, was chilled to room temperature then.Wash in the following order during processing: first water (200ml), use saturated sodium bicarbonate solution (200ml) then, water (200ml) is used dried over sodium sulfate again, and filtration and distillation remove desolvates.Further purify by fractionation at last.
Obtain the chloro ethyl difluoro (boiling point 94-96 ℃) of 488.9g (98%, theoretical value 78.5%).
Embodiment 4:
The preparation of 1-methyl-5-difluoromethyl-pyrazoles-4-carboxylic acid
In the time of-15 ℃ to-5 ℃ 527.8g (11.45mol) methylhydrazine being dissolved in 0.7l alcoholic acid solution splashes into 2394g (10.35mol) 2-(difluoro ethanoyl)-3-ethoxy ethyl acrylate and is dissolved in the 5.4l alcoholic acid solution; 3.5 hours dropping time, continue to stir 16 hours.Add 560g (14mol) sodium hydroxide and 3.5l water then, 50 ℃ are continued down to stir 7 hours.With reaction mixture cooling and reduction vaporization.Resistates is handled in 6l water and 7kg ice, and with washed with dichloromethane (3l, a 2l).Icy water is transferred pH to 2 with concentrated hydrochloric acid, precipitated product is leached and drying in loft drier.Under the reflux conditions thick product is dissolved in the 8l Virahol (heat), cooling was stirred 30 minutes in the time of 0 ℃ to 5 ℃, filtered, and is with 1.4l Virahol (5 ℃) washing, dry in 40 ℃ of loft drier.
Obtain 1-methyl-5-difluoromethyl pyrazole-4-carboxylic acid [Log P (pH 2.3)=0.52] of 1226.4g (99.8%, theoretical value 67.1%).
Embodiment 5:
The preparation of 3-methyl-4-difluoromethyl thiazole-5-carboxylic acid ethyl ester
28g (0.27mol) thioacetamide is added to 500ml 1,2-chloro-4 in the 2-ethylene dichloride, 4-two fluoro-ethyl 3-oxobutanoates (50.4%) and 2,2-two chloro-4, (50.4% monochloro is for compound for 68.2g, 0.2mol for the mixture of 4-two fluoro-ethyl 3-oxobutanoates, 19.2% compound of dichloro) in, reflux left standstill 16 hours in 2 hours then.Stir then and slowly add the 300ml saturated sodium bicarbonate solution down, the separation two-phase.Organic solution is with dried over sodium sulfate and reduction vaporization.Residual solution filters, with 20ml washed with dichloromethane and reduction vaporization.
Obtain 3-methyl-4-difluoromethyl thiazole-5-carboxylic acid ethyl ester [Log P (pH 2.3)=2.18] of 53.4g (72%, theoretical value 86.7%).
The mensuration of the log P value of being reported among last table and the preparation embodiment is undertaken by reversed-phase column (C18) HPLC (high performance liquid chromatography) method according to EEC the 79/831st trumpeter's volume appendix V.A8 (EEC Directive 79/831 Annex V.A8).Temperature: 43 ℃.
Phosphate aqueous solution with 0.1% is measured in the acid district of pH 2.3 (acid region), and acetonitrile is made eluent; Linear gradient from 10% acetonitrile to 90% acetonitrile.
Calibrate the log P value of described compound known (push away by in linear between two successive alkane ketone, determine log P value) based on retention time with unbranched alkane-2-ketone (3 to 16 carbon atoms).
Claims (8)
1. prepare 4 of structural formula (I), the method for 4-difluoro-acetyl-acetic acid alkylesters,
Wherein R represents C
1-C
8Alkyl,
It is characterized in that,
The first stepIn, the 4-chloro-4 of structural formula (II), the trialkyl phosphite reaction of 4-difluoro-acetyl-acetic acid alkylesters and structural formula (III),
Wherein R has aforesaid implication
P(OR
1)
3 (III)
Wherein
R
1Represent C
1-C
4Alkyl, and residue R
1Under any circumstance can be identical or different, the alkyl phosphonates of the structural formula that is obtained (IV) thus
Wherein R and R
1Has aforesaid implication
Second stepIn, randomly in the presence of thinner with the reaction of the amine of structure formula V,
Wherein
R
2And R
3Represent hydrogen or C independently of one another
1-C
8Alkyl or common representative-CH
2-CH
2-O-CH
2-CH
2-,-CH
2-CH
2-S-CH
2-CH
2-or-CH
2-CH
2-N (R
4)-CH
2-CH
2-, R
4Represent hydrogen or C
1-C
8Alkyl,
The enamine of the structural formula that is obtained (VI) thus,
Wherein R, R
2And R
3Has aforesaid implication
The 3rd stepIn hydrolysis in the presence of acid.
2. the method for claim 1 is characterized in that, is used as the 4-chloro-4 of the structural formula (II) of starting raw material in the first step, and the 4-difluoro-acetyl-acetic acid alkylesters prepares by the following method:
The chloro difluoroacetic acid alkyl ester of structural formula (VII) in the presence of alkali and thinner with the reaction of the alkyl acetate of structural formula (VII),
Wherein R has aforesaid implication
Wherein R has aforesaid implication.
3. claim 1 or 2 method is characterized in that R represents C in the described structural formula of employed claim 1 (II) compound
1-C
6Alkyl.
4. claim 1 or 2 method is characterized in that
In the described structural formula of employed claim 1 (II) compound, R represent methylidene, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, and
In the described structural formula of employed claim 1 (III) compound, R
1Represent methylidene, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, and
In the described structure formula V of employed claim 1 compound, R
2And R
3Represent hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl or common representative-CH independently of one another
2-CH
2-O-CH
2-CH
2-.
5. the method for claim 1 is characterized in that, the first step is carried out under the condition of diluent free.
6. the method for claim 1 is characterized in that the hydrolysis in the 3rd step is carried out in the presence of sulfuric acid, phosphoric acid or hydrochloric acid, each dilute with water randomly of described acid.
7. the alkyl phosphonates of structural formula (IV),
Wherein
R represents C
1-C
8Alkyl,
R
1Represent C
1-C
4Alkyl, and residue R
1Under any circumstance can be identical or different.
8. the enamine of structural formula (VI),
Wherein
R represents C
1-C
8Alkyl,
R
2And R
3Represent hydrogen or C independently of one another
1-C
8Alkyl or common representative-CH
2-CH
2-O-CH
2-CH
2-,-CH
2-CH
2-S-CH
2-CH
2-or-CH
2-CH
2-N (R
4)-CH
2-CH
2-, R
4Represent hydrogen or C
1-C
8Alkyl.
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| DE10329450.3 | 2003-07-01 | ||
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| JP (1) | JP4727576B2 (en) |
| CN (1) | CN100427454C (en) |
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| DE102007005296A1 (en) * | 2007-02-02 | 2008-08-07 | Bayer Cropscience Ag | Process for the preparation of dihaloacetacetic acid alkyl esters |
| US8124787B2 (en) * | 2007-05-31 | 2012-02-28 | Syngenta Crop Protection, Inc. | Process for the production of pyrazoles |
| AU2008257515B2 (en) | 2007-06-01 | 2014-01-23 | Basf Se | Method for the production of n-substituted (3-dihalomethyl-1-methyl-pyrazole-4-YL) carboxamides |
| EA200901652A1 (en) * | 2007-06-15 | 2010-06-30 | Басф Се | Method of producing difluoromethyl-substituted pyrazole compounds |
| US8481778B2 (en) * | 2007-08-16 | 2013-07-09 | Solvay (Societe Anonyme) | Process for the preparation of esters of 4-fluorosubstituted 3-oxo-alcanoic acids |
| CN106977457A (en) * | 2016-12-22 | 2017-07-25 | 浙江海正化工股份有限公司 | A kind of formic acid of 1 methylpyrazole of 3 difluoromethyl 4 and its synthetic method |
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| GB2082579B (en) * | 1980-08-23 | 1984-02-08 | Merrell Toraude & Co | Fluorinated diaminobutane derivatives |
| NZ201468A (en) * | 1981-08-10 | 1986-02-21 | Merck & Co Inc | 5-aroyl-4-pyrrolyl-alkanoic acid derivatives and pharmaceutical compositions |
| JPS58152831A (en) * | 1982-03-08 | 1983-09-10 | Daikin Ind Ltd | Production of fluorodiketones |
| JP2509282B2 (en) * | 1987-09-24 | 1996-06-19 | 鹿島石油株式会社 | Optically active difluoro alcohol derivative |
| US5045554A (en) * | 1988-11-29 | 1991-09-03 | Monsanto Company | Substituted thiazoles and their use as fungicides |
| US5093347A (en) * | 1991-01-28 | 1992-03-03 | Monsanto Company | 3-difluoromethylpyrazolecarboxamide fungicides, compositions and use |
| US5223526A (en) * | 1991-12-06 | 1993-06-29 | Monsanto Company | Pyrazole carboxanilide fungicides and use |
| JP2706037B2 (en) * | 1993-04-13 | 1998-01-28 | 帝人株式会社 | Cyano compound and method for producing the same |
| US5498624A (en) * | 1995-05-03 | 1996-03-12 | Monsanto Company | Selected pyrazolyl derivatives |
| PE20011010A1 (en) * | 1999-12-02 | 2001-10-18 | Glaxo Group Ltd | OXAZOLES AND THIAZOLES REPLACED AS AGONIST OF THE RECEPTOR ACTIVATED BY THE HUMAN PEROXISOMAS PROLIFERATOR |
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Non-Patent Citations (4)
| Title |
|---|
| Regiocontrolled synthesisof3-substituted-6-trifluoromethyl-4(3H)-pyrimidinones. Colin M. Tice et al.:.Tetrahedron,Vol.57 . 2001 |
| Regiocontrolled synthesisof3-substituted-6-trifluoromethyl-4(3H)-pyrimidinones. Colin M. Tice et al.:.Tetrahedron,Vol.57 . 2001 * |
| Synthesis of Analogs of Farnesyl Diphosphate. Julia M. Dolence et al.:.Tetrahedron,Vol.52 No.1. 1996 |
| Synthesis of Analogs of Farnesyl Diphosphate. Julia M. Dolence et al.:.Tetrahedron,Vol.52 No.1. 1996 * |
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| Publication number | Publication date |
|---|---|
| DE10331496A1 (en) | 2005-01-27 |
| CN1812959A (en) | 2006-08-02 |
| JP4727576B2 (en) | 2011-07-20 |
| ATE519729T1 (en) | 2011-08-15 |
| JP2007506673A (en) | 2007-03-22 |
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