CN112279821A - Synthesis method of 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl butyrate - Google Patents
Synthesis method of 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl butyrate Download PDFInfo
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- CN112279821A CN112279821A CN202011218857.2A CN202011218857A CN112279821A CN 112279821 A CN112279821 A CN 112279821A CN 202011218857 A CN202011218857 A CN 202011218857A CN 112279821 A CN112279821 A CN 112279821A
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- difluoro
- oxo
- cycloalkyl
- heteroaryl
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- -1 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl Chemical group 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title abstract description 11
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 title abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 48
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims abstract description 45
- CRLSHTZUJTXOEL-UHFFFAOYSA-N 2,2-difluoroacetyl fluoride Chemical compound FC(F)C(F)=O CRLSHTZUJTXOEL-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000003054 catalyst Substances 0.000 claims abstract description 25
- BNRAQZQNLDULNL-UHFFFAOYSA-N ethyl 4,4-difluoro-3-oxo-2-(piperidin-1-ylmethylidene)butanoate Chemical compound CCOC(=O)C(C(=O)C(F)F)=CN1CCCCC1 BNRAQZQNLDULNL-UHFFFAOYSA-N 0.000 claims abstract description 24
- MIZLGWKEZAPEFJ-UHFFFAOYSA-N 1,1,2-trifluoroethene Chemical group FC=C(F)F MIZLGWKEZAPEFJ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims abstract description 18
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 239000000376 reactant Substances 0.000 claims abstract description 3
- 238000010189 synthetic method Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 238000005336 cracking Methods 0.000 claims description 21
- RMRGFFLBZFVNEX-UHFFFAOYSA-N 1-fluoro-2-(fluoromethyl)piperidine Chemical group C1CCN(C(C1)CF)F RMRGFFLBZFVNEX-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 12
- 239000005977 Ethylene Substances 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000003107 substituted aryl group Chemical group 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000001450 anions Chemical class 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910001430 chromium ion Inorganic materials 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- QZFIQARJCSJGEG-UHFFFAOYSA-N 1,1,1,2-tetrafluoro-2-(1,2,2,2-tetrafluoroethoxy)ethane Chemical compound FC(F)(F)C(F)OC(F)C(F)(F)F QZFIQARJCSJGEG-UHFFFAOYSA-N 0.000 claims description 5
- 239000011651 chromium Substances 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical group [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052804 chromium Inorganic materials 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- 229940006460 bromide ion Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 2
- 229940006461 iodide ion Drugs 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- 238000004064 recycling Methods 0.000 abstract description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 abstract description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007789 gas Substances 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000007788 liquid Substances 0.000 description 19
- 229910000856 hastalloy Inorganic materials 0.000 description 13
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000006555 catalytic reaction Methods 0.000 description 9
- 238000005086 pumping Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- ZNMIFKKFGNALHJ-UHFFFAOYSA-N ethyl 3-piperidin-1-ylprop-2-enoate Chemical compound CCOC(=O)C=CN1CCCCC1 ZNMIFKKFGNALHJ-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 229910001506 inorganic fluoride Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 239000003973 paint Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- AZUHIVLOSAPWDM-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)-1h-imidazole Chemical class C1=CNC(C=2NC=CN=2)=N1 AZUHIVLOSAPWDM-UHFFFAOYSA-N 0.000 description 1
- FGSBZZTYGCQZPD-UHFFFAOYSA-N 2-piperidin-1-ylethyl prop-2-enoate Chemical compound C=CC(=O)OCCN1CCCCC1 FGSBZZTYGCQZPD-UHFFFAOYSA-N 0.000 description 1
- RLOHOBNEYHBZID-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)C(C(F)F)=N1 RLOHOBNEYHBZID-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910021556 Chromium(III) chloride Inorganic materials 0.000 description 1
- 239000005788 Fluxapyroxad Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229960000359 chromic chloride Drugs 0.000 description 1
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- SXSGXWCSHSVPGB-UHFFFAOYSA-N fluxapyroxad Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=CC=C1C1=CC(F)=C(F)C(F)=C1 SXSGXWCSHSVPGB-UHFFFAOYSA-N 0.000 description 1
- 239000002920 hazardous waste Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JMANUKZDKDKBJP-UHFFFAOYSA-N imidazo[1,5-a]pyridine Chemical compound C1=CC=CC2=CN=CN21 JMANUKZDKDKBJP-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- JVRMUFJCFLXSMJ-UHFFFAOYSA-N n,2-diphenylbenzamide Chemical compound C=1C=CC=C(C=2C=CC=CC=2)C=1C(=O)NC1=CC=CC=C1 JVRMUFJCFLXSMJ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PXVODSZUJMQPTJ-UHFFFAOYSA-N phenyl-(5-propan-2-ylpyridin-2-yl)methanone Chemical compound CC(C)c1ccc(nc1)C(=O)c1ccccc1 PXVODSZUJMQPTJ-UHFFFAOYSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000012855 volatile organic compound Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2265—Carbenes or carbynes, i.e.(image)
- B01J31/2269—Heterocyclic carbenes
- B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
-
- 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
- C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0225—Complexes comprising pentahapto-cyclopentadienyl analogues
- B01J2531/0233—Aza-Cp ligands, i.e. [CnN(5-n)Rn]- in which n is 0-4 and R is H or hydrocarbyl, or analogous condensed ring systems
-
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Abstract
The invention relates to a synthesis method of 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl butyrate, which comprises the following steps: the method comprises the following steps of firstly, carrying out condensation reaction on difluoroacetyl fluoride and 3- (1-piperidyl) -ethyl acrylate to generate 4, 4-difluoro-3-oxo-2-piperidine-1-ylmethylene butyric acid ethyl ester and hydrogen fluoride, reacting the hydrogen fluoride and trichloroethylene generated in the first step under the action of a fluorination catalyst to generate trifluoroethylene and hydrogen chloride, reacting the trifluoroethylene and oxygen generated in the third step under the action of a complex catalyst to generate difluoroacetyl fluoride, and recycling the difluoroacetyl fluoride generated in the third step as a reactant of the first step. The synthetic method of the ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylene butyrate has the advantages of simple and easily obtained raw materials, high atom utilization rate and high production safety.
Description
Technical Field
The invention relates to a synthetic method of a compound, and belongs to the technical field of chemical synthesis.
Background
4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl butyrate is used as an intermediate compound, can be used for preparing a world mainstream bactericide, such as 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid which is a main raw material of pyrromonazole, fluxapyroxad and biphenylanilide, and is required to be used as a raw material; the paint prepared by using the 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl butyrate as a raw material has better mildew resistance, seepage resistance, acid and alkali resistance, weather resistance and other properties than the conventional paint.
At present, the mainstream production process of the 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl butyrate at home and abroad comprises the following steps: dissolving 3- (1-piperidyl) -ethyl acrylate in an organic solvent (generally toluene, xylene, dichloromethane, dichloroethane, etc.), stirring and cooling to below-25 ℃, and industrially referring to as a solution to be condensed.
And (5) finishing the preparation of the solution to be condensed, and controlling the temperature not to exceed minus 20 ℃. Continuously pumping the tetrafluoroethane into a cracking device loaded with a catalyst at a certain flow rate, wherein the main components of cracking gas generated by cracking are difluoroacetylfluoride, hydrogen fluoride and ethylene, directly introducing the cracking gas into a liquid to be condensed without any treatment, and stopping feeding of the tetrafluoroethane after the 3- (1-piperidyl) -ethyl acrylate finishes the reaction. Ethylene in the cracking gas does not participate in the reaction, the ethylene in the cracking gas escapes from the condensation device and is led to a direct-fired furnace to be combusted or compressed into liquefied gas for sale, hydrogen fluoride in the cracking gas is neutralized with triethylamine to generate triethylamine hydrofluoride, and hydrogen fluoride generated by condensation of difluoroacetyl fluoride and 3- (1-piperidyl) -ethyl acrylate is also neutralized with triethylamine to generate the triethylamine hydrofluoride, wherein the reaction formula is as follows:
and when the condensation reaction is finished, obtaining the mixture of triethylamine hydrofluoride, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl butyrate and organic solvent. And then slowly adding the mixture into water, dissolving triethylamine hydrofluoric acid salt in the mixture into the water, dissolving 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene butyric acid ethyl ester in the mixture into an organic solvent, and washing the mixture with water to enter the next working procedure or sell the mixture. And finally, neutralizing the aqueous solution of triethylamine hydrofluoride with inorganic alkali such as sodium hydroxide or calcium hydroxide to obtain inorganic fluoride salt, and drying the generated triethylamine for applying to the condensation process.
Although the existing process is relatively mature, the utilization rate of fluorine atoms is too low, two fluorine atoms in tetrafluoroethane molecules are converted into inorganic fluoride with low price, the utilization rate of the fluorine atoms is only 50%, the resource waste is serious, and the cost of raw materials is high. In addition, triethylamine has strong ammonia odor, is flammable and explosive, and has higher requirements on labor protection of workers and safety facilities of factories in the using process. Meanwhile, the control difficulty of volatile organic compounds and nitrogen oxides generated in the use process of triethylamine is high, and the increasingly strict ecological environment supervision requirements cannot be met. Moreover, the triethylamine drying procedure also generates waste drying agents, which only increases the cost of hazardous waste disposal.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthesis method of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylene butyrate, which has high fluorine atom utilization rate, small raw material consumption and high production safety.
The invention provides a technical scheme for solving the technical problems, which comprises the following steps: a method for synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate, comprising the steps of:
step one, performing condensation reaction on difluoroacetylfluoride and 3 (1-piperidyl) -ethyl acrylate to generate 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene butyric acid ethyl ester and hydrogen fluoride, wherein the reaction formula is as follows:
step two, reacting the hydrogen fluoride and the trichloroethylene generated in the step one under the action of a fluorination catalyst to generate trifluoroethylene and hydrogen chloride, wherein the reaction formula is as follows:
step three, reacting trifluoroethylene generated in the step two with oxygen under the action of a complex catalyst to generate difluoroacetyl fluoride, wherein the reaction formula is as follows:
and (3) recycling difluoroacetyl fluoride generated in the third step as a reactant in the first step.
The difluoroacetyl fluoride in the first step and the hydrogen fluoride in the second step are generated by the cleavage reaction of tetrafluoroethane, and the reaction formula of the tetrafluoroethane generating difluoroacetyl fluoride, ethylene and hydrogen fluoride by the cleavage reaction is as follows:
the fluorination catalyst is 1-fluoro-2-fluoromethylpiperidine.
The complex catalyst is a chromium complex with a structure shown as a formula I,
wherein the content of the first and second substances,
[ Cr ] is a chromium ion having 2-3 anions, the anion of the chromium ion is one or more of chloride ion, bromide ion, iodide ion, fluoride ion, trifluoromethanesulfonate ion, perchlorate ion and acetate ion,
R1is hydrogen atom, halogen atom, alkyl of C1-C8, cycloalkyl of C3-C8, cycloalkyl of C3-C8 with substituent, aryl with substituent, heteroaryl or heteroaryl with substituent,
R2and R3Each independently represents a hydrogen atom, a halogen atom, an alkyl group having from C1 to C8, a cycloalkyl group having from C3 to C8, a cycloalkyl group having from C3 to C8, an aryl group having a substituent, a heteroaryl group or a heteroaryl group having a substituent, or
R2And R3And the carbon atom to which they are bonded, form a C4-C8 cycloalkyl group, a substituted C4-C8 cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group,
R4、R5and R6Each independently represents a hydrogen atom, a halogen atom, an alkyl group having from C1 to C8, a cycloalkyl group having from C3 to C8, a cycloalkyl group having from C3 to C8, an aryl group having a substituent, a heteroaryl group or a heteroaryl group having a substituent, or
R6Is hydrogen atom, halogen atom, C1-C8 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, R is4And R5Together with the carbon atom to which they are bonded form a C4-C8 cycloalkyl, substituted C4-C8 cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group, or
R4 is hydrogen atom, halogen atom, C1-C8 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, R5 and R6 together with the carbon atom to which they are bonded form C4-C8 cycloalkyl, substituted C4-C8 cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.
The molar ratio of the 1-fluoro-2-fluoromethylpiperidine to the 3- (1-piperidinyl) -acrylic acid ethyl ester is 1: 100 to 1: 2.
Preferably, the molar ratio of the 1-fluoro-2-fluoromethylpiperidine to the 3- (1-piperidinyl) -acrylic acid ethyl ester is 1: 30-1: 10.
The reaction temperature of the first step and the second step is 0-25 ℃.
Preferably, the reaction temperature in the first step and the second step is 0 ℃ to 5 ℃.
The molar ratio of the trichloroethylene to the 3- (1-piperidyl) -ethyl acrylate is 5: 2-5: 1.
The molar ratio of the amount of the tetrafluoroethyl ether to the amount of the 3- (1-piperidyl) -ethyl acrylate is 2: 5-4: 5.
The reaction temperature in the condensation reaction kettle used in the invention is inversely proportional to the feeding speed of the tetrafluoroethyl ether, and the feeding speed of the tetrafluoroethyl ether is reduced when the reaction temperature is high.
The invention has the positive effects that: the synthesis method of the 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene ethyl butyrate takes the tetrafluoroethylene and the 3- (1-piperidyl) -ethyl acrylate as main raw materials, the utilization rate of fluorine atoms in the tetrafluoroethylene ether is up to 90 percent, and is improved by more than 40 percent compared with the prior art, triethylamine is not required to be used as an acid-binding agent in the method, hydrogen fluoride in a reaction system is continuously consumed by reaction to promote the condensation reaction to be carried out towards the positive direction, and the method is favorable for labor protection of operators and ecological environment protection. The circular reaction device can realize the continuity of production, greatly reduce the generation of waste and the disposal cost of the waste, and the obtained byproduct which does not participate in the reaction is ethylene gas which can be introduced to a direct-fired furnace for combustion or compressed into liquefied gas for sale, thereby greatly improving the economic benefit, effectively saving the resources, realizing the recycling of the resources and being suitable for industrial production.
Drawings
FIG. 1 is a schematic diagram showing the structure of a production apparatus used in the method for synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to the present invention;
FIG. 2 is a chromatogram of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate, a product of example 1 of the present invention.
Detailed Description
The present invention is described in detail below by way of examples, it should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and those skilled in the art can make some insubstantial modifications and adaptations of the present invention based on the above-described disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Halogen atoms, such as: bromine atom, iodine atom, fluorine atom and chlorine atom. The alkyl of C1-C8 refers to alkyl with a carbon chain length of 1-8, such as: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like. The cycloalkyl of C3-C8 refers to cycloalkyl with a carbon chain length of 3-8, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. And C3-C8 cycloalkyl groups having a substituent such as 2-methylcyclopropyl, 1-methylcyclopentyl and 4-methylcyclohexyl. Aryl is a monovalent group of an aromatic hydrocarbon having a carbon chain length of 6 to 18, such as: phenyl, naphthyl, anthracenyl, and the like. Aryl having a substituent such as: 3-methylphenyl (m-tolyl), 2, 4-di-t-butylphenyl, 4-chlorophenyl and the like. Heteroaryl, such as: furyl, pyrrolyl, indolyl, carbazolyl, imidazolyl and the like. The substituted heteroaryl group means a group in which 1 or more of the hydrogen atoms of the heteroaryl group are substituted with a substituent.
The preparation of the complex catalysts of the present invention can be found in the following literature and books:
(1) Efficient,Single-Step Access to Imidazo [1,5-a] pyridine N-Heterocyclic Carbene Precursors[J]. ORGANIC LETTERS. 2011 Vol.13, No.19 5256–5259；
(2) (C∧C*)-cyclometalated platinum(II) imidazo [1,5-a] pyridine NHC complexes-Synthesis and characterization[J]. Journal of Organometallic Chemistry. 775(2015). 155-163；
(3) Efficient synthesis of bulky N-Heterocyclic carbene ligands for coinage metal complexes[J]. Journal of Organometallic Chemistry. 820(2016). 1-7；
(4) Synthesis and characterization of novel cyclopentadienyl molybdenum imidazo [1,5-a] pyridine-3-ylidene complexes and their application in olefin epoxidation catalysis[J]. Journal of Catalysis. 319(2014). 119–126；
(5) Chiral imidazo [1,5-a] tetrahydroquinoline N-heterocyclic carbenes and their copper complexes for asymmetric catalysis[J]. Tetrahedron: Asymmetry. 24(2013). 492–498。
the chemical reagents used in the invention are all purchased reagents without special description, and the concentration is chemical purity.
Referring to fig. 1, the production device for synthesizing 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylene-butyric acid ethyl ester of the present invention comprises a condensation reaction kettle 1, an alkali spraying device 2, a drying device 3 and an oxidation device 4; condensation reaction kettle 1's first air inlet passes through the pipeline and links to each other with the gas outlet of cracker 6, and alkali spray set 2's air inlet passes through the pipeline and links to each other with condensation reaction kettle 1's gas outlet, and drying device 3's air inlet passes through the pipeline and links to each other with alkali spray set 2's gas outlet, and oxidation device 4's air inlet passes through the pipeline and links to each other with drying device 3's gas outlet, and oxidation device 4's gas outlet links to each other with condensation reaction kettle 1's second air inlet through being equipped with the pipeline of gas booster pump 5. The part of the condensation reaction kettle 1 contacting with the materials is made of hastelloy materials.
Example 1
The specific steps of the synthesis method of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate of the present example are:
using a production device shown in fig. 1, firstly, sequentially adding 3- (1-piperidyl) -ethyl acrylate (800 kg, 4.37 kmoL), 1-fluoro-2-fluoromethylpiperidine (30 kg, 0.22 kmoL) and trichloroethylene (1988.35 kg, 15.3 kmoL) into a 5000L hastelloy condensation reaction kettle 1, starting a motor to stir, and stirring and cooling to below 5 ℃ for later use to obtain the liquid to be condensed.
Then, tetrafluoroethylene ether gas is continuously pumped into the cracker 6, and cracked gas (main components are difluoroacetylfluoride, ethylene and hydrogen fluoride) generated by cracking is introduced into the 5000L hastelloy condensation reaction kettle 1, and the pumping is stopped when the reaction of the 3- (1-piperidyl) -ethyl acrylate in the condensation reaction kettle 1 is finished. The reaction in the cracker 6 is represented by the following reaction formula:
the condensation reaction of difluoroacetylfluoride and 3- (1-piperidyl) -ethyl acrylate to produce 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutanoic acid ethyl ester and hydrogen fluoride has the following reaction formula:
under the catalysis of 1-fluoro-2-fluoromethyl piperidine, hydrogen fluoride and trichloroethylene react to generate trifluoroethylene and hydrogen chloride, and the consumption reaction formula is as follows:
wherein hydrogen fluoride produced by the cracking and hydrogen fluoride produced by the condensation reaction of difluoroacetylfluoride and 3- (1-piperidyl) -ethyl acrylate participate in the fluorination at the same time and are consumed.
Reacting trifluoroethylene and oxygen under the action of a complex catalyst to generate difluoroacetyl fluoride, wherein the reaction formula is as follows:
since hydrogen fluoride in the reaction system is continuously consumed by the reaction, the condensation reaction proceeds in the forward direction. The trifluoroethylene after the trichloroethylene is fluorinated can be further oxidized into difluoroacetyl fluoride to continuously participate in the condensation reaction.
Finally, 382.85 kg of tetrafluoroethyl ether is consumed accumulatively after the reaction of the raw material 3- (1-piperidyl) -ethyl acrylate in the condensation reaction kettle 1 is finished, 2350.63 kg of light brown transparent liquid which is 4, 4-difluoro-3-oxo-2-piperidine-1-ylmethylenebutyric acid ethyl ester trichloroethylene liquid is obtained, and the gas chromatography purity is 99.23%. The chromatogram of the product ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate is shown in FIG. 2, and the chromatographic analysis results of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate are shown in Table 1.
TABLE 1 chromatographic analysis results Table
The complex catalyst adopted in the embodiment has a structure shown in formula II, wherein R is1Is phenyl, R4Is isopropyl, R2、R3、R5、R6All are hydrogen atoms, and the anion of the chromium ion is three chloride ions, and the chemical formula is as follows:
the preparation method of the complex catalyst comprises the following steps:
step A, 23g of (5-isopropyl-2-pyridyl) phenyl ketone, 200ml of methanol and 5.4g of o-phenylenediamine are sequentially added into a 500ml reaction vessel, gas hydrochloric acid is introduced to the reaction vessel under the condition of fully stirring until the solution is saturated, the reaction vessel is reacted for 5 hours at room temperature and then filtered, and a filter cake is washed three times by 20ml of methanol to obtain 28g of the product of the diimidazole salt, wherein the yield is 90%. The reaction formula is as follows:
and step B, dispersing 6.2g of the bisimidazole salt prepared in the step A in 100ml of tetrahydrofuran, cooling to 0 ℃, adding 0.5g of sodium hydride, naturally heating to room temperature for reaction for 2 hours, then adding 1.6g of anhydrous chromium trichloride, continuing to react at room temperature for 1 hour, then refluxing for reaction for 2 hours, finally cooling to room temperature, filtering, washing a filter cake with 20ml of deionized water for three times, and then washing with 20ml of diethyl ether for three times to obtain 6.3g of a target product with the yield of 86%. The reaction formula is as follows:
example 2
The specific steps of the synthesis method of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate of the present example are:
firstly, sequentially adding 3- (1-piperidyl) -ethyl acrylate (1000 kg, 5.46 kmoL), 1-fluoro-2-fluoromethylpiperidine (33.33 kg, 0.24 kmoL) and trichloroethylene (2500 kg, 19.24 kmoL) into a 5000L Hastelloy condensation reaction kettle 1, starting a motor to stir, and stirring and cooling to below 4 ℃ for later use to obtain the liquid to be condensed.
Then, tetrafluoroethylene ether gas is continuously pumped into the cracker 6, and cracked gas (main components are difluoroacetylfluoride, ethylene and hydrogen fluoride) generated by cracking is introduced into the 5000L hastelloy condensation reaction kettle 1, and the pumping is stopped when the reaction of the 3- (1-piperidyl) -ethyl acrylate in the condensation reaction kettle 1 is finished.
The difluoroacetylfluoride and the 3- (1-piperidyl) -ethyl acrylate are subjected to condensation reaction to generate 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene butyric acid ethyl ester and hydrogen fluoride.
The hydrogen fluoride and the trichloroethylene react to generate trifluoroethylene and hydrogen chloride under the catalysis of the 1-fluoro-2-fluoromethyl piperidine.
Wherein hydrogen fluoride produced by the cracking and hydrogen fluoride produced by the condensation reaction of difluoroacetylfluoride and 3- (1-piperidyl) -ethyl acrylate participate in the fluorination at the same time and are consumed.
Reacting trifluoroethylene and oxygen under the action of a complex catalyst to generate difluoroacetyl fluoride.
Finally, after the reaction of the raw material 3- (1-piperidinyl) -ethyl acrylate in the condensation reaction kettle 1 is finished, 400 kg of tetrafluoroethane is consumed accumulatively, 2455.93 kg of light brown transparent liquid which is 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyric acid ethyl ester trichloroethylene liquid is obtained, and the gas chromatography purity is 98.13%.
The structure of the complex catalyst adopted in the embodiment is shown as a formula III, wherein R1Is furyl, R4Is methyl, R5Is a chlorine atom, R2、R3、R6Both are hydrogen atoms, and the anion of the chromium ion is two chloride ions, and has the following chemical formula:
example 3
The specific steps of the synthesis method of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate of the present example are:
firstly, 3- (1-piperidyl) -ethyl acrylate (1200 kg, 6.56 kmoL), 1-fluoro-2-fluoromethylpiperidine (120 kg, 0.88 kmoL) and trichloroethylene (6000 kg, 46.17 kmoL) are sequentially added into a 5000L Hastelloy condensation reaction kettle 1, a motor is started to stir, and the temperature is reduced to below 3 ℃ for later use, namely the liquid to be condensed.
Then, tetrafluoroethylene ether gas is continuously pumped into the cracker 6, and cracked gas (main components are difluoroacetylfluoride, ethylene and hydrogen fluoride) generated by cracking is introduced into the 5000L hastelloy condensation reaction kettle 1, and the pumping is stopped when the reaction of the 3- (1-piperidyl) -ethyl acrylate in the condensation reaction kettle 1 is finished.
The difluoroacetylfluoride and the 3- (1-piperidyl) -ethyl acrylate are subjected to condensation reaction to generate 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene butyric acid ethyl ester and hydrogen fluoride.
The hydrogen fluoride and the trichloroethylene react to generate trifluoroethylene and hydrogen chloride under the catalysis of the 1-fluoro-2-fluoromethyl piperidine.
Wherein hydrogen fluoride produced by the cracking and hydrogen fluoride produced by the condensation reaction of difluoroacetylfluoride and 3- (1-piperidyl) -ethyl acrylate participate in the fluorination at the same time and are consumed.
Reacting trifluoroethylene and oxygen under the action of a complex catalyst to generate difluoroacetyl fluoride.
Finally, after the reaction of the raw material 3- (1-piperidinyl) -ethyl acrylate in the condensation reaction kettle 1 was completed, 960 kg of tetrafluoroethane was consumed cumulatively to obtain 5894.23 kg of light brown transparent liquid, which is 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutanoic acid ethyl ester trichloroethylene liquid, with a gas chromatography purity of 98.78%.
The structure of the complex catalyst adopted in the embodiment is shown as a formula IV, wherein R is2And R3Together with the carbon atom to which they are bonded form a phenyl radical, R5And R6Together with the carbon atom to which they are bonded form a phenyl radical, R1And R4Is hydrogen atom, and the anion of the chromium ion is three fluorinions, and the chemical formula is as follows:
example 4
The specific steps of the synthesis method of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate of the present example are:
firstly, 3- (1-piperidyl) -ethyl acrylate (700 kg, 3.82 kmoL), 1-fluoro-2-fluoromethylpiperidine (28 kg, 0.21 kmoL) and trichloroethylene (2100 kg, 16.16 kmoL) are sequentially added into a 5000L Hastelloy condensation reaction kettle 1, a motor is started to stir, and the temperature is reduced to below 2 ℃ for later use, namely the liquid to be condensed.
Then, tetrafluoroethylene ether gas is continuously pumped into the cracker 6, and cracked gas (main components are difluoroacetylfluoride, ethylene and hydrogen fluoride) generated by cracking is introduced into the 5000L hastelloy condensation reaction kettle 1, and the pumping is stopped when the reaction of the 3- (1-piperidyl) -ethyl acrylate in the condensation reaction kettle 1 is finished.
The difluoroacetylfluoride and the 3- (1-piperidyl) -ethyl acrylate are subjected to condensation reaction to generate 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene butyric acid ethyl ester and hydrogen fluoride.
The hydrogen fluoride and the trichloroethylene react to generate trifluoroethylene and hydrogen chloride under the catalysis of the 1-fluoro-2-fluoromethyl piperidine.
Wherein hydrogen fluoride produced by the cracking and hydrogen fluoride produced by the condensation reaction of difluoroacetylfluoride and 3- (1-piperidyl) -ethyl acrylate participate in the fluorination at the same time and are consumed.
Reacting trifluoroethylene and oxygen under the action of a complex catalyst to generate difluoroacetyl fluoride.
Finally, after the reaction of the raw material 3- (1-piperidinyl) -ethyl acrylate in the condensation reaction kettle 1 was completed, 420 kg of tetrafluoroethane was cumulatively consumed to obtain 2578.72 kg of light brown transparent liquid, which is 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutanoic acid ethyl ester trichloroethylene liquid, and the gas chromatography purity was 98.89%.
The structure of the complex catalyst adopted in the embodiment is shown as a formula V, wherein R is4Is cyclohexyl, R1、R2、R3、R5、R6All are hydrogen atoms, and the anion of the chromium ion is three acetate ions, and the chemical formula is as follows:
example 5
The specific steps of the synthesis method of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate of the present example are:
firstly, 3- (1-piperidyl) -ethyl acrylate (850 kg, 4.64 kmoL), 1-fluoro-2-fluoromethylpiperidine (42.5 kg, 0.31 kmoL) and trichloroethylene (2975 kg, 22.89 kmoL) are sequentially added into a 5000L Hastelloy condensation reaction kettle 1, a motor is started to stir, and the temperature is reduced to below 1 ℃ for later use, namely the liquid to be condensed.
Then, tetrafluoroethylene ether gas is continuously pumped into the cracker 6, and cracked gas (main components are difluoroacetylfluoride, ethylene and hydrogen fluoride) generated by cracking is introduced into the 5000L hastelloy condensation reaction kettle 1, and the pumping is stopped when the reaction of the 3- (1-piperidyl) -ethyl acrylate in the condensation reaction kettle 1 is finished.
The difluoroacetylfluoride and the 3- (1-piperidyl) -ethyl acrylate are subjected to condensation reaction to generate 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene butyric acid ethyl ester and hydrogen fluoride.
The hydrogen fluoride and the trichloroethylene react to generate trifluoroethylene and hydrogen chloride under the catalysis of the 1-fluoro-2-fluoromethyl piperidine.
Wherein hydrogen fluoride produced by the cracking and hydrogen fluoride produced by the condensation reaction of difluoroacetylfluoride and 3- (1-piperidyl) -ethyl acrylate participate in the fluorination at the same time and are consumed.
Reacting trifluoroethylene and oxygen under the action of a complex catalyst to generate difluoroacetyl fluoride.
Finally, 425 kg of tetrafluoroethane is consumed accumulatively after the raw material 3- (1-piperidyl) -ethyl acrylate in the condensation reaction kettle 1 is reacted, 2609.42 kg of light brown transparent liquid which is 4, 4-difluoro-3-oxo-2-piperidine-1-ylmethylenebutyric acid ethyl ester trichloroethylene liquid is obtained, and the purity of the gas chromatography is 99.09%.
The structure of the chromium complex catalyst adopted in the embodiment is shown as a formula II.
Example 6
The specific steps of the synthesis method of ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate of the present example are:
firstly, 3- (1-piperidyl) -ethyl acrylate (900 kg, 4.92 kmoL), 1-fluoro-2-fluoromethylpiperidine (32.14 kg, 0.24 kmoL) and trichloroethylene (3600 kg, 27.70 kmoL) are sequentially added into a 5000L Hastelloy condensation reaction kettle 1, a motor is started to stir, and the temperature is reduced to below 0 ℃ for later use, namely the liquid to be condensed.
Then, tetrafluoroethylene ether gas is continuously pumped into the cracker 6, and cracked gas (main components are difluoroacetylfluoride, ethylene and hydrogen fluoride) generated by cracking is introduced into the 5000L hastelloy condensation reaction kettle 1, and the pumping is stopped when the reaction of the 3- (1-piperidyl) -ethyl acrylate in the condensation reaction kettle 1 is finished.
The difluoroacetylfluoride and the 3- (1-piperidyl) -ethyl acrylate are subjected to condensation reaction to generate 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene butyric acid ethyl ester and hydrogen fluoride.
The hydrogen fluoride and the trichloroethylene react to generate trifluoroethylene and hydrogen chloride under the catalysis of the 1-fluoro-2-fluoromethyl piperidine.
Wherein hydrogen fluoride produced by the cracking and hydrogen fluoride produced by the condensation reaction of difluoroacetylfluoride and 3- (1-piperidyl) -ethyl acrylate participate in the fluorination at the same time and are consumed.
Reacting trifluoroethylene and oxygen under the action of a complex catalyst to generate difluoroacetylfluoride,
finally, 630 kg of tetrafluoroethane was consumed cumulatively after the reaction of the raw material 3- (1-piperidinyl) -ethyl acrylate in the condensation reactor 1 was completed, to obtain 3868.09 kg of light brown transparent liquid, which was 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutanoic acid ethyl ester trichloroethylene liquid, with a gas chromatography purity of 99.18%.
The structure of the complex catalyst used in this example is shown in formula III.
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious variations or modifications which fall within the spirit of the invention are intended to be covered by the scope of the present invention.
Claims (10)
1. A synthetic method of 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyric acid ethyl ester is characterized by comprising the following steps:
step one, performing condensation reaction on difluoroacetylfluoride and 3- [ 1-piperidyl ] -ethyl acrylate to generate 4, 4-difluoro-3-oxo-2-piperidine-1-yl methylene butyric acid ethyl ester and hydrogen fluoride, wherein the reaction formula is as follows:
step two, reacting the hydrogen fluoride and the trichloroethylene generated in the step one under the action of a fluorination catalyst to generate trifluoroethylene and hydrogen chloride, wherein the reaction formula is as follows:
step three, reacting trifluoroethylene generated in the step two with oxygen under the action of a complex catalyst to generate difluoroacetyl fluoride, wherein the reaction formula is as follows:
and the difluoroacetyl fluoride generated in the third step is recycled as a reactant in the first step.
2. The method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 1, wherein: the difluoroacetyl fluoride in the first step and the hydrogen fluoride in the second step are generated by the tetrafluoro ether through cracking reaction, and the reaction formula of the tetrafluoro ether through cracking reaction to generate difluoroacetyl fluoride, ethylene and hydrogen fluoride is as follows:
3. the method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 1, wherein: the fluorination catalyst is 1-fluoro-2-fluoromethylpiperidine.
4. The method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 1, wherein: the complex catalyst is a chromium complex with a structure shown as a formula I,
wherein the content of the first and second substances,
[ Cr ] is a chromium ion having 2-3 anions, the anion of the chromium ion is one or more of chloride ion, bromide ion, iodide ion, fluoride ion, trifluoromethanesulfonate ion, perchlorate ion and acetate ion,
R1is hydrogen atom, halogen atom, alkyl of C1-C8, cycloalkyl of C3-C8, cycloalkyl of C3-C8 with substituent, aryl with substituent, heteroaryl or heteroaryl with substituent,
R2and R3Each independently represents a hydrogen atom, a halogen atom, an alkyl group having from C1 to C8, a cycloalkyl group having from C3 to C8, a cycloalkyl group having from C3 to C8, an aryl group having a substituent, a heteroaryl group or a heteroaryl group having a substituent, or
R2And R3And the carbon atom to which they are bonded, form a C4-C8 cycloalkyl group, a substituted C4-C8 cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group,
R4、R5and R6Each independently represents a hydrogen atom, a halogen atom, an alkyl group having from C1 to C8, a cycloalkyl group having from C3 to C8, a cycloalkyl group having from C3 to C8, an aryl group having a substituent, a heteroaryl group or a heteroaryl group having a substituent, or
R6Is hydrogen atom, halogen atom, C1-C8 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, R is4And R5Together with the carbon atom to which they are bonded form a C4-C8 cycloalkyl, substituted C4-C8 cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl group, or
R4 is hydrogen atom, halogen atom, C1-C8 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, R5 and R6 together with the carbon atom to which they are bonded form C4-C8 cycloalkyl, substituted C4-C8 cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.
5. The method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 1, wherein: the molar ratio of the 1-fluoro-2-fluoromethylpiperidine to the 3- [ 1-piperidyl ] -ethyl acrylate is 1: 100-1: 2.
6. The method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 5, wherein: the molar ratio of the 1-fluoro-2-fluoromethylpiperidine to the 3- [ 1-piperidyl ] -ethyl acrylate is 1: 30-1: 10.
7. The method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 1, wherein: the reaction temperature of the first step and the second step is 0-25 ℃.
8. The method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 7, wherein: the reaction temperature of the first step and the second step is 0-5 ℃.
9. The method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 1, wherein: the molar ratio of the trichloroethylene to the 3- [ 1-piperidyl ] -ethyl acrylate is 5: 2-5: 1.
10. The method of synthesizing ethyl 4, 4-difluoro-3-oxo-2-piperidin-1-ylmethylenebutyrate according to claim 2, wherein: the molar ratio of the amount of the tetrafluoroethyl ether to the amount of the 3- [ 1-piperidyl ] -ethyl acrylate is 2: 5-4: 5.
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| CN102015653A (en) * | 2008-05-02 | 2011-04-13 | 巴斯夫欧洲公司 | Method for the production of halogen-substituted 2-(aminomethylidene)-3- oxobutyric acid esters |
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| CN102015653A (en) * | 2008-05-02 | 2011-04-13 | 巴斯夫欧洲公司 | Method for the production of halogen-substituted 2-(aminomethylidene)-3- oxobutyric acid esters |
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| BAKER, A. W.等: "Catalytic fluorination of trichloroethene by anhydrous hydrogen fluoride in the presence of fluorinated chromia under static conditions. Synthesis of [18F]-labeled CF3CH2F and [36Cl]-labeled CF3CH2Cl Catalytic dehydrofluorination of CF3CH2F and CF3CH2Cl", 《JOURNAL OF FLUORINE CHEMISTRY》 * |
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