CN110452198A - A kind of preparation method of Fei Luokao former times - Google Patents
A kind of preparation method of Fei Luokao former times Download PDFInfo
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- CN110452198A CN110452198A CN201910826761.5A CN201910826761A CN110452198A CN 110452198 A CN110452198 A CN 110452198A CN 201910826761 A CN201910826761 A CN 201910826761A CN 110452198 A CN110452198 A CN 110452198A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- 239000003960 organic solvent Substances 0.000 claims abstract description 57
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000032050 esterification Effects 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 150000007530 organic bases Chemical class 0.000 claims description 25
- 239000007788 liquid Substances 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- PHSPFUQAZNIVCH-UHFFFAOYSA-M [Mg].[I-].C[N+]1=CC=CC=C1 Chemical compound [Mg].[I-].C[N+]1=CC=CC=C1 PHSPFUQAZNIVCH-UHFFFAOYSA-M 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 239000003223 protective agent Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 238000007254 oxidation reaction Methods 0.000 claims description 13
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 12
- 230000001590 oxidative effect Effects 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 11
- 229940011051 isopropyl acetate Drugs 0.000 claims description 11
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 11
- 238000007069 methylation reaction Methods 0.000 claims description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims description 11
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- -1 tetramethyl ethylene diamin Chemical compound 0.000 claims description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- WGLLSSPDPJPLOR-UHFFFAOYSA-N tetramethylethylene Natural products CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- WPZFLQRLSGVIAA-UHFFFAOYSA-N sodium tungstate dihydrate Chemical compound O.O.[Na+].[Na+].[O-][W]([O-])(=O)=O WPZFLQRLSGVIAA-UHFFFAOYSA-N 0.000 claims description 4
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 150000002978 peroxides Chemical class 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 19
- 238000012360 testing method Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 7
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052794 bromium Inorganic materials 0.000 abstract description 5
- 230000001988 toxicity Effects 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 5
- VWKJBQQBGVSYSK-UHFFFAOYSA-N 2-cyclopropyl-2-ethoxyacetic acid Chemical compound CCOC(C(O)=O)C1CC1 VWKJBQQBGVSYSK-UHFFFAOYSA-N 0.000 abstract description 4
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 239000012071 phase Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000010792 warming Methods 0.000 description 9
- 238000012805 post-processing Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 235000019629 palatability Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- OQVYMXCRDHDTTH-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)-2-[4-(diethoxyphosphorylmethyl)pyridin-2-yl]pyridine Chemical compound CCOP(=O)(OCC)CC1=CC=NC(C=2N=CC=C(CP(=O)(OCC)OCC)C=2)=C1 OQVYMXCRDHDTTH-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- ODJZWVFLHZHURI-UHFFFAOYSA-M [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] Chemical compound [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] ODJZWVFLHZHURI-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000021168 barbecue Nutrition 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- RWGFKTVRMDUZSP-UHFFFAOYSA-N isopropyl-benzene Natural products CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- UYNRPXVNKVAGAN-UHFFFAOYSA-L magnesium;diiodate Chemical compound [Mg+2].[O-]I(=O)=O.[O-]I(=O)=O UYNRPXVNKVAGAN-UHFFFAOYSA-L 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to pharmaceutical technology fields, more particularly to a kind of preparation method of Fei Luokao former times, the preparation method avoids the raw material thioanisole using volatile stink weight, avoids using volatile, corrosivity is strong, the isobutyryl chloride of peculiar smell weight, environment-friendly advantage is obvious；There is the compound of structure shown in formula VI using hydroxylate preparation, it can be to avoid using the bromine that high volatility, toxicity are big, corrosivity is strong；Compound, acetoxy acetyl chloride, alkali and organic solvent with structure shown in formula V are mixed; it carries out esterification and obtains the compound with structure shown in formula VI; and then it avoids making technique be easier to popularize using the cyclopropyl ethoxyacetic acid of non-scale industrialization.Test result show using this method prepare Fei Luokao former times it is more green, environmentally friendly, be more suitable for industrialization promotion, be much better than the prior art.
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to a kind of preparation methods of Fei Luokao former times.
Background technique
Fei Luokao former times is the animal specific non-steroid anti-inflammatory drug of French Cimmeria company exploitation, for the analgesic, bone of performing the operation
The treatment of active chronic inflammation caused by arthritis and pain.The product has the characteristics that absorption is fast, takes orally 10 minutes and works, drug effect is held
Continue more than 24 hours；Product Safety is high, and 5 multiple doses are continuously taken 180 days and have no any adverse reaction；Product palatability is good,
It is sootiness barbecue taste tablet.Since the product has excellent therapeutic effect and palatability, there are extraordinary market prospects.
The International Patent Publication of the Patent No. WO9714691 synthetic method of Fei Luokao former times, is to be with thioanisole
Raw material reacts preparation Fei Luokao former times through F-C acylation, oxidation reaction, bromo-reaction and cyclopropyl ethoxyacetic acid, however the technique is used
To readily volatilized, stink thioanisole, the big isobutyryl chloride of corrosivity, toxicity is big, volatile, corrosivity is big bromine and not
The cyclopropyl ethoxyacetic acid (raw material is not easy to obtain) of large-scale production, whole process pollution is big, high to equipment and environmental requirement, uncomfortable
Close industrialized green production.
Summary of the invention
The purpose of the present invention is to provide the preparation method of Fei Luokao former times a kind of, the raw material used in the preparation method is equal
For common reagent in the market, abandoned the thioanisole of readily volatilized stink weight, it is volatile, corrosivity is big, peculiar smell weight it is different
Butyl chloride and big, volatile, corrosivity the is big bromine of toxicity；It is more suitable for industrialized production.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides the preparation methods of Fei Luokao former times a kind of, comprising the following steps:
4- methyl mercapto ethyl benzoylformate, oxidant and solvent are mixed, oxidation reaction is carried out, obtains with II institute of formula
Show the compound of structure；
The compound with structure shown in formula II, protective agent, p-methyl benzenesulfonic acid and the first organic solvent are mixed, into
The protection reaction of row ketone carbonyl, obtains the compound with structure shown in formula III；
The compound with structure shown in formula III, methylpyridinium iodide magnesium solution and the second organic solvent are mixed, carried out
Methylation reaction obtains the compound with structure shown in formula IV；
Reaction is hydrolyzed in the compound with structure shown in formula IV in acid solution, is obtained with knot shown in formula V
The compound of structure；
The compound with structure shown in formula V, acetoxy acetyl chloride, the first organic base and third is organic molten
Agent mixing, carries out esterification, obtains the compound with structure shown in formula VI；
The compound, the second organic base and the 4th organic solvent of structure shown in the formula VI are mixed, cyclization reaction is carried out,
Obtain the compound with structure shown in formula VII；
The compound with structure shown in formula VII, cyclopropyl bromomethane, highly basic, phase transfer catalyst and the 5th is organic
Solvent mixing, carries out substitution reaction, obtains Fei Luokao former times；The Fei Luokao former times has structure shown in formula I:
Preferably, the solvent includes water and organic solvent；
The organic solvent is isopropyl acetate, ethyl acetate or methylene chloride；
The oxidant is hydrogen peroxide, Disodium tungstate (Na2WO4) dihydrate, potassium permanganate or peroxide list potassium sulfonate.
Preferably, the molar ratio of the 4- methyl mercapto ethyl benzoylformate and oxidant is 1:(1~4).
Preferably, the temperature of the oxidation reaction is room temperature, and the time of the oxidation reaction is 24~72h.
Preferably, the protective agent is ethylene glycol, trimethyl orthoformate or dithioglycol；
The 4- methyl mercapto ethyl benzoylformate, protective agent, p-methyl benzenesulfonic acid molar ratio be 1:(2~12): (0.01
~0.5)；
The ketone carbonyl protection reaction carries out under conditions of being heated to reflux, and the temperature being heated to reflux is first organic
Boiling point ± 5 DEG C of solvent；
The time of the ketone carbonyl protection reaction is 5~10h.
Preferably, mole of the 4- methyl mercapto ethyl benzoylformate and the methylpyridinium iodide magnesium in methylpyridinium iodide magnesium solution
Than for 1:(2~10)；
The temperature of the methylation reaction is -40~30 DEG C, time of the methylation reaction is 5~for 24 hours.
Preferably, the acid solution is hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution, benzoic acid solution or trifluoroacetic acid solution；
The temperature of the hydrolysis is room temperature, and the time of the hydrolysis is 1~10h.
Preferably, first organic base be triethylamine, pyridine, 1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene or
Tetramethyl ethylene diamin(e)；
The molar ratio of the 4- methyl mercapto ethyl benzoylformate, acetoxy acetyl chloride and the first organic base be 1:(1~
3): (1~3)；
The temperature of the esterification is room temperature, and the time of the esterification is 1.5~9h.
Preferably, second organic base is pyridine, 1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene or tetramethyl
Ethylene diamin(e)；
The molar ratio of the compound with structure shown in formula VI and second organic base is 1:(1~4)；
The temperature of the cyclization reaction be the 4th organic solvent boiling temperature ± 5 DEG C, the cyclization reaction when
Between be 5~20h.
Preferably, the highly basic is potassium tert-butoxide, sodium hydride, sodium hydroxide or sodium methoxide；
The phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride or tri-n-octyl methyl ammonium chloride；
The molar ratio of the compound with structure shown in formula VII, highly basic and cyclopropyl bromomethane is 1:(1~8): (1~
8)；
The mass ratio of the compound and phase transfer catalyst with structure shown in formula VII is 100:(0.5~15)；
The temperature of the substitution reaction is 50~100 DEG C, and the time of the substitution reaction is 24~72h.
The present invention provides the preparation method of Fei Luokao former times a kind of, the preparation method, which avoids, uses volatile, stink
The raw material thioanisole of weight, avoids the isobutyryl chloride strong using volatile, corrosivity, environment-friendly advantage is obvious；Use hydroxylate
The compound with structure shown in formula VI is prepared, it can be to avoid using the bromine that high volatility, toxicity are big, corrosivity is strong；It will tool
There are compound, acetoxy acetyl chloride, the first organic base and the organic solvent mixing of structure shown in formula V, carries out esterification and obtain
To the compound with structure shown in formula VI, and then avoid making technique more using the cyclopropyl ethoxyacetic acid of non-scale, industrialization
It is easy to popularize.Test result show using this method prepare Fei Luokao former times it is more green, environmentally friendly, be more suitable for industrialization promotion,
It is much better than the prior art.
Specific embodiment
The present invention provides the preparation methods of Fei Luokao former times a kind of, comprising the following steps:
4- methyl mercapto ethyl benzoylformate, oxidant and solvent are mixed, oxidation reaction is carried out, obtains with II institute of formula
Show the compound of structure；
The compound with structure shown in formula II, protective agent, p-methyl benzenesulfonic acid and the first organic solvent are mixed, into
The protection reaction of row ketone carbonyl, obtains the compound with structure shown in formula III；
The compound with structure shown in formula III, methylpyridinium iodide magnesium solution and the second organic solvent are mixed, carried out
Methylation reaction obtains the compound with structure shown in formula IV；
Reaction is hydrolyzed in the compound with structure shown in formula IV in acid solution, is obtained with knot shown in formula V
The compound of structure；
The compound with structure shown in formula V, acetoxy acetyl chloride, the first organic base and third is organic molten
Agent mixing, carries out esterification, obtains the compound with structure shown in formula VI；
The compound, the second organic base and the 4th organic solvent of structure shown in the formula VI are mixed, cyclization reaction is carried out,
Obtain the compound with structure shown in formula VII；
The compound with structure shown in formula VII, cyclopropyl bromomethane, highly basic, phase transfer catalyst and the 5th is organic
Solvent mixing, carries out substitution reaction, obtains Fei Luokao former times；The Fei Luokao former times has structure shown in formula I:
In the present invention, if without specified otherwise, all raw material components are commercial product well known to those skilled in the art.
The present invention mixes 4- methyl mercapto ethyl benzoylformate, oxidant and solvent, carries out oxidation reaction, is had
The compound of structure shown in formula II；In the present invention, the oxidant is preferably hydrogen peroxide and Disodium tungstate (Na2WO4) dihydrate, potassium permanganate
Or peroxide list potassium sulfonate (OXONE)；The solvent includes water and organic solvent；The organic solvent be preferably isopropyl acetate,
Ethyl acetate or methylene chloride.
In the present invention, the molar ratio of the 4- methyl mercapto ethyl benzoylformate and oxidant is preferably 1:(1~4),
More preferably 1:(1.5~2.5)；The present invention does not have any special restriction to the dosage of the water and organic solvent, and guaranteeing will
Oxidant and 4- methyl mercapto ethyl benzoylformate dissolve while guaranteeing that oxidation reaction is gone on smoothly.
In the present invention, the mixing of the 4- methyl mercapto ethyl benzoylformate, oxidant and solvent is preferably first by 4-
Methyl mercapto ethyl benzoylformate and organic solvent are mixed to dissolution, sequentially add oxidant and water into gained mixture.
In the present invention, the temperature of the oxidation reaction is preferably room temperature, and the time of the oxidation reaction is preferably 24~
72h, more preferably 45~55h.
After the completion of oxidation reaction, the present invention preferably post-processes obtained product system, the preferred packet of post-processing
The split-phase successively carried out is included, organic phase and reduced vacuum concentration are retained.The present invention does not have the split-phase and reduced vacuum concentration
Any special requirement, using process well known to those skilled in the art.
In the present invention, procedure described above avoid thioanisole is used during constructing phenyl ring parent, ring is avoided
Peculiar smell problem rambunctious in border, blowdown.
After obtaining the compound with structure shown in formula II, the present invention by the compound with structure shown in formula II,
Protective agent, p-methyl benzenesulfonic acid and the mixing of the first organic solvent carry out ketone carbonyl protection reaction, obtain having structure shown in formula III
Compound；In the present invention, the protective agent is preferably ethylene glycol, trimethyl orthoformate or dithioglycol；The present invention is to described
The type of first organic solvent does not have any special restriction, using well known to those skilled in the art corresponding with protective agent
Common solvent, such as toluene or paraxylene.
In the present invention, the molar ratio of the 4- methyl mercapto ethyl benzoylformate, protective agent and p-methyl benzenesulfonic acid is preferred
For 1:(2~12): (0.01~0.5), more preferably 1:(8~12): (0.05~0.15)；The present invention is organic molten to described first
The dosage of agent does not have any special requirement, reaction can be protected to provide the liquid environment to react i.e. for the ketone carbonyl
It can.
In the present invention, the compound with structure shown in formula II, protective agent, p-methyl benzenesulfonic acid and first are organic molten
Compound, protective agent and p-methyl benzenesulfonic acid with structure shown in formula II are preferably mixed in the first organic solvent by the mixing of agent
In.
In the present invention, the ketone carbonyl protection reaction preferably carries out under conditions of being heated to reflux；It is described to be heated to reflux
Temperature be preferably the first organic solvent boiling point ± 5 DEG C；The time of the ketone carbonyl protection reaction is preferably 5~10h, more excellent
It is selected as 6~8h.
The water that reaction generates is removed using oil water separator in the ketone carbonyl protection reaction process.Reaction is completed
Afterwards, the present invention preferably post-processes obtained product system, and the post-processing is preferably cooled to room temperature, using alkalescent
Aqueous solution washing, water washing (weak alkaline aqueous solution, water volume with react the volume ratio preferably 0.5 with the first organic solvent~
10mL:1mL), it is dried, is filtered with anhydrous magnesium sulfate, be concentrated under reduced pressure into no liquid outflow.
After obtaining the compound with structure shown in formula III, the present invention by the compound with structure shown in formula III,
Methylpyridinium iodide magnesium solution (3M) and the mixing of the second organic solvent, carry out methylation reaction, obtain the change with structure shown in formula IV
Close object；In the present invention, second organic solvent is preferably ether, methyl tertiary butyl ether(MTBE), toluene or tetrahydrofuran；The first
The concentration of base iodate magnesium solution is preferably 3mol/L.
In the present invention, compound, methylpyridinium iodide magnesium solution and second organic solvent with structure shown in formula III
Mixing preferably first by with structure shown in formula III compound and the second organic solvent mix after, gained mixed liquor is added dropwise
Into -40~30 DEG C of methylpyridinium iodide magnesium solution；The present invention does not have any special restriction to the mode of the dropwise addition, using this
Dropwise addition mode known to the technical staff of field is added dropwise.In the present invention, the hybrid mode helps to promote product
Yield, reduce the generation of by-product.
In the present invention, the 4- methyl mercapto ethyl benzoylformate and the methylpyridinium iodide magnesium in methylpyridinium iodide magnesium solution
Molar ratio is preferably 1:(2~10), more preferably 1:(3~4)；The 4- methyl mercapto ethyl benzoylformate has with described second
The amount ratio of solvent is preferably 1g:(3~20) mL, more preferably 1g:(4~5) mL.
In the present invention, the temperature of the methylation reaction is preferably -40~30 DEG C, more preferably 0~10 DEG C；The first
The time of glycosylation reaction is preferably 5~for 24 hours, more preferably 7.5~12.5h.In the present invention, the methylation reaction includes two
A stage；Described two stages are that the stage of methylpyridinium iodide magnesium is added dropwise and continues the stage of reaction after being added dropwise to complete；Described two ranks
The sum of time of section is the time of methylation reaction；The time in the stage that methylpyridinium iodide magnesium is added dropwise is preferably 1~4h, more excellent
It is selected as 1.5~2.5h；It is described be added dropwise to complete after continue the stage of reaction time be preferably 4~20h, more preferably 6~10h.
After the completion of methylation reaction, the present invention preferably post-processes obtained product system, and the post-processing is preferred
For be added dropwise into reaction system saturated common salt aqueous solution (volume ratio preferably 1 of saturated common salt water volume and the second organic solvent~
10mL:1mL), extracted using methylene chloride (methylene chloride volume and the volume ratio of the second organic solvent be preferably 1~
10mL:1mL；Extraction times preferably 1~3 time), distillation removal solvent.
After obtaining the compound with structure shown in formula IV, the present invention exists the compound with structure shown in formula IV
Reaction is hydrolyzed in acid solution, obtains the compound with structure shown in formula V；In the present invention, the acid solution is preferably hydrochloric acid
Solution, sulfuric acid solution, phosphoric acid solution, benzoic acid solution or trifluoroacetic acid solution, more preferably hydrochloric acid solution；When the acid solution is
When hydrochloric acid solution, in the hydrochloric acid solution molar ratio of HCl and the 4- methyl mercapto ethyl benzoylformate be preferably 1:(1~
10), more preferably 1:(4~6)；When the acid solution is other situations, dosage guarantees protective agent complete hydrolysis.
In the present invention, the detailed process of the hydrolysis is preferred are as follows: under stirring conditions, to shown in formula IV
Acid solution is added in the solution of the compound of structure, continues stirring to hydrolysis and completes.In the present invention, described that there is IV institute of formula
The solvent for showing the solution of the compound of structure is preferably methylene chloride, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether(MTBE), more
Preferably methylene chloride；The mass ratio of the organic solvent and the 4- methyl mercapto ethyl benzoylformate is preferably (3~20)
ML:1g, more preferably (3~6) mL:1g.
In the present invention, the temperature of the hydrolysis is preferably room temperature；The time of the hydrolysis is preferably 1~
10h, more preferably 4~6h.
After the completion of hydrolysis, the present invention preferably post-processes obtained product system, and the post-processing is preferably
Products therefrom system is subjected to split-phase, retain organic phase and is concentrated under reduced pressure into no liquid outflow.
After obtaining the compound with structure shown in formula V, the present invention by the compound with structure shown in formula V,
Acetoxy acetyl chloride, the first organic base and the mixing of third organic solvent, carry out esterification, obtain with structure shown in formula VI
Compound.In the present invention, first organic base is preferably triethylamine, pyridine, 1,8- diazabicyclo [5.4.0] 11
Carbon -7- alkene (DBU) or tetramethyl ethylene diamin(e), more preferably triethylamine；The third organic solvent is preferably methylene chloride, second
Acetoacetic ester, isopropyl acetate or methyl acetate, more preferably methylene chloride.
In the present invention, the compound with structure shown in formula V, acetoxy acetyl chloride, the first organic base and the
The mixing of three organic solvents preferably first mixes the compound with structure shown in formula V with third organic solvent to all molten
Xie Hou sequentially adds the first organic base and acetoxy acetyl chloride into gained mixture；The present invention is to first organic base
Adding manner there is no any special restriction, using adding manner well known to those skilled in the art；In the present invention,
The adding manner of the acetoxy acetyl chloride is preferably added dropwise, and the time of the dropwise addition is preferably 0.5~3h, and more preferably 1
~1.5h.
In the present invention, the amount ratio of the 4- methyl mercapto ethyl benzoylformate and the third organic solvent is preferably
1g:(3~10) mL, more preferably 1g:(3~4) mL；The 4- methyl mercapto ethyl benzoylformate and acetoxy acetyl chloride
Molar ratio is preferably 1:(0.5~3), more preferably 1:(0.8~1.2)；The acetoxy acetyl chloride and described first organic
The molar ratio of alkali is preferably 1:(1~3), more preferably 1:(0.8~1.2).
In the present invention, the temperature of the esterification is preferably room temperature, and the time of the esterification is preferably 1.5~
9h, more preferably 3.5~5h；The esterification is preferably divided into two stages, and described two stages include that acetoxyl group is added dropwise
The stage of chloroacetic chloride and the reaction was continued stage；The temporal summation in described two stages is the time of the esterification；It is described after
The time of continuous reaction is preferably 1~6h, more preferably 2.5~3.5h.
After the completion of the esterification, the present invention preferably post-processes obtained product system；The post-processing is preferred are as follows:
In the product system plus water (volume ratio of the water and the third organic solvent is preferably 1~4:1, more preferably 1~
0.5h is stood after 1.5:1) stirring 10min；Split-phase simultaneously retains organic phase, is concentrated under reduced pressure into no liquid outflow, ethyl acetate is added
(ethyl acetate can be substituted using methyl tertiary butyl ether(MTBE), methyl acetate), (temperature of heating is preferably ethyl acetate for heating
Or boiling temperature ± 5 DEG C of its substitute) after be cooled to 0~40 DEG C overnight, filtering (filtration temperature is preferably 5~25 DEG C, more excellent
It is selected as 10~15 DEG C) and it is dry；In the present invention, the drying is preferably dried in vacuo, and the vacuum drying temperature is preferred
It is 40~80 DEG C, more preferably 50~55 DEG C, the vacuum drying vacuum degree is preferably -0.08~0.1MPa.
After obtaining the compound with structure shown in formula VI, the present invention is by the compound of structure shown in the formula VI, second
Organic base and the mixing of the 4th organic solvent, carry out cyclization reaction, obtain the compound with structure shown in formula VII；In the present invention
In, second organic base is preferably pyridine, DBU or tetramethyl ethylene diamin(e)；4th organic solvent is preferably acetonitrile, second
Acetoacetic ester, isopropyl acetate, benzene or toluene.
In the present invention, the compound with structure shown in formula VI, the second organic base and the 4th organic solvent is mixed
Close preferably first by with structure shown in formula VI compound and the 4th organic solvent mix to after being completely dissolved, being added second has
Machine alkali.
In the present invention, the molar ratio of the compound and second organic base with structure shown in formula VI is preferably
1:(1~4), more preferably 1:(1~2)；The use of the compound with structure shown in formula VI and the 4th organic solvent
Amount is than being preferably 1g:(3~10) mL, more preferably 1g:(4~5) mL.
In the present invention, the temperature of the cyclization reaction is preferably boiling temperature ± 5 DEG C of the 4th organic solvent, institute
The time for stating cyclization reaction is preferably 5~20h, more preferably 10~14h.
After the completion of cyclization reaction, the present invention preferably post-processes obtained product system；The post-processing is preferably
Product system is down to room temperature, (55~60 DEG C, -0.08~0.1MPa) to no liquid is concentrated under reduced pressure and flows out, ethyl acetate is added
(ethyl acetate can be substituted using methyl tertiary butyl ether(MTBE), methyl acetate；It is preferred using solvent volume and compound VI ratio
For 4~5mL:1g), it is cooled to after heating (temperature of heating is preferably ethyl acetate or boiling temperature ± 5 DEG C of its substitute)
Ambient temperature overnight filters (filtration temperature is preferably 5~25 DEG C, more preferably 0~10 DEG C) and dry；In the present invention, described dry
Dry to be preferably dried in vacuo, the vacuum drying temperature is preferably 40~80 DEG C, and more preferably 50~55 DEG C, the vacuum is dry
Dry vacuum degree is preferably -0.08~0.1MPa.
After obtaining the compound with structure shown in formula VII, the present invention by the compound with structure shown in formula VII,
Cyclopropyl bromomethane, highly basic, phase transfer catalyst and the mixing of the 5th organic solvent, carry out substitution reaction, obtain Fei Luokao former times；At this
In invention, the highly basic is preferably potassium tert-butoxide, sodium hydride, sodium hydroxide or sodium methoxide, more preferably sodium hydroxide；The phase
Transfer catalyst is preferably tetrabutylammonium bromide or tetrabutylammonium chloride, more preferably tetrabutylammonium bromide；Described 5th is organic
Solvent is preferably isopropyl acetate, toluene, chlorobenzene or paraxylene, more preferably toluene.
In the present invention, compound, cyclopropyl bromomethane, the highly basic, phase transfer catalyst with structure shown in formula VII
With the 5th organic solvent mixing preferably by with structure shown in formula VII compound and the 5th organic solvent mix to
After being completely dissolved, tetrabutylammonium bromide, sodium hydroxide and Cyclopropylmetyl bromide are sequentially added into gained mixture.
In the present invention, the molar ratio of the compound with structure shown in formula VII, highly basic and cyclopropyl bromomethane is preferred
For 1:(1~8): (1~8), more preferably 1:(1.5~2.5): (1.5~2.5)；The chemical combination with structure shown in formula VII
The mass ratio of object and phase transfer catalyst is preferably 100:(0.5~15), more preferably 100:(3~7)；It is described that there is VII institute of formula
The amount ratio of the compound and the 5th organic solvent that show structure is preferably 1g:(2~10) mL, more preferably 1g:(4~6) mL.
In the present invention, the temperature of the substitution reaction is preferably 50~100 DEG C, and more preferably 75~80 DEG C；It is described to take
The time of reaction in generation is preferably 24~72h, more preferably 40~55h.
After the completion of substitution reaction, the present invention preferably post-processes obtained product system, and the post-processing is preferably
The product system is cooled to room temperature, adds water (volume and the 5th organic solvent volume are than preferred 1mL:0.5~5mL), stands
0.5h split-phase is concentrated under reduced pressure (55~60 DEG C, -0.08~0.1MPa) to no liquid and flows out, and methanol is added, and (methanol can be adopted
Substituted with methyl tertiary butyl ether(MTBE), ethyl alcohol, methyl acetate or ethyl acetate), (temperature of heating is preferably methanol or its substitution for heating
Boiling temperature ± 5 DEG C of object) after be cooled to ambient temperature overnight, (filtration temperature is preferably 5~25 DEG C, more preferably 0~10 for filtering
DEG C) and it is dry；In the present invention, the drying is preferably dried in vacuo, and the vacuum drying temperature is preferably 40~80 DEG C,
More preferably 50~55 DEG C, the vacuum drying vacuum degree is preferably -0.08~0.1MPa.
It is described in detail below with reference to preparation method of the embodiment to Fei Luokao former times of the present invention, but cannot be them
It is interpreted as limiting the scope of the present invention.
Embodiment 1
By 4- methyl mercapto ethyl benzoylformate (224g；It 1mol) mixes with 1L isopropyl acetate to being completely dissolved, is added
OXONE (1200g), water (5L) react at room temperature 48h.Split-phase after completion of the reaction, retains organic phase, and reduced vacuum is concentrated into aneroid
Body flows out to obtain the compound with structure shown in formula II；
By in compound, ethylene glycol (620g), p-methyl benzenesulfonic acid (15g) and toluene (1L) with structure shown in formula II,
It is heated to reflux 6h (temperature being heated to reflux is 110 DEG C), is removed water using oil water separator.It is cooled to room after completion of the reaction
Temperature is washed twice using saturated sodium bicarbonate 500mL, washed once using water 500mL, dry using anhydrous magnesium sulfate 50g, mistake
Filter is concentrated under reduced pressure into no liquid outflow, obtains the compound with structure shown in formula III；
By with structure shown in formula III compound and 1L tetrahydrofuran mix to after being completely dissolved, be added to methylpyridinium iodide
Magnesium diethyl ether solution 1L (concentration 3mol/L, 5 DEG C), about 2h is added dropwise.It is to slowly warm up to room temperature, the reaction was continued 8h, Xiang Fanying
Saturated common salt aqueous solution 4L is slowly added dropwise in system, system is obtained using methylene chloride 2L*3 times extraction with knot shown in formula IV
The compound of structure；
Compound with structure shown in formula IV is mixed with methylene chloride (1L) to after being completely dissolved, under agitation
It is added hydrochloric acid solution (concentration 1mol/L, dosage 5L), system continues to stir 3h, and split-phase retains organic phase, is concentrated under reduced pressure into
No liquid outflow, obtains the compound with structure shown in formula V；
By with structure shown in formula V compound and methylene chloride (800mL) mix to being completely dissolved, triethylamine is added
Acetoxy acetyl chloride (137g) is added dropwise at room temperature in (100g), used time about 1h, the 3h that is added dropwise that the reaction was continued.After completion of the reaction,
800mL water is added in system, stands 0.5h after stirring 10min, and split-phase retains organic phase, is concentrated under reduced pressure into no liquid outflow, system
Ethyl acetate 500mL is added, starts that gray solid powder is obtained by filtration after being cooled to 10 DEG C after being warming up to 80 DEG C, in temperature 55
DEG C, it is dried in vacuo under conditions of vacuum degree -0.1MPa, obtains the compound (220g) with structure shown in formula VI.
1000mL acetonitrile is added in the compound with structure shown in formula VI, DBU (146g) is heated to reflux 12h, cools down
To room temperature, (60 DEG C, vacuum degree -0.1MPa) to no liquid is concentrated under reduced pressure and flows out.Ethyl acetate 500mL is added in system, is warming up to
Start cooling after 80 DEG C overnight, white solid powder is obtained by filtration after being cooled to room temperature, at 55 DEG C of temperature, vacuum degree -0.1MPa
Under conditions of be dried in vacuo, obtain the compound (85g) with structure shown in formula VII.
By with structure shown in formula VII compound and 500mL toluene mix to after being completely dissolved, be added tetrabutyl phosphonium bromide
Ammonium (8g), sodium hydroxide (12g) and Cyclopropylmetyl bromide (80g) are heated to 75-80 DEG C of reaction 48h.It is cooled to after completion of the reaction
600mL water is added in room temperature, stands split-phase after 0.5h, and (60 DEG C, vacuum degree -0.1MPa) to no liquid is concentrated under reduced pressure and flows out.System
Methanol is added, is warming up to 65 DEG C, the used time, about 5h was cooled to room temperature, white solid powder is obtained by filtration, at 55 DEG C of temperature, vacuum
It is dried in vacuo under conditions of degree -0.1MPa, obtains Fei Luokao former times about 48g, 99% or more product purity.
Nuclear-magnetism test, test result are carried out to the compound with structure shown in formula I are as follows: 1HNMR (600MHz,
CDCl3) δ 8.03 (d, J=8.4Hz, 2H), 7.90 (d, J=8.4Hz, 2H), 4.24 (d, J=7.2Hz, 2H), 3.11 (s,
3H), 1.67 (s, 6H), 1.16-1.17 (t, J=6Hz, 1H), 0.59 (d, J=6Hz, 2H), 0.31 (s, 2H)；
13C NMR(CDCl3)δ3.2(2C),δ10.8,δ26.7(2C),δ44.4,δ76.0,δ83.3,δ127.7(2C),δ
129.0(2C),δ135.8,δ140.2,δ141.3,δ166.6。
Embodiment 2
By 4- methyl mercapto ethyl benzoylformate (224g；It 1mol) mixes with 1L isopropyl acetate to being completely dissolved, is added
The hydrogen peroxide (200mL) and Disodium tungstate (Na2WO4) dihydrate (10g), water (5L) that mass concentration is 30%, react at room temperature 48h.End of reaction
Split-phase afterwards, retains organic phase, and reduced vacuum is concentrated into no liquid and flows out to obtain the compound with structure shown in formula II；
By compound, trimethyl orthoformate (1000g), p-methyl benzenesulfonic acid (20g) and methanol with structure shown in formula II
In (2L), it is heated to reflux 6h (temperature being heated to reflux is 65 DEG C), is removed water using oil water separator.Cool down after completion of the reaction
It to room temperature, is added methyl tertiary butyl ether(MTBE) (10L), is washed twice using saturated sodium bicarbonate 500mL, use water 500mL washing one
It is secondary, it is dried, filtered using anhydrous magnesium sulfate 50g, is concentrated under reduced pressure into no liquid outflow, obtains the chemical combination with structure shown in formula III
Object；
By with structure shown in formula III compound and 1L tetrahydrofuran mix to after being completely dissolved, be added to methylpyridinium iodide
Magnesium diethyl ether solution 1L (concentration 3mol/L, 5 DEG C), about 2h is added dropwise.The reaction was continued 8h, is slowly added dropwise full into reaction system
With common salt aqueous solution 4L, system obtains the compound with structure shown in formula IV using methylene chloride 2L*3 times extraction；
Compound with structure shown in formula IV is mixed with methylene chloride (1L) to after being completely dissolved, under agitation
It is added hydrochloric acid solution (concentration 1mol/L, dosage 5L), system continues to stir 4h, and split-phase retains organic phase, is concentrated under reduced pressure into
No liquid outflow, obtains the compound with structure shown in formula V；
By with structure shown in formula V compound and ethyl acetate (800mL) mix to being completely dissolved, pyridine is added
Acetoxy acetyl chloride (137g) is added dropwise at room temperature in (79g), used time about 1h, the 3h that is added dropwise that the reaction was continued.After completion of the reaction,
800mL water is added in system, stands 0.5h after stirring 10min, and split-phase retains organic phase, is concentrated under reduced pressure into no liquid outflow, system
Ethyl acetate 500mL is added, starts that gray solid powder is obtained by filtration after being cooled to 10 DEG C after being warming up to 55 DEG C, in temperature 55
DEG C, it is dried in vacuo under conditions of vacuum degree -0.1MPa, obtains the compound (210g) with structure shown in formula VI.
1000mL toluene is added in the compound with structure shown in formula VI, DBU (146g) is heated to reflux 12h, cools down
To room temperature, (60 DEG C, vacuum degree -0.1MPa) to no liquid is concentrated under reduced pressure and flows out.Ethyl acetate 500mL is added in system, is warming up to
Start cooling after 75 DEG C overnight, white solid powder is obtained by filtration after being cooled to room temperature, at 55 DEG C of temperature, vacuum degree -0.1MPa
Under conditions of be dried in vacuo, obtain the compound (81g) with structure shown in formula VII.
By with structure shown in formula VII compound and 450mL paraxylene mix to after being completely dissolved, be added the tetrabutyl
Ammonium bromide (10g), potassium tert-butoxide (70g) and Cyclopropylmetyl bromide (83g) are heated to 75-80 DEG C of reaction 48h.After completion of the reaction
It is cooled to room temperature, 600mL water is added, stands split-phase after 0.5h, (60 DEG C, vacuum degree -0.1MPa) are concentrated under reduced pressure to no liquid stream
Out.Methanol is added in system, is warming up to 65 DEG C, the used time, about 5h was cooled to room temperature, white solid powder was obtained by filtration, in temperature 55
DEG C, it is dried in vacuo under conditions of vacuum degree -0.1MPa, obtains Fei Luokao former times about 43g, 99% or more product purity.
Nuclear-magnetism test is carried out to the product that the present embodiment obtains, test result and embodiment 1 are almost the same.
Embodiment 3
By 4- methyl mercapto ethyl benzoylformate (224g；It 1mol) mixes with 1L methylene chloride to being completely dissolved, is added high
Potassium manganate (300g), water (5L) react at room temperature 48h.Split-phase after completion of the reaction, retains organic phase, and reduced vacuum is concentrated into aneroid
Body flows out to obtain the compound with structure shown in formula II；
By in compound, ethylene glycol (600g), p-methyl benzenesulfonic acid (15g) and toluene (1L) with structure shown in formula II,
It is heated to reflux 6h (temperature being heated to reflux is 110 DEG C), is removed water using oil water separator.It is cooled to room after completion of the reaction
Temperature is washed twice using saturated sodium bicarbonate 1000mL, washed once using water 500mL, dry using anhydrous magnesium sulfate 50g,
Filtering is concentrated under reduced pressure into no liquid outflow, obtains the compound with structure shown in formula III；
By with structure shown in formula III compound and 1L ether mix to after being completely dissolved, be added to methylpyridinium iodide magnesium second
Ethereal solution 1.3L (concentration 3mol/L, 5 DEG C), about 2h is added dropwise.Temperature the reaction was continued 8h is controlled, slowly into reaction system
Saturated common salt aqueous solution 4L is added dropwise, system obtains the compound with structure shown in formula IV using methylene chloride 2L*3 times extraction；
Compound with structure shown in formula IV is mixed with ethyl acetate (1L) to after being completely dissolved, under agitation
It is added hydrochloric acid solution (concentration 1mol/L, dosage 5L), system continues to stir 3h, and split-phase retains organic phase, is concentrated under reduced pressure into
No liquid outflow, obtains the compound with structure shown in formula V；
By with structure shown in formula V compound and isopropyl acetate (800mL) mix to being completely dissolved, DBU is added
Acetoxy acetyl chloride (137g) is added dropwise at room temperature in (152g), used time about 1h, the 3h that is added dropwise that the reaction was continued.After completion of the reaction,
800mL water is added in system, stands 0.5h after stirring 10min, and split-phase retains organic phase, is concentrated under reduced pressure into no liquid outflow, system
Ethyl acetate 500mL is added, starts that gray solid powder is obtained by filtration after being cooled to 10 DEG C after being warming up to 80 DEG C, in temperature 55
DEG C, it is dried in vacuo under conditions of vacuum degree -0.1MPa, obtains the compound (190g) with structure shown in formula VI.
800mL ethyl acetate is added in the compound with structure shown in formula VI, tetramethyl ethylene diamin(e) (150g) adds
Heat reflux 12h, is cooled to room temperature, and (60 DEG C, vacuum degree -0.1MPa) to no liquid is concentrated under reduced pressure and flows out.Acetic acid second is added in system
Ester 500mL starts cooling overnight, white solid powder is obtained by filtration after being cooled to room temperature after being warming up to 75 DEG C, at 55 DEG C of temperature,
It is dried in vacuo under conditions of vacuum degree -0.1MPa, obtains the compound (72g) with structure shown in formula VII.
By with structure shown in formula VII compound and 350mL isopropyl acetate mix to after being completely dissolved, be added four fourths
Base ammonium bromide (8g), sodium methoxide (12g) and Cyclopropylmetyl bromide (80g) are heated to 75-80 DEG C of reaction 48h.It drops after completion of the reaction
It warms to room temperature, 600mL water is added, stand split-phase after 0.5h, (60 DEG C, vacuum degree -0.1MPa) to no liquid is concentrated under reduced pressure and flows out.
Methanol is added in system, is warming up to 65 DEG C, the used time, about 5h was cooled to room temperature, white solid powder was obtained by filtration, at 55 DEG C of temperature, very
It is dried in vacuo under conditions of reciprocal of duty cycle -0.1MPa, obtains Fei Luokao former times about 39g, 99% or more product purity.
Nuclear-magnetism test is carried out to the product that the present embodiment obtains, test result and embodiment 1 are almost the same.
As seen from the above embodiment, the present invention provides the preparation method of Fei Luokao former times a kind of, the preparation method is avoided
Using the raw material thioanisole of volatile stink weight, the isobutyryl chloride strong using volatile, corrosivity, environment-friendly advantage are avoided
Obviously；There is the compound of structure shown in formula VI using hydroxylate preparation, it can be to avoid using high volatility, toxicity big, rotten
The strong bromine of corrosion；Compound, acetoxy acetyl chloride, the first organic base and organic solvent with structure shown in formula V are mixed
It closes, carries out esterification and obtain the compound with structure shown in formula VI, and then avoid the cyclopropyl using non-scale industrialization
Ethoxyacetic acid makes technique be easier to popularize.Test result show using this method prepare Fei Luokao former times it is more green, environmentally friendly,
It is more suitable for industrialization promotion, is much better than the prior art.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Fei Luokao former times, which comprises the following steps:
4- methyl mercapto ethyl benzoylformate, oxidant and solvent are mixed, oxidation reaction is carried out, is obtained with knot shown in formula II
The compound of structure；
The compound with structure shown in formula II, protective agent, p-methyl benzenesulfonic acid and the first organic solvent are mixed, ketone is carried out
Carbonyl-protection reaction, obtains the compound with structure shown in formula III；
The compound with structure shown in formula III, methylpyridinium iodide magnesium solution and the second organic solvent are mixed, methyl is carried out
Change reaction, obtains the compound with structure shown in formula IV；
Reaction is hydrolyzed in the compound with structure shown in formula IV in acid solution, obtains that there is structure shown in formula V
Compound；
Compound, acetoxy acetyl chloride, the first organic base and the third organic solvent with structure shown in formula V is mixed
It closes, carries out esterification, obtain the compound with structure shown in formula VI；
The compound, the second organic base and the 4th organic solvent of structure shown in the formula VI are mixed, cyclization reaction is carried out, obtains
Compound with structure shown in formula VII；
By compound, cyclopropyl bromomethane, highly basic, phase transfer catalyst and the 5th organic solvent with structure shown in formula VII
Mixing carries out substitution reaction, obtains Fei Luokao former times；The Fei Luokao former times has structure shown in formula I:
2. preparation method as described in claim 1, which is characterized in that the solvent includes water and organic solvent；
The organic solvent is isopropyl acetate, ethyl acetate or methylene chloride；
The oxidant is hydrogen peroxide, Disodium tungstate (Na2WO4) dihydrate, potassium permanganate or peroxide list potassium sulfonate.
3. preparation method as claimed in claim 1 or 2, which is characterized in that the 4- methyl mercapto ethyl benzoylformate and oxygen
The molar ratio of agent is 1:(1~4).
4. preparation method as described in claim 1, which is characterized in that the temperature of the oxidation reaction is room temperature, the oxidation
The time of reaction is 24~72h.
5. preparation method as described in claim 1, which is characterized in that the protective agent be ethylene glycol, trimethyl orthoformate or
Dithioglycol；
The 4- methyl mercapto ethyl benzoylformate, protective agent, p-methyl benzenesulfonic acid molar ratio be 1:(2~12): (0.01~
0.5)；
The ketone carbonyl protection reaction carries out under conditions of being heated to reflux, and the temperature being heated to reflux is the first organic solvent
Boiling point ± 5 DEG C；
The time of the ketone carbonyl protection reaction is 5~10h.
6. preparation method as described in claim 1, which is characterized in that the 4- methyl mercapto ethyl benzoylformate and methyl iodide
The molar ratio for changing the methylpyridinium iodide magnesium in magnesium solution is 1:(2~10)；
The temperature of the methylation reaction is -40~30 DEG C, time of the methylation reaction is 5~for 24 hours.
7. preparation method as described in claim 1, which is characterized in that the acid solution is that hydrochloric acid solution, sulfuric acid solution, phosphoric acid are molten
Liquid, benzoic acid solution or trifluoroacetic acid solution；
The temperature of the hydrolysis is room temperature, and the time of the hydrolysis is 1~10h.
8. preparation method as described in claim 1, which is characterized in that first organic base is triethylamine, pyridine, 1,8- bis-
11 carbon -7- alkene of azabicyclo [5.4.0] or tetramethyl ethylene diamin(e)；
The molar ratio of the 4- methyl mercapto ethyl benzoylformate, acetoxy acetyl chloride and the first organic base is 1:(1~3):
(1~3)；
The temperature of the esterification is room temperature, and the time of the esterification is 1.5~9h.
9. preparation method as described in claim 1, which is characterized in that second organic base is pyridine, 1,8- diaza pair
11 carbon -7- alkene of ring [5.4.0] or tetramethyl ethylene diamin(e)；
The molar ratio of the compound with structure shown in formula VI and second organic base is 1:(1~4)；
The temperature of the cyclization reaction is boiling temperature ± 5 DEG C of the 4th organic solvent, and the time of the cyclization reaction is 5
~20h.
10. preparation method as described in claim 1, which is characterized in that the highly basic is potassium tert-butoxide, sodium hydride, hydroxide
Sodium or sodium methoxide；
The phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride or tri-n-octyl methyl ammonium chloride；
The molar ratio of the compound with structure shown in formula VII, highly basic and cyclopropyl bromomethane is 1:(1~8): (1~8)；
The mass ratio of the compound and phase transfer catalyst with structure shown in formula VII is 100:(0.5~15)；
The temperature of the substitution reaction is 50~100 DEG C, and the time of the substitution reaction is 24~72h.
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