CN106748921A - A kind of fragrant sulfuryl difluoroacetic acid salt compounds, preparation method and applications - Google Patents
A kind of fragrant sulfuryl difluoroacetic acid salt compounds, preparation method and applications Download PDFInfo
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- CN106748921A CN106748921A CN201611166969.1A CN201611166969A CN106748921A CN 106748921 A CN106748921 A CN 106748921A CN 201611166969 A CN201611166969 A CN 201611166969A CN 106748921 A CN106748921 A CN 106748921A
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- Prior art keywords
- phenyl
- sulfuryl
- acid salt
- salt compounds
- difluoroacetic acid
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- -1 sulfuryl difluoroacetic acid salt compounds Chemical class 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000006467 substitution reaction Methods 0.000 claims abstract description 21
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 11
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 4
- 239000002585 base Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N phenyl mercaptan Natural products SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 229940117975 chromium trioxide Drugs 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical class OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000003739 neck Anatomy 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- DSCJETUEDFKYGN-UHFFFAOYSA-N 2-Methoxybenzenethiol Chemical compound COC1=CC=CC=C1S DSCJETUEDFKYGN-UHFFFAOYSA-N 0.000 description 2
- WJTZZPVVTSDNJJ-UHFFFAOYSA-N 2-fluorobenzenethiol Chemical compound FC1=CC=CC=C1S WJTZZPVVTSDNJJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 0 C*1C(CC2C*CC2)CC1 Chemical compound C*1C(CC2C*CC2)CC1 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- AHIBWURJLGCHAY-UHFFFAOYSA-N [S].C1=CC=CC=C1 Chemical compound [S].C1=CC=CC=C1 AHIBWURJLGCHAY-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical class O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- INYGCQMOMATNOD-UHFFFAOYSA-N BrCC(=O)O.[F] Chemical compound BrCC(=O)O.[F] INYGCQMOMATNOD-UHFFFAOYSA-N 0.000 description 1
- OJXBNAJFKBPXOG-UHFFFAOYSA-N CCOC(N(C)NC(C=CC1)=CC=C1O)=O Chemical compound CCOC(N(C)NC(C=CC1)=CC=C1O)=O OJXBNAJFKBPXOG-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XBAQRWCLOYSSTH-UHFFFAOYSA-N S(=O)(=O)=C(F)F.C1=CC=CC=C1 Chemical compound S(=O)(=O)=C(F)F.C1=CC=CC=C1 XBAQRWCLOYSSTH-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CPZZKNJKGDORHK-UHFFFAOYSA-N [K].OC(=O)C(F)F Chemical compound [K].OC(=O)C(F)F CPZZKNJKGDORHK-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- CDEYVOCQCMNRRX-UHFFFAOYSA-N difluoromethyl diethoxy phosphate Chemical compound P(=O)(OC(F)F)(OOCC)OOCC CDEYVOCQCMNRRX-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of fragrant sulfuryl difluoroacetic acid salt compounds, preparation method and applications.Fragrant sulfuryl difluoroacetic acid salt compounds of the invention react at room temperature with aldehyde, can obtain the α difluoromethyl alcohol compounds of fragrant sulfuryl substitution.The beneficial effects of the present invention are：When preparing the α difluoromethyl alcohol compounds that fragrant sulfuryl replaces using fragrant sulfuryl difluoroacetic acid salt compounds, reaction condition is gentle, and product yield high, side reaction is few, and universality is high.
Description
Technical field
The present invention relates to a kind of fragrant sulfuryl difluoroacetic acid salt compounds, preparation method and applications, belong to organic synthesis
Technical field.
Background technology
Due to the unique physicochemical property of fluorine atom, can significantly change after introducing fluorine atom or fluoro-containing group to intramolecular
The physiologically active of original molecule.At present in about 30% new drug molecule and the pesticide molecule of 30-40% all containing fluorine atom or
Fluorine-containing functional group.Difluoromethyl (CF2H) there is strong electrophilic inductive effect and methylol (CH2OH) there is isopolarity and body is waited
Property, while still lipophilic hydrogen bond donor, this cause difluoromethyl compound design in life science, pharmacy and Pesticide Science and
Had great significance in material development.During alpha-difluoromethyl alcohol construction unit is universally present in multiple biological activities molecule,
It is also simultaneously the synthesis precursors of many medicine and agricultural chemicals, therefore becomes industrial production to the high-efficiency synthesis method of this quasi-molecule
One important current demand.([1]E.P.Gillis,K.J.Eastman,M.D.Hill,D.J.Donnelly and
N.A.Meanwell J.Med.Chem.2015,58,8315.[2]P.Kirsch,Modern fluoroorganic
chemistry:Synthesis,reactivity,applications,Wiely-VCH,Weinheim,2013.[3]
J.A.Erickson and J.I.McLoughlin J.Org.Chem.1995,60,1626.)
It is to synthesize the most succinct method of such compound that alpha-difluoromethyl alcohol compound is directly prepared by carbonyls,
The main method of development has at present：
1. the difluoromethane of mono-/bis-silylation substitution reacts with the nucleophilic difluoromethylization of carbonyls.([1]
T.Hagiwara and T.Fuchikami Synlett 1995,717.[2]A.K.Yudin,G.K.S.Prakash,
D.Deffieux,M.Bradeyl,R.Bau and G.A.Olah J.Am.Chem.Soc.1997,119,1572.)
2. benzene sulfuryl difluoromethane reacts with carbonyls under strongly alkaline conditions, then removes benzene sulphur under the reducing conditions
Acyl group, formation-difluoromethyl alcohol.([1]G.K.S.Prakash and J.Hu Acc.Chem.Res.2007,40,921.[2]
J.Hu,W.Zhang and F.Wang Chem.Commun.2009,7465.)
3. the nucleophilic difluoromethyl of difluoromethyl diethoxy phosphate and carbonyls under the effect of the highly basic such as LDA
Reaction.([1]S.R.Piettre,C.Girol and C.G.Schelcher Tetrahedron Lett.1996,37,4711.
[2]P.Beier,A.V.Alexandrova,M.Zibinsky and G.K.S.Prakash Tetrahedron 2008,64,
10977.)
4. benzene sulphur/seleno trimethyl silicon substrate difluoromethane or benzene sulfuryl trimethyl silicon substrate difluoromethane and carbonyls
Nucleophilic difluoromethylization is reacted.([1]G.K.S.Prakash,J.Hu,Y.Wang and G.A.Olah J.Fluorine
Chem.2005,126,529.[2]C.Ni and J.Hu Terahedron Lett.2005,46,8237.[3]Y.-Y.Qin,
X.-L.Qiu,Y.-Y.Yang,W.-D.Meng and F.-L.Qing J.Org.Chem.2005,70,9040.[4]Y.-
Y.Qin,Y.-Y.Yang,X.-L.Qiu and F.-L.Qing Synthesis 2006,1475.)
In above-mentioned these methods, the strong basic reagents such as LDA, t-BuOK are used the need for having, and reacting needs control to exist
Carried out under low temperature, reaction condition requirement is harsh, some reaction reagents prepare difficulty, expensive.Cheap efficient, mild condition
The method of preparation-difluoromethyl alcohol compound rare report so far.Additionally, Xiao Jichang et al. once reported pyridine in 2014
The preparation of sulfuryl difluoroacetic acid potassium and application (X.-P Wang, J.-H.Lin, J.-C.Xiao and X.Zheng
Eur.J.Org.Chem.2014,928.), but need to use valuable metal Ru oxidant, valency in the preparation process of the compound
Lattice are expensive, and it mainly generates difluoro alkenes compounds with the reactive applications of aldehyde.
The content of the invention
In order to overcome the deficiencies in the prior art, it is an object of the invention to provide a kind of fragrant sulfuryl difluoroacetic acid salt chemical combination
Thing, preparation method and applications.Fragrant sulfuryl difluoroacetic acid salt compounds of the invention are used to prepare the α-two of fragrant sulfuryl substitution
Methyl fluoride alcohol compound, reaction condition is gentle, and product yield high, universality is high.
Technical scheme is specifically described as follows.
The present invention provides a kind of fragrant sulfuryl difluoroacetic acid salt compounds, and structure is as follows：
Wherein：Ar groups are phenyl or substituted-phenyl, and the substitution base in described substituted-phenyl is o-, m-, contraposition substitution
Or polysubstituted methyl, ethyl, phenyl, methoxyl group, ethyoxyl, benzyloxy, nitro, cyano group, trifluoromethyl, fluorine, chlorine, bromine,
Acetyl group or dimethylamino；M is Li, Na or K.Preferably, the substitution base of the substituted-phenyl for it is o-, m-, contraposition substitution or
Polysubstituted methyl, ethyl, methoxyl group, ethyoxyl or dimethylamino.
The present invention also provides a kind of preparation method of above-mentioned fragrant sulfuryl difluoroacetic acid salt compounds, chemical reaction equation
It is as follows：
Comprise the following steps that：Aryl thiophenol ArSH and Bromodifluoroacetic acid ethyl ester are reacted under the effect of sodium hydrogen first, is obtained
Arylthio ethyl difluoro class compound；Then in acetum, under heating condition, with chromium trioxide as oxidant, oxygen
It is fragrant sulfuryl ethyl difluoro class compound to change arylthio ethyl difluoro class compound；It is last at ambient temperature, with
Alkali metal hydroxide is alkali, and the fragrant sulfuryl ethyl difluoro class compound of hydrolysis is made corresponding virtue sulfuryl difluoroacetic acid salt
Compound.
Preferably, the mol ratio of described aryl thiophenol, Bromodifluoroacetic acid ethyl ester and NaH is followed successively by 1：(1.2~1.5)：
(1.1~1.5).Described arylthio ethyl difluoro and CrO3Mol ratio be 1：2~1：5.Described fragrant sulfuryl difluoro
Ethyl acetate is with the mol ratio of alkali metal hydroxide:1：1~1：3.
The present invention further provides a kind of application of above-mentioned fragrant sulfuryl difluoroacetic acid salt compounds, by fragrant sulfuryl difluoro
Acetates compound and aldehyde room temperature reaction in a solvent, obtain the alpha-difluoromethyl alcohol compound of fragrant sulfuryl substitution.
Preferably, the structure of aldehyde is usedRepresent, R refers to hydrogen, phenyl, heteroaryl, substituted-phenyl, C1-30Alkyl,
C1-30Alkenyl, C1-30Alkynyl；Substitution base in described substituted-phenyl is o-, m-, contraposition substitution or polysubstituted first
Base, ethyl, phenyl, methoxyl group, ethyoxyl, benzyloxy, nitro, cyano group, trifluoromethyl, fluorine, chlorine, bromine, acetyl group or diformazan ammonia
Base.It is further preferred that R refers to hydrogen, phenyl, heteroaryl, substituted-phenyl, C1-15Alkyl, C1-15Alkenyl, C1-15Alkynyl；
Substitution base in described substituted-phenyl is o-, m-, contraposition substitution or polysubstituted methyl, ethyl, phenyl, methoxyl group, second
Epoxide or benzyloxy.
Preferably, the mol ratio of fragrant sulfuryl difluoroacetic acid salt compounds and aldehyde is 1：1.5~1：2.
Preferably, solvent is any one or several in DMSO, DMF, NMP or THF；Reaction time is 12-14 hours.
Compared to the prior art, the beneficial effects of the present invention are：The present invention is using fragrant sulfuryl difluoroacetic acid salt chemical combination
When thing prepares the alpha-difluoromethyl alcohol compound of fragrant sulfuryl substitution, reaction condition is gentle (room temperature), product yield high (90% with
On), side reaction is few, and universality is high.Simultaneously；Fragrant sulfuryl difluoroacetic acid salt compounds preparation cost of the invention is low, technique is simple
Single, reaction condition is gentle.
Specific embodiment
Technical solution of the present invention is described in detail using following embodiments will be helpful to understand the present invention, but do not limited
Present disclosure processed.
Embodiment 1
1) under room temperature normal pressure, by 2.25g (55mmol) NaH (60%) input two necks bottle, 40ml DMSO are added.Cold
Under solidifying water backflow, 5.50g (50mmol) benzenethiol, room temperature reaction 1h are slowly dropped into.Under condensate return, delay in mixture
It is slow to instill 12.20g (60mmol) Bromodifluoroacetic acid ethyl ester, room temperature reaction 16h.With 50ml saturations NH4Cl solution is quenched reaction, two
Chloromethanes is extracted, and is washed with water, the saturation NaCl aqueous solution successively after merging organic phase, anhydrous sodium sulfate drying, is concentrated under reduced pressure, post
Chromatography, obtains product10.26g, yield 88%.
2) under normal pressure, by the 10.26g (40mmol) of above-mentioned gained17.60g(176mmol)
CrO3, 50ml acetic acid is put into two necks bottle successively, and under condensate water circulatory, 60 DEG C of stirring reactions are monitored with TLC and reacted, raw material
Stop reaction after being wholly absent.During reaction solution poured into 100ml water, dichloromethane extraction, merge after organic phase successively with water,
The saturation NaCl aqueous solution is washed, anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifying, obtains product9.89g, yield 85%.
3) to 2.10g (37.4mmol) KOH is put into the two necks bottle for filling 50ml absolute ethyl alcohols under normal temperature and pressure, stirring makes
Its dissolving.It is slowly added dropwise above-mentioned gained9.89g (37.4mmol), stirring reaction.Monitored with TLC
Reaction, raw material stops reaction after being wholly absent.Entire contents in reaction bulb are collected, solvent residue 1/4 is concentrated under reduced pressure into, added
100ml absolute ethers, suction filtration, successively with absolute ethyl alcohol, absolute ether washing filter cake, vacuum decompression is dried, and obtains product benzene sulfone
Base difluoroacetic acid potassium9.56g, yield 93%.
Embodiment 2
1) as described in Example 1, add to methoxybenzenethiol 7.00g (50mmol), it is added to methoxybenzenethiol, hydrogen
It is 1.0 to change sodium, ethyl bromide difluoride：1.1：1.2, react 16 hours at room temperature, obtain
12.06g, yield 92%.
2) as shown in Example 1, addChromium trioxide is 1：4, stirred at 60 DEG C
Reaction is mixed, is monitored with TLC and reacted.Raw material stops reaction after disappearing, and obtains11.91g, receives
Rate 88%.
3) as shown in Example 1, addKOH is 1：1, react at room temperature, with
TLC monitoring reactions.Raw material stops reaction after disappearing, and obtains11.20g, yield 91%.
Embodiment 3
1) as described in Example 1, add to fluoro thiophenol 6.40g (50mmol), it is added to fluoro thiophenol, sodium hydride, two
Fluorine bromoacetate is 1.0：1.1：Reacted 16 hours at 1.2,40 DEG C, obtained7.04g, yield
56%.
2) as shown in Example 1, addChromium trioxide is 1：4, it is anti-in 60 DEG C of stirrings
Should, monitored with TLC and reacted.Raw material stops reaction after disappearing, and obtains6.52g, yield 82%.
3) as shown in Example 1, addNaOH is 1：1, react at room temperature, with TLC
Monitoring reaction.Raw material stops reaction after disappearing, and obtains5.49g, yield 86%.
Embodiment 4
Under nitrogen protection, successively to input 82.0mg benzene sulfuryl difluoroacetic acids potassium, 60 μ l benzaldehydes and 1.5ml in reaction bulb
DMF, stirring reaction 14h under room temperature condition, adds water and is quenched, ethyl acetate extraction, merges organic phase, successively with water, saturation NaCl
The aqueous solution washs organic phase, and column chromatography for separation obtains product86.1mg, yield 96%.
Embodiment 5
Under nitrogen protection, successively to input 82.2mg benzene sulfuryl difluoroacetic acids potassium, 72 μ l in reaction bulb to methoxybenzene first
Aldehyde and 1.5ml DMF, stirring reaction 14h under room temperature condition add water and are quenched, ethyl acetate extraction, merge organic phase, successively with
Water, saturation NaCl aqueous solution washing organic phase, column chromatography for separation obtain product76.8mg,
Yield 78%.
Embodiment 6
Under nitrogen protection, successively to input 82.4mg benzene sulfuryl difluoroacetic acids potassium, 91.7mg p-nitrophenyl first in reaction bulb
Aldehyde (99%) and 1.5ml DMF, stirring reaction 14h under room temperature condition add water and are quenched, ethyl acetate extraction, merge organic phase, according to
Secondary to wash organic phase with water, the saturation NaCl aqueous solution, column chromatography for separation obtains product
98.0mg, yield 95%.
Embodiment 7
Under nitrogen protection, successively to input 82.4mg benzene sulfuryl difluoroacetic acids potassium, 76 μ l benzenpropanals (95%) in reaction bulb
With 1.5ml DMF, stirring reaction 12h under room temperature condition, add water and be quenched, ethyl acetate extraction, merge organic phase, successively with water,
The saturation NaCl aqueous solution washs organic phase, and column chromatography for separation obtains product60.8mg, yield
62%.
Claims (8)
1. a kind of fragrant sulfuryl difluoroacetic acid salt compounds, it is characterised in that structure is as follows：
Wherein：Ar is phenyl or substituted-phenyl, and the substitution base in described substituted-phenyl is for o-, m-, contraposition replaces or takes more
The methyl in generation, ethyl, phenyl, methoxyl group, ethyoxyl, benzyloxy, nitro, cyano group, trifluoromethyl, fluorine, chlorine, bromine, acetyl group or
Dimethylamino；M is Li, Na or K.
2. virtue sulfuryl difluoroacetic acid salt compounds as claimed in claim 1, it is characterised in that the substitution of the substituted-phenyl
Base is o-, m-, contraposition substitution or polysubstituted methyl, ethyl, methoxyl group, ethyoxyl or dimethylamino.
3. a kind of preparation method of fragrant sulfuryl difluoroacetic acid salt compounds as claimed in claim 1, it is characterised in that specific
Step is as follows：Aryl thiophenol ArSH and Bromodifluoroacetic acid ethyl ester are reacted under the effect of sodium hydrogen first, arylthio difluoro second is obtained
Acetoacetic ester class compound；Then in acetum, under heating condition, with chromium trioxide as oxidant, arylthio difluoro is aoxidized
Ethyl acetate class compound is fragrant sulfuryl ethyl difluoro class compound；At ambient temperature, with alkali metal hydroxide finally
Thing is alkali, and the fragrant sulfuryl ethyl difluoro class compound of hydrolysis is made corresponding virtue sulfuryl difluoroacetic acid salt compounds.
4. a kind of application of fragrant sulfuryl difluoroacetic acid salt compounds as claimed in claim 1, it is characterised in that by fragrant sulfuryl
Difluoroacetic acid salt compounds and aldehyde room temperature reaction in a solvent, obtain the alpha-difluoromethyl alcohol compound of fragrant sulfuryl substitution.
5. application as claimed in claim 4, it is characterised in that the structure of aldehyde is usedRepresent, R refers to hydrogen, phenyl, heteroaryl
Base, substituted-phenyl, C1-30Alkyl, C1-30Alkenyl, C1-30Alkynyl；Substitution base in described substituted-phenyl for it is o-, m-,
Contraposition substitution or polysubstituted methyl, ethyl, phenyl, methoxyl group, ethyoxyl, benzyloxy, nitro, cyano group, trifluoromethyl,
Fluorine, chlorine, bromine, acetyl group or dimethylamino.
6. application as claimed in claim 5, it is characterised in that R refers to hydrogen, phenyl, heteroaryl, substituted-phenyl, C1-15Alkane
Base, C1-15Alkenyl, C1-15Alkynyl；Substitution base in described substituted-phenyl is o-, m-, contraposition substitution or polysubstituted
Methyl, ethyl, phenyl, methoxyl group, ethyoxyl or benzyloxy.
7. application as claimed in claim 4, it is characterised in that the mol ratio of fragrant sulfuryl difluoroacetic acid salt compounds and aldehyde is
1：1.5~1：2.
8. application as claimed in claim 4, it is characterised in that solvent is any one or several in DMSO, DMF, NMP or THF；
Reaction time is 12-14 hours.
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| CN111018708A (en) * | 2019-11-22 | 2020-04-17 | 浙江工业大学 | Synthesis method of difluoroalkyl substituted aromatic ketone compound under photocatalysis |
| CN111793019A (en) * | 2020-07-30 | 2020-10-20 | 上海应用技术大学 | Preparation method of polyfluoro-substituted phenylsulfonyl indolone compounds |
| CN111793020A (en) * | 2020-07-30 | 2020-10-20 | 上海应用技术大学 | Preparation method of N-benzyl substituted 3-phenylsulfonyl oxindole compound |
| CN111875532A (en) * | 2020-07-30 | 2020-11-03 | 上海应用技术大学 | Preparation method of 4-bromo-3-hydroxy-3-difluorobenzenesulfonyl-1-methylindoline-2-one compound |
| CN114539107A (en) * | 2022-03-31 | 2022-05-27 | 平顶山学院 | Aromatic sulfonyl modified difluoromethyl reaction building block and synthesis method thereof |
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| CN111018708A (en) * | 2019-11-22 | 2020-04-17 | 浙江工业大学 | Synthesis method of difluoroalkyl substituted aromatic ketone compound under photocatalysis |
| CN111018708B (en) * | 2019-11-22 | 2022-05-27 | 浙江工业大学 | Synthesis method of difluoroalkyl substituted aromatic ketone compound under photocatalysis |
| CN111793019A (en) * | 2020-07-30 | 2020-10-20 | 上海应用技术大学 | Preparation method of polyfluoro-substituted phenylsulfonyl indolone compounds |
| CN111793020A (en) * | 2020-07-30 | 2020-10-20 | 上海应用技术大学 | Preparation method of N-benzyl substituted 3-phenylsulfonyl oxindole compound |
| CN111875532A (en) * | 2020-07-30 | 2020-11-03 | 上海应用技术大学 | Preparation method of 4-bromo-3-hydroxy-3-difluorobenzenesulfonyl-1-methylindoline-2-one compound |
| CN114539107A (en) * | 2022-03-31 | 2022-05-27 | 平顶山学院 | Aromatic sulfonyl modified difluoromethyl reaction building block and synthesis method thereof |
| CN114539107B (en) * | 2022-03-31 | 2023-09-15 | 平顶山学院 | Aromatic sulfonyl modified difluoromethyl reaction building block and synthesis method thereof |
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