CN104592181B - 2-fluorine polysubstituted 4H-pyran derivate and preparation method thereof - Google Patents

2-fluorine polysubstituted 4H-pyran derivate and preparation method thereof Download PDF

Info

Publication number
CN104592181B
CN104592181B CN201510047442.6A CN201510047442A CN104592181B CN 104592181 B CN104592181 B CN 104592181B CN 201510047442 A CN201510047442 A CN 201510047442A CN 104592181 B CN104592181 B CN 104592181B
Authority
CN
China
Prior art keywords
pyrans
fluoro
methyl
carboxylic acid
ethyl ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201510047442.6A
Other languages
Chinese (zh)
Other versions
CN104592181A (en
Inventor
肖元晶
杨洁茹
毛傲
岳振亭
张俊良
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China Normal University
Original Assignee
East China Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by East China Normal University filed Critical East China Normal University
Priority to CN201510047442.6A priority Critical patent/CN104592181B/en
Publication of CN104592181A publication Critical patent/CN104592181A/en
Application granted granted Critical
Publication of CN104592181B publication Critical patent/CN104592181B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention relates to a kind of 2 fluorine polysubstituted 4H pyran derivate, shown in its structure such as formula (III).Its preparation method is, under the effect of alkali, containing trifluoromethyl vinyl compound and 1,3 dicarbonyl compound generation cyclizations, obtains described 2 fluorine polysubstituted 4H pyran derivate through extraction, concentration, column chromatography；Shown in the reaction equation of described preparation method such as formula (1).Preparation method reaction condition of the present invention is gentle, simple to operate, it is thus achieved that 2 fluorine polysubstituted 4H pyrylium compound structural framework.

Description

2-fluorine polysubstituted 4H-pyran derivate and preparation method thereof
Technical field
The present invention relates to the preparation method of fluorine pyran derivate, be specifically related to a class 2-fluorine polysubstituted 4H-pyran derivate And preparation method thereof, belong to chemical substance and preparing technical field thereof.
Background technology
There is the highest chemical bond energy, not easy fracture due to self in C-F key, it is more difficult to the sense realizing self converts, and therefore develops Method gentle, efficient realizes activation and the fracture of C-F key, thus prepares fluorine-containing or fluorine-free compounds with practical value The focus becoming current organic synthesis field (sees: (a) H.Amii, K.Uneyama, Chem.Rev.2009,109,2119 –2183；(b)E.Clot,O.Eisenstein,N.Jasim,S.A.Macgregor,J.E.McGrady,R.N.Perutz,Acc. Chem.Res.2011,44,333–348；(c)T.Stahl,H.F.T.Klare,M.Oestreich,ACS Catal.2013,3,1578 –1587；(d)M.F.Kuehnel,D.Lentz,T.Braun,Angew.Chem.2013,125,3412–3433；Angew. Chem.Int.Ed.2013,52,3328–3348.).2-Trifluoromethyl-1-alkene, end together with difluoro alkenes compounds due to solely Special chemical constitution can pass through S with nucleopilic reagentN2’Or SNV reaction realizes self through carbon-fluorine bond activation fracture and converts, for part Fluorine-containing or without fluoride compound matter synthesis provides a shortcut ((a) J.Ichikawa, Chim.Oggi 2007,25 (4), 54 57；(b)J.Ichikawa,Y.Wada,M.Fujiwara,K.Sakoda,Synthesis 2002,1917–1936.).Recently, Ichikawa group uses hydrazine compound as double nucleophile, passes through S with 2-Trifluoromethyl-1-alkenes compoundsN2 ' and SNV Two kinds of reaction patterns, two step regioselectivity ground have synthesized 3-fluorine pyrazole compound (K.Fuchibe, M.Takahashi, J. Ichikawa.Angew.Chem.2012,124,12225-12228；Angew.Chem.Int.Ed.2012,51,12059 –12062.).It is well known that 4H-pyrylium compound is considered as potential and specific IKCa channel blocker (K.Urbahns, E. Horv á th, J.-P.Stasch, F.Mauler, Bioorg.Med.Chem.Lett., 2003,13,2637-2639.), and thin as falciform Born of the same parents' anaemia, secretory diarrhea, potential medicine ((a) B.S.Jensen, D.Strobaek, S.P.Olesen, the P. of autoimmune disease Christophersen,Curr.Drug Targets,2001,2,401-422；(b)R.Kohler,H.Wulff,I.Eichler,M.Kneifel,D. Neumann,A.Knorr,I.Grgic,D.Kampfe,H.Si,J.Wibawa,R.Real,K.Borner,S.Brakemeier,H.D. Orzechowski,H.P.Reusch,M.Paul,K.G.Chandy,J.Hoyer,Circulation,2003,108,1119-1125.).On the other hand, Fluorochemical often has higher reactivity and physiologically active ((a) J.-P.B é gu é, D. compared with not fluorochemical Bonnet-Delpon,Bioorganic and Medicinal Chemistry of Fluorine；Wiley-VCH:Weinheim,2008；(b)A.Tressaud, G.Haufe,Fluorine and Health:Molecular Imaging,Biomedical Materials and Pharmaceuticals；Elsevier:Oxford, 2008；c)Uneyama,K.Organofluorine Chemistry；Blackwell:Oxford, 2006.), the therefore synthesis of fluorinated organic compound Research is the most greatly paid close attention at life science related fields.In numerous fluorinated organic compounds, single fluorine heterocyclic compound In terms of medicine and commercial synthesis intermediate, had shown that wide application prospect ((a) A.A.Gakh, K.L.Kirk, Fluorinated heterocycles.American Chemical Society,Washington DC,2009；(b)V.A.Petrov,Fluorinated heterocyclic Compounds:synthesis, chemistry, and applications.Wiley, Hoboken, 2009), but, single fluorine 4H-pyrans heterocyclic compound Study on the synthesis the most rarely found report ((a) A.E.Feiring.J.Org.Chem.1980,45,1962-1964 of thing；(b)A.A.Gakh. Top Heterocycl Chem,2012,27,33–64.)。
Summary of the invention
The present invention enriches the synthetic methodology of single fluorine heterocyclic compound further, it is provided that a kind of raw material is easy to get, reaction condition is gentle, The synthetic method of single fluorine 4H-pyranoid ring derivative that chemo-selective is good, prepares the 2-fluorine polysubstituted 4H-pyrans that a class is new Derivative.
The invention provides the 2-fluorine polysubstituted 4H-pyran derivate shown in a kind of formula (III), shown in structure such as formula (III),
Wherein, R1For ester group, carbonyl, aryl, alkynyl；R2For aryl, heteroaryl, alkyl, hydrogen；R3For aryl, alkyl, Cycloalkyl, trifluoromethyl etc.；EWG includes ester group, carbonyl.
Preferably, described aryl includes phenyl or o-, m-, the substituted-phenyl of contraposition；Described heteroaryl is furans, thiophene.
Further, described R1For carbethoxyl group, phenyl, 4-methoxyphenyl, 4-carboethoxyphenyl, 3-nitrobenzophenone, Phenylene-ethynylene, thiophene-2-ethyl-acetylene base, benzoyl, naphthalene-1-ethyl-acetylene base；Described R2For phenyl, 4-methoxyphenyl, 4-chlorphenyl, 4-bromophenyl, 4-nitrobenzophenone, 4-cyano-phenyl, 4-trifluoromethyl, 2-bromophenyl, naphthalene-2-base, furan Mutter-2-base, thiophene-2-base, isobutyl group, hydrogen；Described R3For methyl, ethyl, propyl group, isopropyl, cyclohexyl, phenyl, Trifluoromethyl.
In the present invention, the 2-fluorine polysubstituted 4H-pyran derivate shown in described formula (III) includes, the fluoro-6-of 5-acetyl group-2- Methyl 4-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-methoxyphenyl)-6-methyl-4H-pyrans-3- Carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-chlorphenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2- (4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-nitrobenzophenone)-6-methyl-4H- Pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-cyano-phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl The fluoro-4-of base-2-(4-trifluoromethyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl group-2-fluoro-4-(2-bromobenzene Base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl group-2-fluoro-6-methyl-4-(naphthalene-2-base)-4H-pyrans-3-carboxylic acid Ethyl ester, the fluoro-4-of 5-acetyl group-2-(furans-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2- (thiophene-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl group-2-fluoro-4-isobutyl group-6-methyl-4H-pyrans-3- Carboxylic acid, ethyl ester, 1-(6-fluoro-2-methyl-5-phenyl-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-5-of 6-(4-methoxyphenyl) -2-methyl-4H-pyrans-3-base) ethyl ketone, 4-(5-acetyl group-2-fluoro-6-methyl-4H-pyrans-3-base) ethyl benzoate, 1-(6-fluoro-2-methyl-5-(3-nitrobenzophenone)-4H-pyrans-3-base) ethyl ketone, 1-(6-fluoro-2-methyl-5-(phenylacetylene Base)-4H-pyrans-3-base) ethyl ketone, 1-(6-fluoro-2-methyl-5-(thiophene-2-ethyl-acetylene base)-4H-pyrans-3-base) ethyl ketone, 1-(5-benzoyl-6-fluoro-2-methyl 4-phenyl-4H-pyrans-3-base) ethyl ketone, 5-methoxycarbonyl group base-2-fluoro-4-(4-bromine Phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl)-6-methyl-4H-pyrans-3- Carboxylic acid, ethyl ester, the fluoro-4-of 5-tertbutyloxycarbonyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-is to benzyl chloride oxygen The fluoro-4-of carbonyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-hexichol methoxycarbonyl group-2-fluoro-4-(4-bromine Phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-(naphthalene-9-methoxycarbonyl group) the fluoro-4-of-2-(4-bromophenyl)-6-methyl -4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl)-6-ethyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5- The fluoro-4-of benzyloxycarbonyl group-2-(4-bromophenyl)-6-propyl group-4H-pyrans-3-carboxylic acid, ethyl ester, 5-methoxycarbonyl group-2-fluoro-4-(4-bromine Phenyl)-6-isopropyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl)-6-isopropyl-4H- Pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl)-6-cyclohexyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5- The fluoro-4-of carbethoxyl group-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl group-2-fluoro-4-(4-bromobenzene Base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl)-6-trifluoromethyl-4H-pyrans -3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-benzoyl-2- Fluoro-4-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-bromophenyl)-6-phenyl -4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-benzoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 2- Fluoro-7,7-dimethyl-3-(naphthalene-1-ethyl-acetylene base)-7,8-dihydro-4H-chromene-5 (6H)-one etc..
The present invention propose preparation method with 2-Trifluoromethyl-1-alkene (that is, the vinyl compound containing trifluoromethyl group), 1,3- Dicarbonyl compound is raw material, is dissolved in organic solvent, eliminates cascade reaction through addition and obtain the present invention's under the effect of alkali Single fluorine 4H pyran derivate of polysubstituted multifunctional dough.
The single fluorine as shown in formula (III) that the present invention provides replaces the preparation method of 4H-pyran derivate, under the effect of alkali, Containing trifluoromethyl vinyl compound and shown in formula (II) 1 shown in formula (I), 3-dicarbonyl compound generation cyclization, through extracting, Concentrate, column chromatography obtains described 2-fluorine polysubstituted 4H-pyran derivate；Shown in the reaction equation of described preparation method such as formula (1),
Wherein, R1For ester group, carbonyl, aryl, alkynyl；R2For aryl, heteroaryl, alkyl, hydrogen；R3For aryl, alkyl, Cycloalkyl, trifluoromethyl etc.；EWG includes ester group, carbonyl.
Preferably, described aryl includes phenyl or o-, m-, the substituted-phenyl of contraposition；Described heteroaryl is furans, thiophene.
Further, described R1For carbethoxyl group, phenyl, 4-methoxyphenyl, 4-carboethoxyphenyl, 3-nitrobenzophenone, Phenylene-ethynylene, thiophene-2-ethyl-acetylene base, benzoyl, naphthalene-1-ethyl-acetylene base；Described R2For phenyl, 4-methoxyphenyl, 4-chlorphenyl, 4-bromophenyl, 4-nitrobenzophenone, 4-cyano-phenyl, 4-trifluoromethyl, 2-bromophenyl, naphthalene-2-base, furan Mutter-2-base, thiophene-2-base, isobutyl group, hydrogen；Described R3For methyl, ethyl, propyl group, isopropyl, cyclohexyl, phenyl, Trifluoromethyl.
Wherein, the 2-fluorine polysubstituted 4H-pyran derivate shown in formula (III) obtained prepared according to the methods of the invention, including, 5-acetyl group-2-fluoro-6-methyl 4-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-methoxyphenyl) -6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-chlorphenyl)-6-methyl-4H-pyrans-3-carboxylic acid second Ester, the fluoro-4-of 5-acetyl group-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl group-2-fluoro-4-(4- Nitrobenzophenone)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-cyano-phenyl)-6-methyl-4H- Pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-trifluoromethyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5- The fluoro-4-of acetyl group-2-(2-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl group-2-fluoro-6-methyl-4-(naphthalene -2-base)-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(furans-2-base)-6-methyl-4H-pyrans-3-carboxylic acid second Ester, the fluoro-4-of 5-acetyl group-2-(thiophene-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl group-2-fluoro-4-isobutyl Base-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 1-(6-fluoro-2-methyl-5-phenyl-4H-pyrans-3-base) ethyl ketone, 1-(6- Fluoro-5-(4-methoxyphenyl)-2-methyl-4H-pyrans-3-base) ethyl ketone, 4-(5-acetyl group-2-fluoro-6-methyl-4H-pyrrole Mutter-3-base) ethyl benzoate, 1-(6-fluoro-2-methyl-5-(3-nitrobenzophenone)-4H-pyrans-3-base) ethyl ketone, 1-(6- Fluoro-2-methyl-5-(phenylene-ethynylene)-4H-pyrans-3-base) ethyl ketone, 1-(6-fluoro-2-methyl-5-(thiophene-2-ethyl-acetylene Base)-4H-pyrans-3-base) ethyl ketone, 1-(5-benzoyl-6-fluoro-2-methyl 4-phenyl-4H-pyrans-3-base) ethyl ketone, 5- The fluoro-4-of methoxycarbonyl group base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-carbethoxyl group-2-fluoro-4-(4- Bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-tertbutyloxycarbonyl-2-(4-bromophenyl)-6-methyl-4H- Pyrans-3-carboxylic acid, ethyl ester, 5-is to the benzyloxycarbonylchloride fluoro-4-of base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5- The fluoro-4-of hexichol methoxycarbonyl group-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-(naphthalene-9-methoxycarbonyl group)-2- Fluoro-4-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl)-6-second Base-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-benzyloxycarbonyl group-2-(4-bromophenyl)-6-propyl group-4H-pyrans-3-carboxylic acid, ethyl ester, The fluoro-4-of 5-methoxycarbonyl group-2-(4-bromophenyl)-6-isopropyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-carbethoxyl group-2-fluoro-4-(4- Bromophenyl)-6-isopropyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl)-6-cyclohexyl-4H- Pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-acetyl The fluoro-4-of base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbethoxyl group-2-(4-bromophenyl) -6-trifluoromethyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic Acetoacetic ester, the fluoro-4-of 5-benzoyl-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-acetyl group-2- (4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-benzoyl-2-(4-bromophenyl)-6-methyl-4H- Pyrans-3-carboxylic acid, ethyl ester, 2-fluoro-7,7-dimethyl-3-(naphthalene-1-ethyl-acetylene base)-7,8-dihydro-4H-chromene-5 (6H)-one Deng.
In one embodiment, the preparation process of the 2-fluorine polysubstituted 4H-pyran derivate shown in formula (III) of the present invention For, trifluoromethyl vinyl compound will be contained and dissolve in organic solvent, under the effect of inorganic base, at ambient temperature with 1,3- Dicarbonyl compound generation cyclization, extracts after having reacted, and concentrates, obtains the 2-as shown in formula (III) through column chromatography Fluorine polysubstituted 4H-pyran derivate.
In preparation method of the present invention, reaction is carried out in organic solvent.Specifically, at the preparation polysubstituted 4H-of formula (III) 2-fluorine In the step of pyran derivate, described organic solvent is N, N-dimethylformamide (DMF).Described organic solvent is not limited to Above-mentioned organic solvent.
In preparation method of the present invention, the consumption of described organic solvent is 8.0～10.0mL/mmol 1,3-dicarbonyl compound.
In preparation method of the present invention, described alkali is inorganic base, is alkali salt further, selected from potassium carbonate, sodium carbonate.Specifically Ground, in the step of preparation formula (III) 2-fluorine polysubstituted 4H-pyran derivate, described alkali salt includes potassium carbonate, sodium carbonate etc.. Preferably, described alkali is potassium carbonate.
In preparation method of the present invention, described containing trifluoromethyl vinyl compound, 1,3-dicarbonyl compound, the mol ratio of alkali are three Methyl fluoride vinyl compound: 1,3-dicarbonyl compound: alkali=3.0:1.0:1.2.
In preparation method of the present invention, the mode removing solvent includes: first extract with the reactant liquor after ether or acetic acid ethyl reaction Take, be dried and rotation boils off except solvent, or directly rotation boils off except solvent, thus obtain thick product.
In preparation method of the present invention, described column chromatography be use volume ratio be petroleum ether: the eluent of ethyl acetate=20:1～5:1.
One of innovation of preparation method of the present invention is, preparation method of the present invention is carried out under specific reaction temperature, e.g., and preparation Formula (III) 2-fluorine polysubstituted 4H-pyran derivate is to carry out under 50 DEG C to room temperature condition；Preferably, at room temperature carry out.
In preparation method of the present invention, the reaction time is about 3～41 hours.
Each raw material in preparation method of the present invention, include organic solvent, alkali etc., all can buy and directly use in market, such as, Organic solvent uses DMF, and alkali uses inorganic base.In one embodiment, preparation method of the present invention For, first weigh a certain amount of molecular sieve, formula (II) 1, the potassium carbonate of the amount of 3-dicarbonyl compound material 1.2 times, be placed in dry In dry reaction tube.Under argon atmosphere, weigh the formula (I) vinyl compound containing trifluoromethyl group, formula (II) by a certain percentage 1,3-dicarbonyl compound.Such as: the formula (I) vinyl compound containing trifluoromethyl group: formula (II) 1,3-dicarbapentaborane chemical combination Thing mol ratio=3.0:1.0.Vinyl compound containing trifluoromethyl group, 1,3-dicarbonyl compound are dissolved in 1mL DMF respectively In, added in above-mentioned reaction tube by syringe.Then, react under the conditions of room temperature reaction, or react at 50 DEG C, stir Carrying out degree by tlc silica gel plate (TLC) monitoring reaction during mixing, the reaction time is about 3～41 hours, reaction Being dried after first extracting with ether or ethyl acetate after end and revolving boils off except solvent, then, thick product is carried out column chromatography, Obtain formula (III) 2-fluorine polysubstituted 4H-pyran derivate sterling.Wherein, such as, it is petroleum ether by volume ratio: ethyl acetate The eluent of=20:1～5:1 carries out column chromatography.
The preparation method of 2-fluorine of the present invention polysubstituted 4H-pyran derivate, with the vinyl compound containing trifluoromethyl group, 1,3- Dicarbonyl compound is raw material, reacts and obtain comprising alkyl, heteroaryl, aryl and substituted aryl under inorganic base effect, ester group, The 2-fluorine polysubstituted 4H-pyran derivate of the groups such as alkynyl, shown in product structure such as formula (III).Beneficial effect of the present invention includes, Raw material is easy to get, and reaction condition is gentle, simple to operate, can quickly and efficiently synthesize 2-fluorine polysubstituted 4H-pyran derivate.This Invention has opened up a series of synthesis application of product by other path, it is achieved that the reduction of carbonyl, aoxidizes defluorinate, defluorinate Nucleophilic displacement of fluorine etc., 2-fluorine polysubstituted 4H-pyrylium compound prepared by the present invention, may be used for synthesizing in the enol of multifunctional dough Ester, a series of bioactive molecules such as α-pyranone, have great importance in pharmacy, organic synthesis field.
The present invention provides single fluorine pyrylium compound skeleton of various structures, and not only the synthesis to single fluorine substituted pyrane compounds has Significance, and the synthesis screening and drug research to new drug all has extremely important meaning.
Detailed description of the invention
In conjunction with specific examples below, the present invention is described in further detail, and the protection content of the present invention is not limited to following Embodiment.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art it is conceivable that change and advantage all wrapped Include in the present invention, and with appending claims as protection domain.Implement the process of the present invention, condition, reagent, reality Proved recipe methods etc., outside the lower content mentioned specially, are universal knowledege and the common knowledge of this area, and the present invention does not has spy Do not limit content.
The preparation method of 2-fluorine polysubstituted 4H-pyran derivate that the present invention proposes, will as shown in formula (I) containing trifluoromethyl base The vinyl compound compound of group, 1 as shown in formula (II), 3-dicarbonyl compound is dissolved in DMF respectively, wherein, containing three The vinyl compound of fluoromethyl group: 1,3-dicarbonyl compound mol ratio=3.0:1.0, is injected equipped with molecular sieve by syringe With formula (II) 1, in the dry reaction pipe of the potassium carbonate of the amount of 3-dicarbonyl compound material 1.2 times, in room temperature to 50 DEG C temperature Under the conditions of react, remove solvent, obtain the 2-fluorine polysubstituted 4H-pyran derivate as shown in formula (III) through column chromatography；
Wherein, R1For ester group, carbonyl, aryl, alkynyl；R2For aryl, heteroaryl, alkyl, hydrogen；R3For aryl, alkyl, Cycloalkyl, trifluoromethyl etc.；EWG is ester group, carbonyl.Wherein, described aryl includes taking of phenyl or o-, m-, contraposition For phenyl；Described heteroaryl is furans, thiophene substituent.
Embodiment 1
By raw material 3-phenyl-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is dissolved in respectively 1.0mLN, dinethylformamide, injected equipped with molecular sieve and formula (II) 1 by syringe, 3-dicarbonyl compound material In the dry reaction pipe of the potassium carbonate measuring 1.2 times, fully react under 50 DEG C to room temperature, react 6 hours, detected by TLC Reaction, is wholly absent to acetylacetone,2,4-pentanedione.Reaction adds 5.0ml distilled water cancellation reaction after terminating, with ether or ethyl acetate (3*5.0ml) extract, merge organic relevant dry and revolve and boil off except solvent, then by thick product directly with silica gel quick post look Spectrum purifies (petroleum ether: ethyl acetate=20:1) and obtains single fluorine replacement 4H-pyran derivate sterling I II-1 (44mg, 73%).
1H NMR(400MHz,CDCl3) δ 7.33-7.25 (m, 4H), 7.24-7.18 (m, 1H), 4.87 (d, J=6.2Hz, 1H), 4.30 3.99 (m, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.23 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ -78.53.13C NMR(100MHz,CDCl3) δ 198.39 (d, J=1.2Hz), 164.00 (d, J=6.9Hz), 157.74 (d, J= 279.9Hz), 155.11,142.74 (d, J=1.2Hz), 128.64,128.27,127.47,117.16,87.03 (d, J=6.7Hz), (d, J=2.0Hz), 60.84,40.59 29.97,18.15,14.08.MS (70eV): m/z (%): 304 (M+,5.18),84(100). HRMS calculates C17H17O4F:304.1111, actual measurement: 304.1110.
Embodiment 2
By 3-(4-methoxyphenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) As raw material, other operate reference example 1, react and stir 7h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-2 (45mg, 68%).
1H NMR(400MHz,CDCl3) δ 7.18 (d, J=8.7Hz, 2H), 6.82 (d, J=8.7Hz, 2H), 4.81 (d, J=6.1Hz, 1H), 4.43 3.99 (m, 2H), 3.76 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H), 1.24 (t, J=7.1Hz, 3H).19F NMR (377MHz,CDCl3)δ-78.73.13C NMR(100MHz,CDCl3) δ 198.59 (d, J=1.3Hz), 164.13 (d, J= 6.8Hz), 158.83,157.61 (d, J=279.7Hz), 154.78,134.96,129.39,117.26,113.98,87.15 (d, J=6.2 Hz), 60.81,55.19,39.81 (d, J=2.0Hz), 29.88,18.11,14.11.MS (70eV): m/z (%): 334 (M+,3.04), 84 (100) .HRMS calculate C18H19O5F:334.1217, actual measurement: 334.1219.
Embodiment 3
By 3-(4-chlorphenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) conduct Raw material, other operate reference example 1, reaction stirring 7h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), obtain 4H-pyran derivate sterling III-3 (46mg, 68%) is replaced to single fluorine.
1H NMR(400MHz,CDCl3) δ 7.26 (d, J=8.6Hz, 2H), 7.21 (d, J=8.6Hz, 2H), 4.87 (d, J=6.1Hz, 1H), 4.25 3.96 (m, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.23 (t, J=7.1Hz, 3H).19F NMR(377MHz, CDCl3)δ-78.00.13C NMR(100MHz,CDCl3) δ 197.94 (d, J=1.3Hz), 163.89 (d, J=6.9Hz), 157.81 (d, J=280.2Hz), 155.29,141.32,133.33,129.66,128.81,117.03,86.75 (d, J=7.0Hz), (d, J=2.0Hz), 60.96,40.07 30.04,18.23,14.09.MS (70eV): m/z (%): 338 (M+,2.50),84(100). HRMS calculates C17H16O4FCl:338.0721, actual measurement: 338.0718.
Embodiment 4
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) conduct Raw material, other operate reference example 1, reaction stirring 5h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), obtain 4H-pyran derivate sterling III-4 (76mg, 99%) is replaced to single fluorine.
1H NMR(400MHz,CDCl3) δ 7.41 (d, J=8.4Hz, 2H), 7.15 (d, J=8.4Hz, 2H), 4.86 (d, J=6.1Hz, 1H), 4.39 3.88 (m, 2H), 2.33 (s, 3H), 2.15 (s, 3H), 1.23 (t, J=7.1Hz, 3H).19F NMR(377MHz, CDCl3)δ-77.97.13C NMR(100MHz,CDCl3) δ 197.89 (d, J=1.2Hz), 163.88 (d, J=6.8Hz), 157.82 (d, J=280.3Hz), 155.32,141.85,131.77,130.02,121.49,116.99,86.69 (d, J=7.1Hz), (d, J=2.0Hz), 60.97,40.15 30.05,18.24,14.10.MS (70eV): m/z (%): 382 (M+,7.63),384(M++2, 7.56), 43 (100) .HRMS calculate C17H16O4FBr:382.0216, actual measurement: 382.0219.
Embodiment 5
By 3-(4-nitrobenzophenone)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is made For raw material, other operate reference example 1, reaction stirring 5h, silica gel chromatography (petroleum ether: ethyl acetate=5:1), obtain 4H-pyran derivate sterling III-5 (69mg, 99%) is replaced to single fluorine.
1H NMR(400MHz,CDCl3) δ 8.14 (d, J=8.7Hz, 2H), 7.46 (d, J=8.7Hz, 2H), 5.02 (d, J=6.1Hz, 1H), 4.46 3.82 (m, 2H), 2.37 (s, 3H), 2.18 (s, 3H), 1.22 (t, J=7.1Hz, 3H).19F NMR(377MHz, CDCl3)δ-77.07.13C NMR(100MHz,CDCl3) δ 197.05 (d, J=1.2Hz), 163.59 (d, J=6.9Hz), 158.09 (d, J=281.0Hz), 156.04,150.01 (d, J=1.4Hz), 147.12,129.26,123.85,116.94,86.24 (d, J=7.9Hz), 61.14,40.44 (d, J=1.9Hz), 30.32,18.48,14.05.MS (70eV): m/z (%): 349 (M+,5.20), 43 (100) .HRMS calculate C17H16NO5F:349.0962, actual measurement: 349.0961.
Embodiment 6
By 3-(4-cyano-phenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is made For raw material, other operate reference example 1, reaction stirring 6h, silica gel chromatography (petroleum ether: ethyl acetate=5:1), obtain 4H-pyran derivate sterling III-6 (45mg, 69%) is replaced to single fluorine.
1H NMR(400MHz,CDCl3) δ 7.58 (d, J=8.1Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 4.96 (d, J=6.0Hz, 1H), 4.37 3.93 (m, 2H), 2.35 (s, 3H), 2.17 (s, 3H), 1.22 (t, J=7.1Hz, 3H).19F NMR(377MHz, CDCl3)δ-77.20.13C NMR(100MHz,CDCl3) δ 197.17 (d, J=1.1Hz), 163.62 (d, J=6.9Hz), 158.05 (d, J=280.9Hz), 155.92,148.04,132.43,129.11,118.49,116.87,111.37,86.29 (d, J=7.8 Hz), 61.10,40.65,30.24,18.40,14.05.MS (70eV): m/z (%): 329 (M+, 34.40), 43 (100) .HRMS meters Calculate C18H16NO4F:329.1063, actual measurement: 329.1064.
Embodiment 7
By 3-(4-trifluoromethyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) As raw material, other operate reference example 1, react and stir 5h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-7 (54mg, 73%).
1H NMR(400MHz,CDCl3) δ 7.55 (d, J=8.2Hz, 2H), 7.40 (d, J=8.1Hz, 2H), 4.97 (d, J=6.1Hz, 1H), 4.40 3.95 (m, 2H), 2.35 (s, 3H), 2.17 (s, 3H), 1.23 (t, J=7.1Hz, 3H).19F NMR(377MHz, CDCl3)δ-62.59(s,3F),-77.62(s,1F).13C NMR(100MHz,CDCl3) δ 197.60 (d, J=1.2Hz), 163.78 (d, J=6.9Hz), 157.99 (d, J=280.6Hz), 155.69,146.75,129.70 (q, J=32.5Hz), 128.67, 125.63 (q, J=3.7Hz), 123.95 (q, J=272.1Hz), 117.01,86.58 (d, J=7.5Hz), 61.05,40.45,30.13, 18.30,14.06.MS (70eV): m/z (%): 372 (M+, 25.37), 43 (100) .HRMS calculate C18H16O4F4: 372.0985, actual measurement: 372.0982.
Embodiment 8
By 3-(2-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) conduct Raw material, other operate reference example 1, reaction stirring 3h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), obtain 4H-pyran derivate sterling III-8 (51mg, 67%) is replaced to single fluorine.
1H NMR(400MHz,CDCl3) δ 7.31 7.10 (m, 4H), 5.31 (d, J=5.0Hz, 1H), 4.41 3.90 (m, 2H), 2.21 (s, 3H), 2.19 (s, 3H), 1.17 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ-78.78.13C NMR (100MHz,CDCl3) δ 198.87 (d, J=1.3Hz), 163.60 (d, J=6.8Hz), 158.42 (d, J=278.7Hz), 153.10 (d, J=1.3Hz), 139.94,132.96,131.49,130.12,128.76,127.39,117.21,85.98 (d, J=6.9 Hz), 60.77,38.08,30.08,17.78,14.03.MS (70eV): m/z (%): 382 (M+,7.63),384(M++2,7.56),43 (100) .HRMS calculates C17H16O4FBr:382.0216, actual measurement: 382.0219.
Embodiment 9
By 3-(2-naphthyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is as former Material, other operate reference example 1, reaction stirring 3h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), obtain Single fluorine replaces 4H-pyran derivate sterling III-9 (55mg, 78%).
1H NMR(400MHz,CDCl3) δ 7.80 (t, J=6.9Hz, 3H), 7.72 (s, 1H), 7.55 7.38 (m, 3H), 5.07 (d, J =6.2Hz, 1H), 4.29 3.98 (m, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.22 (t, J=7.1Hz, 3H).19F NMR (377MHz,CDCl3)δ-78.44.13C NMR(100MHz,CDCl3) δ 198.29 (d, J=1.1Hz), 163.99 (d, J= 6.8Hz), 157.79 (d, J=279.9Hz), 155.13,140.13,133.24,132.69,128.56,127.93,127.57,127.26, (d, J=6.7Hz), 126.21,126.12,126.05,117.18,86.97 60.85,40.81,30.04,18.21,14.07.MS (70 EV): m/z (%): 354 (M+, 100) and .HRMS calculates C21H19O4F:354.1267, actual measurement: 354.1265.
Embodiment 10
By 3-(furans-2-base)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is made For raw material, other operate reference example 1, reaction stirring 3h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-10 (49mg, 84%).
1H NMR(400MHz,CDCl3) δ 7.28 (d, J=1.0Hz, 1H), 6.26 (dd, J=3.1,1.9Hz, 1H), 6.12 (d, J= 3.2Hz, 1H), 5.02 (d, J=6.1Hz, 1H), 4.39 4.07 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 1.27 (t, J=7.1 Hz,3H).19F NMR(377MHz,CDCl3)δ-76.69.13C NMR(100MHz,CDCl3) δ 197.81 (d, J=1.1 Hz), 163.79 (d, J=6.9Hz), 158.36 (d, J=280.4Hz), 156.55,154.48 (d, J=1.6Hz), 142.16, (d, J=7.9Hz), 114.50,110.51,106.80,84.35 60.94,34.30,29.62,18.25,14.12.MS (70eV): m/z (%): 294 (M+, 51.71), 43 (100) .HRMS calculate C15H15O5F:294.0904, actual measurement: 294.0902.
Embodiment 11
By 3-(thiophene-2-base)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is made For raw material, other operate reference example 1, reaction stirring 3h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-11 (46mg, 74%).
1H NMR(400MHz,CDCl3) δ 7.21 7.15 (m, 1H), 6.90 (d, J=3.6Hz, 2H), 5.21 (d, J=6.4Hz, 1H), 4.31-4.15 (m, 2H), 2.35 (s, 3H), 2.23 (s, 3H), 1.29 (t, J=7.1Hz, 3H).19F NMR(377MHz, CDCl3)δ-77.45.13C NMR(100MHz,CDCl3) δ 197.79 (d, J=0.9Hz), 163.88 (d, J=7.0Hz), 157.79 (d, J=280.9Hz), 156.20,146.77 (d, J=1.4Hz), 126.96,125.43,125.18,116.63,87.15 (d, J=7.0Hz), 61.04,35.48 (d, J=2.2Hz), 29.64,18.22,14.15.MS (70eV): m/z (%): 310 (M+, 79.40), 43 (100) .HRMS calculate C15H15O4FS:310.0675, actual measurement: 310.0676.
Embodiment 12
By 3-isobutyl group-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) as raw material, Other operate reference example 1, reaction stirring 12h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), obtain list Fluorine replaces 4H-pyran derivate sterling III-12 (39mg, 68%).
1H NMR(400MHz,CDCl3) δ 4.33 4.15 (m, 2H), 3.81 (dd, J=12.9,7.0Hz, 1H), 2.32 (s, 3H), 2.20 (s, 3H), 1.52-1.40 (m, 1H), 1.30 (t, J=7.1Hz, 3H), 1.27 1.20 (m, 2H), 0.91 (d, J=6.5Hz, 3H), 0.85 (d, J=6.6Hz, 3H).13C NMR(126MHz,CDCl3) δ 198.70 (d, J=1.3Hz), 164.58 (d, J= 7.1Hz), 158.41 (d, J=282.3Hz), 155.64,119.54,86.68 (d, J=6.4Hz), 60.77,47.53,32.36 (d, J= 1.4Hz), 29.46,24.31,23.29,22.45,17.87,14.17.MS (70eV): m/z (%): 284 (M+,1.05),227(100). HRMS calculates C15H21O4F:284.1424, actual measurement: 284.1426.
Embodiment 13
By (3,3,3-trifluoropropyl-1-alkene-2-base) benzene (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is as raw material, and other are grasped Make reference example 1, at 50 DEG C, stir 4h, silica gel chromatography (petroleum ether: ethyl acetate=15:1), obtain single fluorine and replace 4H-pyran derivate sterling III-13 (32mg, 70%).
1H NMR(400MHz,CDCl3) δ 7.43-7.32 (m, 4H), 7.24 (t, J=7.2Hz, 1H), δ 3.42 (dd, J=5.0,1.0 Hz,2H),2.29(s,3H),2.25(s,3H).19F NMR(377MHz,CDCl3)δ-98.11.13C NMR(100MHz, CDCl3) δ 198.20,157.28 (d, J=3.1Hz), 150.84 (d, J=260.6Hz), 133.49 (d, J=4.6Hz), 128.35, 126.92,126.55 (d, J=5.7Hz), 110.90,85.58 (d, J=12.1Hz), 30.01,27.62 (d, J=3.4Hz), 18.59. MS (70eV): m/z (%): 232 (M+, 63.90), 43 (100) .HRMS calculate C14H13O2F:232.0900, actual measurement: 232.0899.
Embodiment 14
By 1-methoxyl group-4-(3,3,3-trifluoropropyl-1-alkene-2-base) benzene (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) conduct Raw material, stirring 10h at other operation reference examples 1,50 DEG C, silica gel chromatography (petroleum ether: ethyl acetate=15:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-14 (20mg, 38%).
1H NMR(500MHz,CDCl3) δ 7.36 (d, J=8.5Hz, 2H), 6.91 (d, J=8.5Hz, 2H), 3.82 (s, 3H), 3.42 (dd, J=5.1,1.1Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H).19F NMR(377MHz,CDCl3)δ-99.66.13C NMR(126MHz,CDCl3) δ 198.35 (d, J=1.3Hz), 158.45,157.40 (d, J=3.1Hz), 150.37 (d, J= 259.1Hz), 127.79 (d, J=5.7Hz), 125.86 (d, J=4.5Hz), 113.85,110.82,85.21 (d, J=12.5Hz), (d, J=3.5Hz), 55.26,30.10,27.86 18.72.MS (70eV): m/z (%): 262 (M+,65.26),180(100). HRMS calculates C15H15O3F:262.1005, actual measurement: 262.1004.
Embodiment 15
By 1-carbethoxyl group-4-(3,3,3-trifluoropropyl-1-alkene-2-base) benzene (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is made For raw material, other operate reference example 1, stir 5h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=10:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-15 (52mg, 86%).
Mp 119-121℃.1H NMR(400MHz,CDCl3) δ 8.02 (d, J=8.5Hz, 2H), 7.47 (d, J=8.5Hz, 2H), 4.37 (q, J=7.1Hz, 2H), 3.45 (dd, J=4.9,0.9Hz, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 1.39 (t, J=7.1 Hz,3H).19F NMR(377MHz,CDCl3)δ-94.78.13C NMR(100MHz,CDCl3) δ 198.01 (d, J=1.3 Hz), 166.22,157.16 (d, J=3.1Hz), 151.68 (d, J=263.2Hz), 138.11 (d, J=5.1Hz), 129.55, 128.63 (d, J=1.3Hz), 126.27 (d, J=6.4Hz), 111.15,85.21 (d, J=11.4Hz), 60.94,30.12,27.29 (d, J=3.3Hz), 18.59,14.28.MS (70eV): m/z (%): 304 (M+, 16.58), 44 (100) .HRMS calculate C17H17O4F:304.1111, actual measurement: 304.1109.
Embodiment 16
By 1-nitro-3-(3,3,3-trifluoropropyl-1-alkene-2-base) benzene (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) is as former Material, other operate reference example 1, stir 7h, silica gel chromatography (petroleum ether: ethyl acetate=10:1), obtain under room temperature 4H-pyran derivate sterling III-16 (44mg, 79%) is replaced to single fluorine.
1H NMR(400MHz,CDCl3) δ 8.24 (s, 1H), 8.14 7.98 (m, 1H), 7.75 (dd, J=7.9,0.7Hz, 1H), 7.53 (t, J=8.1Hz, 1H), 3.47 (dd, J=5.0,1.0Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H).19F NMR(377 MHz,CDCl3)δ-94.72.13C NMR(101MHz,CDCl3) δ 197.78 (d, J=1.3Hz), 157.11 (d, J=3.1 Hz), 151.91 (d, J=262.9Hz), 148.36,135.36 (d, J=4.9Hz), 132.43 (d, J=7.0Hz), 129.30, 121.56,121.09 (d, J=6.2Hz), 111.16 (d, J=0.8Hz), 84.26 (d, J=11.3Hz), 30.16,27.21 (d, J= 3.1Hz), 18.56.MS (70eV): m/z (%): 277 (M+, 24.25), 43 (100) .HRMS calculate C14H12NO4F: 277.0750, actual measurement: 277.0751.
Embodiment 17
By (3-(trifluoromethyl) butyl-3-alkene-1-alkynyl) benzene (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) as raw material, Other operate reference example 1, stir 5h, silica gel chromatography (petroleum ether: ethyl acetate=15:1), obtain list under room temperature Fluorine replaces 4H-pyran derivate sterling I II-17 (36mg, 70%).
Mp 88-90℃.1H NMR(400MHz,CDCl3) δ 7.48-7.42 (m, 2H), 7.34-7.25 (m, 3H), 3.31 (dd, J= 4.8,1.1Hz,2H),2.27(s,3H),2.22(s,3H).19F NMR(377MHz,CDCl3)δ-88.77.13C NMR(100 MHz,CDCl3) δ 198.09 (d, J=1.2Hz), 157.00 (d, J=2.3Hz), 156.13 (d, J=264.0Hz), 131.31, 128.30 (2C), 122.89,110.48,93.68 (d, J=4.6Hz), 81.21 (d, J=3.1Hz), 72.00 (d, J=16.0Hz), (d, J=1.7Hz), 29.98,28.04 18.61.MS (70eV): m/z (%): 256 (M+, 48.31), 43 (100) .HRMS calculate C16H13O2F:256.0900, actual measurement: 256.0901.
Embodiment 18
By (3-(trifluoromethyl) butyl-3-alkene-1-alkynyl) thiophene (0.6mmol), acetylacetone,2,4-pentanedione (0.2mmol) as raw material, Other operate reference example 1, stir 7h, silica gel chromatography (petroleum ether: ethyl acetate=15:1), obtain list under room temperature Fluorine replaces 4H-pyran derivate sterling III-18 (25mg, 48%).
Mp 63-65℃.1H NMR(400MHz,CDCl3) δ 7.27 (dd, J=5.0,1.0Hz, 1H), 7.21 (dd, J=3.6,1.0 Hz, 1H), 6.98 (dd, J=5.1,3.7Hz, 1H), 3.30 (dd, J=4.8,1.2Hz, 2H), 2.26 (s, 3H), 2.22 (s, 3H).19F NMR(377MHz,CDCl3)δ-87.85.13C NMR(100MHz,CDCl3) δ 198.00,156.93 (d, J=2.3Hz), 156.10 (d, J=264.6Hz), 131.84,127.31,127.03,122.82,110.43,86.71 (d, J=4.5Hz), 84.81 (d, J =3.2Hz), 71.86 (d, J=15.8Hz), 29.95,27.83 (d, J=1.7Hz), 18.56.MS (70eV): m/z (%): 262 (M+, 31.96), 43 (100) .HRMS calculate C14H11O2FS:262.0464, actual measurement: 262.0462.
Embodiment 19
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), methyl acetoacetate (0.2mmol) As raw material, other operate reference example 1, stirring 4h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=15:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-19 (64mg, 81%).
1H NMR(400MHz,CDCl3) δ 7.39 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 4.84 (d, J=6.4Hz, 1H), 4.37 3.89 (m, 2H), 3.65 (s, 3H), 2.39 (s, 3H), 1.21 (t, J=7.1Hz, 3H).19F NMR(377MHz, CDCl3)δ-78.91.13C NMR(100MHz,CDCl3) δ 165.74 (d, J=2.0Hz), 163.63 (d, J=7.0Hz), 158.06 (d, J=280.3Hz), 157.31 (d, J=1.4Hz), 142.61 (d, J=1.7Hz), 131.39 (d, J=6.9Hz), 129.95 (d, J=7.6Hz), 121.08 (d, J=6.4Hz), 109.64,86.50 (d, J=6.7Hz), 60.84,51.80 (d, J=1.6 Hz), 39.51 (d, J=2.2Hz), 18.04 (d, J=1.5Hz), 14.03.MS (70eV): m/z (%): 398 (M+,16.42), 400(M++ 2,16.26), 243 (100) .HRMS calculate C17H16O5FBr:398.0165, actual measurement: 398.0167.
Embodiment 20
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), ethyl acetoacetate (0.2mmol) As raw material, other operate reference example 1, stirring 5h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=20:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-20 (65mg, 79%).
1H NMR(400MHz,CDCl3) δ 7.38 (d, J=8.4Hz, 2H), 7.15 (d, J=8.4Hz, 2H), 4.84 (d, J=6.3Hz, 1H), 4.45 3.97 (m, 4H), 2.39 (s, 3H), 1.21 (t, J=7.2Hz, 3H), 1.19 (t, J=7.2Hz, 3H).19F NMR (377MHz,CDCl3)δ-78.90.13C NMR(100MHz,CDCl3) δ 165.22 (d, J=1.6Hz), 163.68 (d, J= 6.8Hz), 158.04 (d, J=280.0Hz), 157.07 (d, J=1.3Hz), 142.67 (d, J=1.3Hz), 131.24,130.12, (120.97,109.71,86.44 d, J=6.6Hz), 60.88,60.80,39.57 (d, J=1.8Hz), 17.95,14.01,13.93.MS (70eV): m/z (%): 412 (M+,17.39),442(M++ 2,17.41), 257 (100) .HRMS calculate C18H18O5FBr: 412.0322, actual measurement: 412.0324.
Embodiment 21
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), tert-butyl acetoacetate (0.2mmol) As raw material, other operate reference example 1, stirring 7h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=20:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-21 (69mg, 78%).
Mp 78-79℃.1H NMR(400MHz,CDCl3) δ 7.39 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 4.78 (d, J=6.2Hz, 1H), 4.34 3.90 (m, 2H), 2.36 (s, 3H), 1.34 (s, 9H), 1.21 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ-78.80.13C NMR(100MHz,CDCl3) δ 164.45 (d, J=1.6Hz), 163.90 (d, J=6.9Hz), 158.06 (d, J=279.5Hz), 156.08,142.78 (d, J=1.3Hz), 131.18,130.21,120.89, (d, J=6.7Hz), 110.90,86.30 81.80,60.78,39.94 (d, J=1.9Hz), 27.95,17.84,14.06.MS (70eV): M/z (%): 440 (M+,1.19),442(M++ 2,1.27), 229 (100) .HRMS calculate C20H22O5FBr:440.0635, actual measurement: 440.0632.
Embodiment 22
3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), acetoacetate is to benzyl chloride ester (0.2mmol) As raw material, other operate reference example 1, stirring 7h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=20:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-22 (61mg, 60%).
1H NMR(400MHz,CDCl3) δ 7.34 (d, J=8.4Hz, 2H), 7.27 (d, J=8.4Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 7.03 (d, J=8.4Hz, 2H), 5.08 (d, J=12.4Hz, 1H), 4.96 (d, J=12.4Hz, 1H), 4.83 (d, J=6.2 Hz, 1H), 4.22 3.99 (m, 2H), 2.40 (s, 3H), 1.20 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ -78.87.13C NMR(126MHz,CDCl3) δ 165.00 (d, J=1.5Hz), 163.65 (d, J=6.9Hz), 157.86 (d, J= 1.4Hz), 157.85 (d, J=280.1Hz), 142.49,134.27,133.72,131.32,130.16,129.58,128.69,121.09, (d, J=6.7Hz), 109.24,86.54 65.85,60.90,39.56 (d, J=1.8Hz), 18.11,14.05.HRMS (ESI) calculate C23H19BrClFNaO5[M+Na+]: 530.9981, actual measurement: 531.0045.
Embodiment 23
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), benzhydryl-3-oxobutanoic acid esters (0.2mmol) as raw material, other operate reference example 1, stir 3h, silica gel chromatography (petroleum ether: second under room temperature Acetoacetic ester=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-23 (79mg, 72%).
1H NMR(500MHz,CDCl3) δ 7.37 7.28 (m, 3H), 7.35 (d, J=8.5Hz, 2H), δ 7.25 7.17 (m, 5H), 7.12 (d, J=8.5Hz, 2H), 6.88-6.84 (m, 2H), 6.81 (s, 1H), 4.94 (d, J=6.1Hz, 1H), 4.42 3.80 (m, 2H), 2.42 (s, 3H), 1.23 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ-78.63.13C NMR(126 MHz,CDCl3) δ 164.39 (d, J=1.6Hz), 163.79 (d, J=6.9Hz), 158.12 (d, J=1.4Hz), 157.76 (d, J= 280.1Hz),142.54,139.40,139.34,131.41,130.30,128.54,128.35,128.00,127.89,126.95,126.94, (121.07,109.19,86.60 d, J=6.8Hz), 77.92,60.90,39.63 (d, J=1.7Hz), 18.13,14.05.HRMS (ESI) Calculate C29H24BrFNaO5[M+Na+]: 573.0683, actual measurement: 573.0747.
Embodiment 24
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), anthracene-9-ylmethyl-3-ketobutyric acid Ester (0.2mmol) is as raw material, and other operate reference example 1, stirring 7h under room temperature, silica gel chromatography (petroleum ether: Ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-24 (72mg, 63%).
1H NMR(500MHz,CDCl3) δ 8.54 (s, 1H), 8.08-8.04 (m, 4H), 7.69 7.42 (m, 4H), 6.95 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4Hz, 2H), 6.12 (d, J=12.6Hz, 1H), 6.04 (d, J=12.6Hz, 1H), 4.63 (d, J= 5.9Hz, 1H), 4.12 3.81 (m, 2H), 2.39 (s, 3H), 1.09 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3) δ-79.16.13C NMR(126MHz,CDCl3) δ 165.49 (d, J=1.6Hz), 163.55 (d, J=6.8Hz), 157.80 (d, J =279.6Hz), 157.55 (d, J=1.6Hz), 142.15,131.26,130.96,130.91,129.92,129.33,129.07,126.68, (125.28,125.14,123.58,120.74,109.36,86.41 d, J=6.6Hz), 60.70,59.02,39.55 (d, J=1.7Hz), 18.04,13.92.MS (70eV): m/z (%): 574 (M+,6.88),576(M++ 2,6.98), 44 (100) .HRMS calculate C31H24O5FBr:574.0791, actual measurement: 574.0789.
Embodiment 25
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), Propionylacetic acid ethyl ester (0.2mmol) As raw material, other operate reference example 1, stirring 4h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=20:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-25 (57mg, 67%).
1H NMR(400MHz,CDCl3) δ 7.39 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 4.84 (d, J=6.4Hz, 1H), 4.42 3.91 (m, 4H), 2.79 (q, J=7.4Hz, 2H), 1.28 1.14 (m, 9H).19F NMR(377MHz, CDCl3)δ-78.74.13C NMR(126MHz,CDCl3) δ 165.11 (d, J=1.6Hz), 163.76 (d, J=6.9Hz), 161.73,158.32 (d, J=280.2Hz), 142.78,131.31,130.09,121.00,109.08,86.35 (d, J=6.7Hz), (d, J=1.8Hz), 60.92,60.82,39.65 24.70,14.07,13.94,11.46.MS (70eV): m/z (%): 426 (M+, 29.03),428(M++ 2,28.98), 271 (100) .HRMS calculate C19H20O5FBr:426.0478, actual measurement: 426.0474.
Embodiment 26
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), benzyl-3-oxo-caproate (0.2mmol) As raw material, other operate reference example 1, stirring 7h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=20:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-26 (69mg, 69%).
1H NMR(500MHz,CDCl3) δ 7.35-7.30 (m, 3H), 7.33 (d, J=8.5Hz, 2H), 7.17-7.12 (m, 2H), 7.06 (d, J=8.5Hz, 2H), 5.11 (d, J=12.2Hz, 1H), 5.01 (d, J=12.2Hz, 1H), 4.85 (d, J=6.3Hz, 1H), 4.25 4.01 (m, 2H), 2.74 (t, J=7.2Hz, 2H), 1.71 1.60 (m, 2H), 1.20 (t, J=7.1Hz, 3H), 0.94 (t, J =7.4Hz, 3H).19F NMR(377MHz,CDCl3)δ-78.73.13C NMR(126MHz,CDCl3) δ 165.02 (d, J= 1.6Hz), 163.72 (d, J=6.9Hz), 160.99,158.16 (d, J=280.2Hz), 142.60,135.15,131.33,130.14, (128.51,128.37,128.32,121.01,109.51,86.32 d, J=6.7Hz), 66.80,60.83,39.71 (d, J=1.8Hz), 32.85,20.57,14.05,13.57.HRMS (ESI) calculate C25H24BrFNaO5[M+Na+]: 525.0683, actual measurement: 525.0743.
Embodiment 27
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), methyl-4-methyl-3-oxopentanoic acid Ester (0.2mmol) is as raw material, and other operate reference example 1, stirring 7h under room temperature, silica gel chromatography (petroleum ether: Ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-27 (66mg, 78%).
Mp 95-96℃.1H NMR(400MHz,CDCl3) δ 7.39 (d, J=8.4Hz, 2H), 7.12 (d, J=8.4Hz, 2H), 4.83 (d, J=6.5Hz, 1H), 4.35 3.96 (m, 2H), 3.86-3.75 (m, 1H), 3.64 (s, 3H), 1.23 (d, J=6.8Hz, 3H), 1.21 (t, J=7.1Hz, 3H), 1.16 (d, J=6.8Hz, 3H).19F NMR(377MHz,CDCl3)δ-78.76.13C NMR (100MHz,CDCl3) δ 165.75 (d, J=2.1Hz), 164.16,163.71 (d, J=7.1Hz), 158.52 (d, J=280.6 Hz), 142.75 (d, J=1.6Hz), 131.44,129.84,121.05,108.14,86.28 (d, J=7.1Hz), 60.81,51.85, 39.66 (d, J=2.2Hz), 29.08,19.39,19.07,14.07.MS (70eV): m/z (%): 426 (M+,25.31),428(M++2, 25.15), 271 (100) .HRMS calculate C19H20O5FBr:426.0478, actual measurement: 426.0480.
Embodiment 28
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), ethyl-4-methyl-3-oxopentanoic acid Ester (0.2mmol) is as raw material, and other operate reference example 1, stirring 10h under room temperature, silica gel chromatography (petroleum ether: Ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-28 (76mg, 86%).
Mp 109-111℃.1H NMR(500MHz,CDCl3) δ 7.39 (d, J=8.4Hz, 2H), 7.12 (d, J=8.5Hz, 2H), 4.83 (d, J=6.4Hz, 1H), 4.30 3.93 (m, 4H), 3.93 3.62 (m, 1H), 1.23 (d, J=6.8Hz, 3H), 1.21 (t, J=7.1Hz, 3H), 1.18 (t, J=7.1Hz, 3H), 1.16 (d, J=6.8Hz, 3H).19F NMR(377MHz,CDCl3)δ -78.73.13C NMR(126MHz,CDCl3) δ 165.24 (d, J=1.6Hz), 163.91,163.78 (d, J=7.0Hz), 158.51 (d, J=280.4Hz), 142.81,131.34,130.00,121.00,108.24,86.21 (d, J=6.9Hz), 60.93, (d, J=1.7Hz), 60.79,39.74 29.00,19.37,19.05,14.07,13.92.MS (70eV): m/z (%): 440 (M+, 31.61),442(M++ 2,31.76), 285 (100) .HRMS calculate C20H22O5FBr:440.0635, actual measurement: 440.0637.
Embodiment 29
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), 3-cyclohexyl-3-oxopropanoate (0.2mmol) as raw material, other operate reference example 1, stirring 11h under room temperature, silica gel chromatography (petroleum ether: Ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-29 (55mg, 57%).
1H NMR(500MHz,CDCl3) δ 7.38 (d, J=8.4Hz, 2H), 7.12 (d, J=8.5Hz, 2H), 4.83 (d, J=6.4Hz, 1H),4.32–3.96(m,4H),3.52-3.45(m,1H),1.93–1.78(m,3H),1.77–1.66(m,2H),1.67–1.43 (m, 3H), 1.39 1.27 (m, 2H), 1.21 (t, J=7.1Hz, 3H), 1.19 (d, J=6.8Hz, 3H).19F NMR(377MHz, CDCl3)δ-78.68.13C NMR(126MHz,CDCl3) δ 165.33 (d, J=1.7Hz), 163.81 (d, J=6.9Hz), 163.63,158.48 (d, J=280.2Hz), 142.89,131.33,130.00,120.97,108.34,86.21 (d, J=6.9Hz), (60.89,60.79,39.70 d, J=1.7Hz), 39.14,29.43,29.05,25.94,25.80,25.60,14.09,13.94.MS (70 EV): m/z (%): 480 (M+,27.79),482(M++ 2,27.85), 325 (100) .HRMS calculate C23H26O5FBr: 480.0948, actual measurement: 480.0944.
Embodiment 30
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), ethyl benzoylacetate (0.2mmol) As raw material, other operate reference example 1, stirring 5h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=20:1), Obtain single fluorine and replace 4H-pyran derivate sterling III-30 (56mg, 59%).
1H NMR(400MHz,CDCl3) δ 7.48-7.36 (m, 5H), 7.43 (d, J=7.9Hz, 2H), 7.26 (d, J=7.9Hz, 2H), 4.95 (d, J=6.2Hz, 1H), 4.50 3.96 (m, 2H), 3.88 (q, J=7.1Hz, 2H), 1.22 (t, J=7.1Hz, 3H), 0.87 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ-78.10.13C NMR(100MHz,CDCl3)δ165.46(d, J=1.6Hz), 163.62 (d, J=6.8Hz), 158.61 (d, J=281.3Hz), 154.79,142.25,131.86,131.55, (130.43,130.09,128.66,128.09,121.32,110.99,86.33 d, J=6.7Hz), 61.00,60.94,40.69,14.08, 13.41.MS (70eV): m/z (%): 474 (M+,4.78),476(M++ 2,4.84), 105 (100) .HRMS calculate C23H20O5FBr:474.0478, actual measurement: 474.0475.
Embodiment 31
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), trifluoroacetic ethyl acetoacetate (0.2mmol) As raw material, other operate reference example 1, stir 41h, silica gel chromatography (petroleum ether: ethyl acetate under room temperature =15:1), obtain single fluorine and replace 4H-pyran derivate sterling III-31 (28mg, 30%).
1H NMR(400MHz,CDCl3) δ 7.46 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 4.88 (d, J=6.8Hz, 1H), 4.34 3.87 (m, 4H), 1.19 (t, J=7.1Hz, 3H), 1.12 (t, J=7.1Hz, 3H).19F NMR(377MHz, CDCl3)δ-66.86(s,3F),-78.39(s,1F).13C NMR(100MHz,CDCl3) δ 163.06,162.69 (d, J=6.7 Hz), 157.50 (d, J=282.4Hz), 139.09,137.57 (q, J=36.9Hz), 131.94,130.00,122.18 (d, J=28.9 Hz), 117.95 (q, J=274.2Hz), 117.63,85.76 (d, J=6.9Hz), 62.45,61.33,41.67 (d, J=2.0Hz), 13.98,13.57.HRMS (ESI) calculate C18H15BrF4NaO5[M+Na+]: 488.9931, actual measurement: 489.0008.
Embodiment 32
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), 1,3-diphenyl propane-1,3-diketone (0.2mmol) as raw material, other operate reference example 1, stir 6h, silica gel chromatography (petroleum ether: second under room temperature Acetoacetic ester=15:1), obtain single fluorine and replace 4H-pyran derivate sterling III-32 (42mg, 42%).
Mp 144-146℃.1H NMR(400MHz,CDCl3) δ 7.45 (d, J=8.4Hz, 2H), 7.38 (d, J=8.4Hz, 2H), 7.32 7.06 (m, 10H), 5.06 (d, J=6.2Hz, 1H), 4.24 4.05 (m, 2H), 1.21 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ-77.12.13C NMR(126MHz,CDCl3) δ 195.23 (d, J=1.1Hz), 163.63 (d, J=6.6Hz), 159.24 (d, J=280.4Hz), 150.06,141.51,136.43,132.95,131.71,130.80,130.42, (129.87,129.07,128.55,128.22,128.12,121.39,116.94,85.73 d, J=6.8Hz), 60.91,42.76,14.08. HRMS (ESI) calculates C27H20BrFNaO4[M+Na+]: 529.0421, actual measurement: 529.0424.
Embodiment 33
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl acrylate (0.6mmol), 1-phenyl butane-1,3-diketone (0.2mmol) As raw material, other operate reference example 1, stirring 3h under room temperature, silica gel chromatography (petroleum ether: ethyl acetate=20:1), The single fluorine obtaining isomery each other replaces 4H-pyran derivate sterling III-33-1, III-33-2 (altogether 47mg, 52%, dr=1.2:1).
III-33-1Mp 99-101℃.1H NMR(400MHz,CDCl3) δ 7.61 7.50 (m, 3H), 7.39 (t, J=7.7Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.06 (d, J=8.4Hz, 2H), 4.95 (d, J=5.8Hz, 1H), 4.26 3.88 (m, 2H), 1.80 (s, 3H), 1.16 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ-77.94.13C NMR(100 MHz,CDCl3) δ 195.31 (d, J=1.3Hz), 163.69 (d, J=6.7Hz), 158.88 (d, J=278.9Hz), 148.87, 141.50,137.41,133.43,131.66,129.67,128.83,128.77,121.25,116.85,85.36 (d, J=6.9Hz), (d, J=2.0Hz), 60.78,41.92 17.66,14.02.MS (70eV): m/z (%): 444 (M+,8.67),446(M++2,4.91), 105 (100) .HRMS calculate C22H18O4FBr:444.0372, actual measurement: 444.0373.
III-33-2Mp 95-97℃.1H NMR(500MHz,CDCl3)δ7.55–7.50(m,1H),7.48–7.45(m,4H), 7.43 (d, J=8.4Hz, 2H), 7.24 (d, J=8.4Hz, 2H), 4.97 (d, J=6.3Hz, 1H), 4.25 4.05 (m, 2H), 1.65 (s, 3H), 1.22 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ-78.27.13C NMR(126MHz, CDCl3) δ 199.60 (d, J=1.1Hz), 163.51 (d, J=6.8Hz), 158.71 (d, J=281.3Hz), 153.36,142.15, 131.65,131.46,131.36,129.98,129.03,128.93,121.28,119.96,86.47 (d, J=6.4Hz), 60.90,41.08 (d, J=2.0Hz), 31.00,14.08.MS (70eV): m/z (%): 444 (M+,8.67),446(M++2,8.57),43(100). HRMS calculates C22H18O4FBr:444.0372, actual measurement: 444.0377.
Embodiment 34
Under argon atmosphere, weigh 1H-indoles (0.31mmol) and be placed in dry reaction tube, inject 2.0ml tetrahydrochysene wherein Furans and methyl-magnesium-bromide (0.29mmol), after stirring 0.5h under room temperature, single fluorine previous embodiment 1 prepared replaces 4H-pyran derivate sterling III-1 (0.26mmol) is dissolved in a small amount of oxolane, is dropwise injected above-mentioned mixed by syringe Close in liquid, continue stirring 1h.Reaction completes, and directly solvent is removed in decompression rotation, and thick product is directly used silica gel flash column chromatography (petroleum ether: ethyl acetate=10:1) obtains indoles and replaces 4H-pyran derivate IV (58mg, 56%).
1H NMR(500MHz,CDCl3) δ 7.63 7.56 (m, 1H), 7.45 (d, J=7.5Hz, 2H), 7.35 (t, J=7.6Hz, 2H), 7.27 (t, J=7.6Hz, 1H), 7.18 7.12 (m, 3H), 7.12 7.06 (m, 1H), 6.63 (d, J=3.4Hz, 1H), 4.97 (s, 1H), 3.88 3.75 (m, 2H), 2.47 (s, 3H), 2.26 (s, 3H), 0.65 (t, J=7.1Hz, 3H).13C NMR(126 MHz,CDCl3)δ198.34,165.07,157.07,148.14,143.74,136.27,129.10,128.86,127.98,127.44, 127.07,123.12,121.41,121.08,117.20,111.00,105.48,102.59,60.80,40.34,29.95,18.64,13.26. HRMS (ESI) calculates C25H23NNaO4[M+Na+]: 424.1519, actual measurement: 424.1532.
Embodiment 35
Under argon atmosphere, inject in the dry reaction pipe equipped with 4A molecular sieve (100mg) and potassium carbonate (0.4mmol) The DMF solution (1.0mL) of 4-methylbenzene phenyl-sulfhydrate (0.24mmol), stirs half an hour under room temperature, by front State single fluorine that embodiment 1 prepares to replace 4H-pyran derivate sterling III-1 (0.2mmol) and be dissolved in 1.0mLDMF, Dropwise inject in above-mentioned mixed liquor by syringe, at 50 DEG C, continue stirring 3h.Reaction completes, and goes out with 5.0mL shrend, second Acetoacetic ester (5.0mL*3 time) extracts.After organic phase is washed with saturated aqueous common salt, dried over magnesium sulfate, solvent is removed in rotation, will be thick Product directly obtains methylbenzene phenyl-sulfhydrate is replaced 4H-pyrans with silica gel flash column chromatography (petroleum ether: dichloromethane=1:2) Derivative V (71mg, 87%).
Mp.133-134℃.1H NMR(500MHz,CDCl3) δ 7.44 (d, J=6.9Hz, 2H), 7.30-7.19 (m, 5H), 7.21 (d, J=6.9Hz, 2H), 4.86 (s, 1H), 4.36 4.14 (m, 2H), 2.41 (s, 3H), 2.16 (s, 3H), 1.98 (s, 3H), 1.32 (t, J =6.5Hz, 3H).13C NMR(100MHz,CDCl3)δ198.51,165.92,157.77,157.76,143.66,139.44, 135.29,129.53,128.47,128.12,127.00,125.18,116.48,106.25,60.73,39.75,29.95,21.29,18.24, 14.24.HRMS (ESI) calculates C24H24NaO4S[M+Na+]: 431.1288, actual measurement: 431.1292.
Embodiment 36
Under argon atmosphere, in-20 DEG C, in dry reaction tube, it is sequentially added into the oxolane of n-butanol (0.24mmol) (1.0mL) solution, n-BuLi (0.24mmol), after stirring 0.5h under room temperature, the list that previous embodiment 4 is prepared Fluorine replaces 4H-pyran derivate sterling III-4 (0.2mmol) and is dissolved in 1.0mL oxolane, is dropwise injected by syringe In above-mentioned mixed liquor, continue stirring 3h.Reaction completes, and goes out with 5.0mL shrend, and ethyl acetate (5.0mL*3 time) extracts. After organic phase is washed with saturated aqueous common salt, dried over magnesium sulfate, solvent is removed in rotation, and thick product is directly pure with silica gel flash column chromatography Change (petroleum ether: ethyl acetate=10:1) and obtain alkoxyl replacement 4H-pyran derivate VI (48mg, 55%).
1H NMR(400MHz,CDCl3) δ 7.37 (d, J=8.4Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 4.80 (s, 1H), 4.29 4.03 (m, 4H), 2.34 (s, 3H), 2.16 (s, 3H), 1.75-1.66 (m, 2H), 1.52 1.41 (m, 2H), 1.23 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.4Hz, 1H).13C NMR(100MHz,CDCl3)δ198.61,165.99,158.92,155.94, 143.45,131.50,129.79,120.74,117.26,86.68,69.55,60.13,39.73,31.24,29.97,18.89,18.36, 14.24,13.66.HRMS (ESI) calculate C21H25BrNaO5[M+Na+]: 459.0783, actual measurement: 459.079.
Embodiment 37
Under room temperature condition, single fluorine previous embodiment 4 prepared replaces 4H-pyran derivate sterling III-4 (0.2mmol) It is dissolved in DMF (2.0ml), is added thereto to tetrabutylammonium acetate ammonium (0.3mmol), stir under room temperature, until III-4 is almost Reaction completely, is gone out with 5.0mL shrend, and ethyl acetate (5.0mL*3 time) extracts.After organic phase is washed with saturated aqueous common salt, Dried over magnesium sulfate, solvent is removed in rotation, by thick product directly with silica gel flash column chromatography (petroleum ether: ethyl acetate=5:1) Obtain enol lactone derivative VII (61mg, 80%).
1H NMR(400MHz,CDCl3) δ 7.46 (d, J=8.3Hz, 2H), 7.05 (d, J=8.5Hz, 2H), 4.56 (s, 1H), 4.32 4.15 (m, 2H), 3.72 (d, J=2.3Hz, 1H), 2.41 (s, 3H), 2.15 (s, 3H), 1.25 (t, J=7.1Hz, 3H).13C NMR(100MHz,CDCl3)δ196.81,165.86,161.66,160.53,136.37,132.67,128.64,122.37,115.32, 62.86,53.70,41.95,29.73,18.78,13.98.HRMS (ESI) calculate C17H17BrNaO5[M+Na+]:403.0152, Actual measurement: 403.0172.
Embodiment 38
Single fluorine of previous embodiment 32 being prepared replaces 4H-pyran derivate sterling III-32 (0.2mmol) as raw material, Other operate reference example 37, obtain enol lactone VIII (74mg, 74%).
Bai Gu (White solid.) Mp 135-136 DEG C.1H NMR(400MHz,CDCl3)δ7.54–7.09(m,14H),4.76(d,J =2.6Hz, 1H), 4.38 4.21 (m, 2H), 3.96 (d, J=2.6Hz, 1H), 1.26 (t, J=7.1Hz, 3H).13C NMR (100MHz,CDCl3)δ194.82,166.36,162.55,156.07,136.79,136.61,132.78,132.47,131.34, 130.66,129.10,128.93,128.83,128.14,128.09,122.17,115.65,62.87,53.35,43.84,14.02. HRMS (ESI) calculates C27H21BrNaO5[M+Na+]: 527.0465, actual measurement: 527.0507.
Embodiment 39
Under argon atmosphere, in-20 DEG C, single fluorine previous embodiment 4 prepared replaces 4H-pyran derivate sterling III-4 (0.2mmol) it is dissolved in dry oxolane (2.0ml), is added dropwise over ethylmagnesium bromide (0.24mmol) wherein, After reaction 3h, it is to slowly warm up to 0 DEG C, until III-4 almost reacts complete, goes out with 5.0mL shrend, ethyl acetate (5.0mL*3 Secondary) extraction.After organic phase is washed with saturated aqueous common salt, dried over magnesium sulfate, solvent is removed in rotation, and thick product is directly fast with silica gel Speed column chromatography purifies (petroleum ether: ethyl acetate=10:1) alkyl and replaces 4H-pyran derivate IX (41mg, 52%).
1H NMR(500MHz,CDCl3) δ 7.37 (d, J=8.4Hz, 2H), 7.11 (d, J=8.4Hz, 2H), 4.74 (s, 1H), 4.23 4.04 (m, 2H), 2.84-2.74 (m, 1H), 2.72-2.63 (m, 1H), 2.33 (s, 3H), 2.16 (s, 3H), 1.24 (t, J=7.1Hz, 3H), 1.16 (t, J=7.1Hz, 3H).13C NMR(126MHz,CDCl3)δ198.32,166.24,162.94,157.46, 143.87,131.47,130.00,120.71,115.74,107.55,60.54,38.52,30.06,25.27,19.12,14.10,11.60. HRMS (ESI) calculates C19H21BrNaO4[M+Na+]: 415.0529, actual measurement: 415.0515.
Embodiment 40
Under room temperature condition, single fluorine previous embodiment 4 prepared replaces 4H-pyran derivate sterling III-4 (0.2mmol) Dissolve with a small amount of oxolane, wherein inject 2.0mL ethanol as solvent, sodium borohydride (0.2mmol) as reducing agent, Stirring 0.5h under room temperature, until III-4 reaction is completely, directly decompression rotation removes solvent, by thick product directly with silica gel quick post look Spectrum purifies (petroleum ether: ethyl acetate=5:1) and obtains single fluorine 4H-pyran derivate X of a pair diastereoisomeric carbonyl reduction And X ' (76mg, 99%, dr=2:1).
Main isomers X1H NMR(400MHz,CDCl3) δ 7.39 (d, J=8.3Hz, 2H), 7.17 (d, J=8.3Hz, 2H), 4.59 (q, J=3.1Hz, 1H), 4.49 (d, J=6.5Hz, 1H), 4.20 4.01 (m, 2H), 2.06 (s, 3H), 1.26 (d, J =6.5Hz, 3H), 1.22 (t, J=7.1Hz, 3H).19F NMR(377MHz,CDCl3)δ-76.81.13C NMR(100MHz, CDCl3) δ 164.38 (d, J=6.9Hz), 159.21 (d, J=279.2Hz), 144.18,143.98,131.58,129.92,120.89, (d, J=7.2Hz), 117.94,85.88 66.91,60.60,38.93 (d, J=2.1Hz), 21.63,15.22,14.10.HRMS (ESI) Calculate C17H18BrFNaO4[M+Na+]: 407.0265, actual measurement: 407.0316.
Secondary isomers X '1H NMR(400MHz,CDCl3) δ 7.40 (d, J=8.3Hz, 2H), 7.18 (d, J=8.3Hz, 2H), 4.59 (d, J=6.5Hz, 1H), 4.53 (q, J=3.6Hz, 1H), 4.19 4.03 (m, 2H), 2.06 (s, 3H), 1.21 (t, J =7.1Hz, 3H), 0.92 (d, J=6.7Hz, 3H).19F NMR(377MHz,CDCl3)δ-76.75.13C NMR(100MHz, CDCl3) δ 164.43 (d, J=6.9Hz), 159.40 (d, J=279.3Hz), 143.84 (d, J=1.1Hz), 143.79,131.49, (130.20,120.89,118.11,85.79 d, J=6.9Hz), 66.01,60.55,38.69 (d, J=2.0Hz), 22.78,15.23, 14.13.HRMS (ESI) calculates C17H18BrFNaO4[M+Na+]: 407.0265, actual measurement: 407.0316.
Embodiment 41
Under the conditions of 50 DEG C, single fluorine previous embodiment 1 prepared replaces 4H-pyran derivate sterling III-1 (0.2mmol) It is dissolved in the mixed solvent (9:1, v/v, 5mL) of oxolane and water, is added thereto to DDQ DDQ (1.2mmol) As oxidant, after stirring 5h, solvent is removed in rotation, adds a small amount of dichloromethane, filter out solid suspension in concentrate, punching Washing filtrate.After dried over sodium sulfate, solvent is removed in rotation, by thick product directly with silica gel flash column chromatography (petroleum ether: acetic acid Ethyl ester=3:1) obtain α-pyrone derivative XI (25mg, 42%).
Mp 128-130℃.1H NMR(400MHz,CDCl3) δ 8.06 (d, J=8.5Hz, 2H), 7.88 (s, 1H), 7.72 (d, J= 8.5Hz, 2H), 4.37 (q, J=7.1Hz, 2H), 2.65 (s, 3H), 2.52 (s, 3H), 1.39 (t, J=7.1Hz, 3H).13C NMR (100MHz,CDCl3)δ194.78,169.49,165.97,159.54,140.46,138.04,130.50,129.62,127.93, 123.00,116.97,61.08,29.36,20.74,14.23.MS (70eV): m/z (%): 300 (M+,24.22),43(100). HRMS calculates C17H16O5: 300.0998, actual measurement: 300.1001.
The present invention is not limited to above example.Under the spirit and scope of inventive concept, those skilled in the art can Change and the advantage expected are included in the present invention, and with appending claims as protection domain.

Claims (14)

1. the preparation method of a 2-fluorine polysubstituted 4H-pyran derivate, it is characterised in that under the effect of alkali, at organic solvent In, containing trifluoromethyl vinyl compound and 1,3-dicarbonyl compound generation cyclization, through extraction, concentration, column chromatography Obtain described 2-fluorine polysubstituted 4H-pyran derivate；Shown in the reaction equation of described preparation method such as formula (1),
Wherein, R1For ester group, aryl, alkynyl；R2For aryl, heteroaryl, alkyl, hydrogen；R3For aryl, alkyl, cycloalkyl, Trifluoromethyl；EWG is ester group.
2. preparation method as claimed in claim 1, it is characterised in that described organic solvent is DMF.
3. preparation method as claimed in claim 1, it is characterised in that the consumption of described organic solvent is 8.0～10.0mL/mmol 1,3-dicarbonyl compound.
4. preparation method as claimed in claim 1, it is characterised in that described alkali is inorganic base, selected from potassium carbonate, sodium carbonate.
5. preparation method as claimed in claim 1, it is characterised in that described reaction is carried out under 50 DEG C to room temperature condition.
6. preparation method as claimed in claim 1, it is characterised in that the reaction time is 3～41 hours.
7. preparation method as claimed in claim 1, it is characterised in that described containing trifluoromethyl vinyl compound, 1,3-dicarbapentaborane Compound, the mol ratio of alkali are trifluoromethyl vinyl compound: 1,3-dicarbonyl compound: alkali=3.0:1.0:1.2.
8. the preparation method of a 2-fluorine polysubstituted 4H-pyran derivate, it is characterised in that under the effect of alkali, at organic solvent In, containing trifluoromethyl vinyl compound and 1,3-dicarbonyl compound generation cyclization, through extraction, concentration, column chromatography Obtain described 2-fluorine polysubstituted 4H-pyran derivate；Shown in the reaction equation of described preparation method such as formula (1),
Wherein, described 2-fluorine polysubstituted 4H-pyran derivate is:
5-acetyl group-2-fluoro-6-methyl 4-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(4-methoxyphenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(4-chlorphenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(4-nitrobenzophenone)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(4-cyano-phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(4-trifluoromethyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(2-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
5-acetyl group-2-fluoro-6-methyl-4-(naphthalene-2-base)-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(furans-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(thiophene-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
5-acetyl group-2-fluoro-4-isobutyl group-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester,
1-(6-fluoro-2-methyl-5-phenyl-4H-pyrans-3-base) ethyl ketone,
1-(the fluoro-5-of 6-(4-methoxyphenyl)-2-methyl-4H-pyrans-3-base) ethyl ketone,
4-(5-acetyl group-2-fluoro-6-methyl-4H-pyrans-3-base) ethyl benzoate,
1-(6-fluoro-2-methyl-5-(3-nitrobenzophenone)-4H-pyrans-3-base) ethyl ketone,
1-(6-fluoro-2-methyl-5-(phenylene-ethynylene)-4H-pyrans-3-base) ethyl ketone,
1-(6-fluoro-2-methyl-5-(thiophene-2-ethyl-acetylene base)-4H-pyrans-3-base) ethyl ketone,
The fluoro-4-of 5-benzoyl-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-acetyl group-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester,
The fluoro-4-of 5-benzoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester；
Wherein, R1、R2、R3, EWG group definition corresponding with formula III compound.
9. preparation method as claimed in claim 8, it is characterised in that described organic solvent is DMF.
10. preparation method as claimed in claim 8, it is characterised in that the consumption of described organic solvent is 8.0～10.0 ML/mmol 1,3-dicarbonyl compound.
11. preparation methods as claimed in claim 8, it is characterised in that described alkali is inorganic base, selected from potassium carbonate, carbonic acid Sodium.
12. preparation methods as claimed in claim 8, it is characterised in that described reaction is carried out under 50 DEG C to room temperature condition.
13. preparation methods as claimed in claim 8, it is characterised in that the reaction time is 3～41 hours.
14. preparation methods as claimed in claim 8, it is characterised in that described containing trifluoromethyl vinyl compound, 1,3-bis-carbonyl Based compound, the mol ratio of alkali are trifluoromethyl vinyl compound: 1,3-dicarbonyl compound: alkali=3.0:1.0:1.2.
CN201510047442.6A 2015-01-29 2015-01-29 2-fluorine polysubstituted 4H-pyran derivate and preparation method thereof Expired - Fee Related CN104592181B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510047442.6A CN104592181B (en) 2015-01-29 2015-01-29 2-fluorine polysubstituted 4H-pyran derivate and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510047442.6A CN104592181B (en) 2015-01-29 2015-01-29 2-fluorine polysubstituted 4H-pyran derivate and preparation method thereof

Publications (2)

Publication Number Publication Date
CN104592181A CN104592181A (en) 2015-05-06
CN104592181B true CN104592181B (en) 2016-08-24

Family

ID=53118285

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510047442.6A Expired - Fee Related CN104592181B (en) 2015-01-29 2015-01-29 2-fluorine polysubstituted 4H-pyran derivate and preparation method thereof

Country Status (1)

Country Link
CN (1) CN104592181B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105481748B (en) * 2016-02-01 2018-05-15 华东师范大学 Polysubstituted dihydro pyrrole derivates of 5- fluorine and preparation method thereof
CN105646422A (en) * 2016-03-18 2016-06-08 华东师范大学 Chiral multi-substituted 4H-pyran derivative and preparation method thereof
CN111233666A (en) * 2020-01-16 2020-06-05 山东师范大学 Method for efficiently synthesizing trifluoromethyl compound, trifluoromethyl compound and application
CN114181182B (en) * 2021-12-20 2023-06-16 青岛科技大学 Synthesis method of polysubstituted 4H-pyran compound
CN115043807A (en) * 2022-07-12 2022-09-13 山西天宏达安医药科技有限公司 Mono-fluorinated 4H-pyran compound and synthetic method thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
1-(Trifluoromethy1)ethenyl Phenyl Selenide and 1-(Trifluoromethy1)ethenyl Phenyl Sulfide;Andrew E. Feiring et al.;《J . Org. Chem.》;19801231;第45卷;第1962-1964页 *
Polyhalogenoheterocyclic Compounds. Part 35. Reactions of Fluorinated Alkenes and Cycloalkenes with Enolate Anions;Richard D. Chambers et al.;《J. Chem. Soc. Perkin Trans. I》;19830101;第1239-1242页 *
Synthesis of geminal-bis(trifluoromethyl)-substituted dienes, heterodienes, 7,7,7,8,8,8-hexafluoro-β-cyclocitral and -safranal;K. Brandt et al.;《Journal of Fluorine Chemistry》;19991231;第97卷;第115-125页 *

Also Published As

Publication number Publication date
CN104592181A (en) 2015-05-06

Similar Documents

Publication Publication Date Title
CN104592181B (en) 2-fluorine polysubstituted 4H-pyran derivate and preparation method thereof
AU2014241390B2 (en) GPR120 agonists for the treatment of type II diabetes
CN105481748B (en) Polysubstituted dihydro pyrrole derivates of 5- fluorine and preparation method thereof
CN105884663A (en) Preparation method of (Z)-sulfonyl olefine acid ester
CN106866707B (en) A kind of preparation method of benzimidazole simultaneously [2,1-b] thiazole
CN107324982B (en) 1-trifluoromethyl-tetrasubstituted cyclopentene derivative and preparation method and application thereof
CN106045952B (en) A kind of synthetic method of the benzofuran ketone compound containing sulfuryl
Sutariya et al. A domino synthetic approach for new, angular pyrazol-and isoxazol-heterocycles using [DBU][Ac] as an effective reaction medium
CA3147078A1 (en) (2-acetamidyl)thio-beta-d-galactopyranoside derivatives
Zhu et al. Electronic tuning cyclization of aryl-1, 4-enediones: AlCl3-mediated Nazarov-type cyclization to synthesize polysubstituted-1-indanones
CN102167674B (en) 3-aryl (alkyl) sulfur substituted-1-propylene compound and method of synthesizing same
CN107118140B (en) A kind of β-acyl group-allyl methyl sulfide derivative and preparation method thereof
CN105732648A (en) Nitrogen heterocyclic ring compound of pyrrolofuran and synthetic method
CN103739574B (en) A kind of synthetic method of 5H-furans-2-ketone compounds of replacement
CN109293700A (en) Chiral diphosphine ligand, preparation method, intermediate and application
CN1326926A (en) Preparing D-(-)-Su's 1-R-substituted phenyl-2-difluoro acetoamino-3-fluoro-1-propanol from L type substituted phenyl serine ester
CN105646422A (en) Chiral multi-substituted 4H-pyran derivative and preparation method thereof
CN108285415A (en) A kind of preparation method of 1,5- dione compounds
CN108299198A (en) A kind of preparation method of 1,4- dione compounds
Pavlik et al. A Short Entry to α-Substituted γ-Alkylidene Pentenolides. Synthesis and Preliminary Biological Evaluation of Novel Gelastatin Analogues
CN105753910A (en) Preparation method of canagliflozin intermediate
CN103992301B (en) The preparation method of 2-hydroxyl-5-oxo-4-aryl-2-trifluoromethyl-3,4,5,6,7,8-six hydrogen-2H-chromene-3-carboxylate compound
Shi et al. Unusual reaction of β-hydroxy α-diazo carbonyl compounds with TsNHN CHCOCl/Et3N
CN105481806A (en) Synthetic method and application of five-membered ring compound containing sulfone group
Rao et al. Nitroketene dithioacetal chemistry: Synthesis of coumarins incorporating nitrothiophene moiety

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160824

Termination date: 20190129