CN104592181A - 2-fluoro-polysubstituted-4H-pyran derivatives and preparation method thereof - Google Patents

2-fluoro-polysubstituted-4H-pyran derivatives and preparation method thereof Download PDF

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CN104592181A
CN104592181A CN201510047442.6A CN201510047442A CN104592181A CN 104592181 A CN104592181 A CN 104592181A CN 201510047442 A CN201510047442 A CN 201510047442A CN 104592181 A CN104592181 A CN 104592181A
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fluoro
pyrans
methyl
carboxylic acid
ethyl ester
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CN104592181B (en
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肖元晶
杨洁茹
毛傲
岳振亭
张俊良
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East China Normal University
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    • 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

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  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The invention relates to 2-fluoro-polysubstituted-4H-pyran derivatives. The structure of the 2-fluoro-polysubstituted-4H-pyran derivatives is as shown in the formula (III). A preparation method of the 2-fluoro-polysubstituted-4H-pyran derivatives comprises the following steps: performing cyclization reaction on trifluoromethyl-containing alkene compounds and 1,3-dicarbonyl compounds under the action of alkali, extracting, concentrating, and performing column chromatography to obtain the 2-fluoro-polysubstituted-4H-pyran derivatives. The reaction formula of the preparation method is as shown in the formula (I). The preparation method is mild in reaction condition and simple to operate, the structural skeleton of the 2-fluoro-polysubstituted-4H-pyran derivative compounds is obtained.

Description

Polysubstituted 4H-pyran derivate of 2-fluorine and preparation method thereof
Technical field
The present invention relates to the preparation method of fluorine pyran derivate, be specifically related to polysubstituted 4H-pyran derivate of a class 2-fluorine and preparation method thereof, belong to chemical substance and preparing technical field thereof.
Background technology
Very high chemical bond energy is there is in C-F key due to self, not easy fracture, the more difficult sense realizing self transforms, therefore develop gentleness, efficiently method and realize activation and the fracture of C-F key, thus prepare fluorine-containing or fluorine-free compounds with practical value and become focus in current organic synthesis field (see (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 because the chemical structure of uniqueness can pass through S with nucleophilic reagent n2 'or S nv reaction realizes self through carbon-fluorine bond activation fracture and transforms, for part is fluorine-containing or synthesis without fluoride compound matter 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 adopts hydrazine compound as double nucleophile, passes through S with 2-Trifluoromethyl-1-alkenes compounds n2 ' and S nv 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.).As everyone knows, 4H-pyrylium compound is considered to 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 as potential medicine ((a) B.S.Jensen, the D.Strobaek of sicklemia, secretory diarrhea, autoimmune disorder, S.P.Olesen, P.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, compared with fluorochemicals and not fluorochemicals, often there is higher reactive behavior and physiologically active ((a) J.-P.B é gu é, D.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.), therefore the study on the synthesis of fluorinated organic compound is also greatly paid close attention at life science related fields.In numerous fluorinated organic compounds, single fluorine heterogeneous ring compound has demonstrated wide application prospect ((a) A.A.Gakh in medicine and commercial synthesis intermediate, K.L.Kirk, Fluorinatedheterocycles.American Chemical Society, Washington DC, 2009; (b) V.A.Petrov, Fluorinated heterocycliccompounds:synthesis, chemistry, and applications.Wiley, Hoboken, 2009), but, study on the synthesis rarely found report ((a) A.E.Feiring.J.Org.Chem.1980,45, the 1962-1964 of single fluorine 4H-pyrans heterogeneous ring compound; (b) A.A.Gakh.Top Heterocycl Chem, 2012,27,33 – 64.).
Summary of the invention
The present invention has enriched the synthetic methodology of single fluorine heterogeneous ring compound further, the synthetic method of single fluorine 4H-pyranoid ring derivative that a kind of raw material is easy to get, reaction conditions gentle, chemo-selective is good is provided, prepares the polysubstituted 4H-pyran derivate of the new 2-fluorine of a class.
The invention provides the polysubstituted 4H-pyran derivate of 2-fluorine shown in a kind of formula (III), structure such as formula shown in (III),
Wherein, R 1for ester group, carbonyl, aryl, alkynyl; R 2for aryl, heteroaryl, alkyl, hydrogen; R 3for aryl, alkyl, cycloalkyl, trifluoromethyl etc.; EWG comprises ester group, carbonyl.
Preferably, described aryl comprise phenyl or neighbour, the substituted-phenyl of contraposition; Described heteroaryl is furans, thiophene.
Further, described R 1for ethoxycarbonyl, phenyl, 4-p-methoxy-phenyl, 4-carboethoxyphenyl, 3-nitrophenyl, phenylene-ethynylene, thiophene-2-ethyl-acetylene base, benzoyl, naphthalene-1-ethyl-acetylene base; Described R 2for phenyl, 4-p-methoxy-phenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-nitrophenyl, 4-cyano-phenyl, 4-trifluoromethyl, 2-bromophenyl, naphthalene-2-base, furans-2-base, thiophene-2-base, isobutyl-, hydrogen; Described R 3for methyl, ethyl, propyl group, sec.-propyl, cyclohexyl, phenyl, trifluoromethyl.
In the present invention, the polysubstituted 4H-pyran derivate of 2-fluorine shown in described formula (III) comprises, the fluoro-6-methyl 4-phenyl of 5-ethanoyl-2--4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-p-methoxy-phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-chloro-phenyl-)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-nitrophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-cyano-phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-trifluoromethyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(2-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-6-methyl of 5-ethanoyl-2--4-(naphthalene-2-base)-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(furans-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(thiophene-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-isobutyl-of 5-ethanoyl-2--6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 1-(the fluoro-2-methyl of 6--5-phenyl-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-5-of 6-(4-p-methoxy-phenyl)-2-methyl-4H-pyrans-3-base) ethyl ketone, 4-(the fluoro-6-methyl of 5-ethanoyl-2--4H-pyrans-3-base) ethyl benzoate, 1-(the fluoro-2-methyl of 6--5-(3-nitrophenyl)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl of 6--5-(phenylene-ethynylene)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl of 6--5-(thiophene-2-ethyl-acetylene base)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl 4-phenyl of 5-benzoyl-6--4H-pyrans-3-base) ethyl ketone, the fluoro-4-of 5-methoxycarbonyl base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-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 the fluoro-4-of benzyloxycarbonylchloride base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-hexichol methoxycarbonyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-(naphthalene-9-methoxycarbonyl) the fluoro-4-of-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-ethyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbobenzoxy-(Cbz)-2-(4-bromophenyl)-6-propyl group-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-methoxycarbonyl-2-(4-bromophenyl)-6-sec.-propyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-sec.-propyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-cyclohexyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-trifluoromethyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-benzoyl-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-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 preparation method that the present invention proposes with 2-Trifluoromethyl-1-alkene (namely, vinyl compound containing trifluoromethyl group), 1,3-dicarbonyl compound is raw material, be dissolved in organic solvent, under the effect of alkali, eliminated through addition single fluorine 4H pyran derivate that cascade reaction obtains polysubstituted multifunctional dough of the present invention.
Preparation method such as formula the single fluorine replacement 4H-pyran derivate shown in (III) provided by the invention is, under the effect of alkali, containing trifluoromethyl vinyl compound and formula (II) shown 1 shown in formula (I), 3-dicarbonyl compound generation cyclization, obtains the polysubstituted 4H-pyran derivate of described 2-fluorine through extraction, concentrated, column chromatography; The reaction formula of described preparation method such as formula shown in (1),
Wherein, R 1for ester group, carbonyl, aryl, alkynyl; R 2for aryl, heteroaryl, alkyl, hydrogen; R 3for aryl, alkyl, cycloalkyl, trifluoromethyl etc.; EWG comprises ester group, carbonyl.
Preferably, described aryl comprise phenyl or neighbour, the substituted-phenyl of contraposition; Described heteroaryl is furans, thiophene.
Further, described R 1for ethoxycarbonyl, phenyl, 4-p-methoxy-phenyl, 4-carboethoxyphenyl, 3-nitrophenyl, phenylene-ethynylene, thiophene-2-ethyl-acetylene base, benzoyl, naphthalene-1-ethyl-acetylene base; Described R 2for phenyl, 4-p-methoxy-phenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-nitrophenyl, 4-cyano-phenyl, 4-trifluoromethyl, 2-bromophenyl, naphthalene-2-base, furans-2-base, thiophene-2-base, isobutyl-, hydrogen; Described R 3for methyl, ethyl, propyl group, sec.-propyl, cyclohexyl, phenyl, trifluoromethyl.
Wherein, the polysubstituted 4H-pyran derivate of the 2-fluorine shown in formula (III) obtained prepared according to the methods of the invention, comprise, the fluoro-6-methyl 4-phenyl of 5-ethanoyl-2--4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-p-methoxy-phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-chloro-phenyl-)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-nitrophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-cyano-phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-trifluoromethyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(2-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-6-methyl of 5-ethanoyl-2--4-(naphthalene-2-base)-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(furans-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(thiophene-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-isobutyl-of 5-ethanoyl-2--6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 1-(the fluoro-2-methyl of 6--5-phenyl-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-5-of 6-(4-p-methoxy-phenyl)-2-methyl-4H-pyrans-3-base) ethyl ketone, 4-(the fluoro-6-methyl of 5-ethanoyl-2--4H-pyrans-3-base) ethyl benzoate, 1-(the fluoro-2-methyl of 6--5-(3-nitrophenyl)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl of 6--5-(phenylene-ethynylene)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl of 6--5-(thiophene-2-ethyl-acetylene base)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl 4-phenyl of 5-benzoyl-6--4H-pyrans-3-base) ethyl ketone, the fluoro-4-of 5-methoxycarbonyl base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-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 the fluoro-4-of benzyloxycarbonylchloride base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-hexichol methoxycarbonyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-(naphthalene-9-methoxycarbonyl) the fluoro-4-of-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-ethyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbobenzoxy-(Cbz)-2-(4-bromophenyl)-6-propyl group-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-methoxycarbonyl-2-(4-bromophenyl)-6-sec.-propyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-sec.-propyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-cyclohexyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-trifluoromethyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-benzoyl-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-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.
In one embodiment, the preparation process of the polysubstituted 4H-pyran derivate of the 2-fluorine shown in formula of the present invention (III) is, to dissolve in organic solvent containing trifluoromethyl vinyl compound, under the effect of mineral alkali, at ambient temperature with 1,3-dicarbonyl compound generation cyclization, react rear extraction, concentrated, obtain such as formula the polysubstituted 4H-pyran derivate of the 2-fluorine shown in (III) through column chromatography.
In preparation method of the present invention, reaction is carried out in organic solvent.Particularly, in the step of the polysubstituted 4H-pyran derivate of preparation formula (III) 2-fluorine, 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 mineral alkali, is alkali salt further, is selected from salt of wormwood, sodium carbonate.Particularly, in the step of the polysubstituted 4H-pyran derivate of preparation formula (III) 2-fluorine, described alkali salt comprises salt of wormwood, sodium carbonate etc.Preferably, described alkali is salt of wormwood.
In preparation method of the present invention, the described mol ratio containing trifluoromethyl vinyl compound, 1,3-dicarbonyl compound, alkali is trifluoromethyl vinyl compound: 1,3-dicarbonyl compound: alkali=3.0:1.0:1.2.
In preparation method of the present invention, remove the mode of solvent and comprise: first extract with the reaction solution after ether or acetic acid ethyl reaction, dry and revolve to boil off and desolventize, or directly revolve to boil off and desolventize, thus obtain thick product.
In preparation method of the present invention, described column chromatography adopts volume ratio to be sherwood oil: 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 carries out under specific temperature of reaction, and e.g., the polysubstituted 4H-pyran derivate of preparation formula (III) 2-fluorine carries out under 50 DEG C to room temperature condition; Preferably, at room temperature carry out.
In preparation method of the present invention, the reaction times is about 3 ~ 41 hours.
Each raw material in preparation method of the present invention, comprise organic solvent, alkali etc., all can buy and directly use in market, such as, organic solvent adopts DMF, and alkali adopts mineral alkali.In one embodiment, preparation method of the present invention is, first takes a certain amount of molecular sieve, the salt of wormwood of formula (II) 1,3-dicarbonyl compound amount of substance 1.2 times, is placed in dry reaction tubes.Under argon atmosphere, take the vinyl compound of formula (I) containing trifluoromethyl group by a certain percentage, formula (II) 1,3-dicarbonyl compound.Such as: formula (I) is containing the vinyl compound of trifluoromethyl group: formula (II) 1,3-dicarbonyl compound mol ratio=3.0:1.0.The vinyl compound, 1, the 3-dicarbonyl compound that contain trifluoromethyl group are dissolved in 1mL DMF respectively, are added in above-mentioned reaction tubes by syringe.Then, react under room temperature reaction condition, or react at 50 DEG C, monitor reaction by tlc silica gel plate (TLC) in whipping process and carry out degree, reaction times is about 3 ~ 41 hours, reaction terminate rear first undertaken extracting rear drying by ether or ethyl acetate and revolve to boil off desolventize, then, thick product is carried out column chromatography, obtains formula (III) 2-fluorine polysubstituted 4H-pyran derivate sterling.Wherein, such as, be sherwood oil by volume ratio: the eluent of ethyl acetate=20:1 ~ 5:1 carries out column chromatography.
The preparation method of the polysubstituted 4H-pyran derivate of 2-fluorine of the present invention, with the vinyl compound containing trifluoromethyl group, 1,3-dicarbonyl compound is raw material, is obtained by reacting and comprises alkyl, heteroaryl under mineral alkali effect, aryl and substituted aryl, ester group, the polysubstituted 4H-pyran derivate of 2-fluorine of the groups such as alkynyl, product structure is such as formula shown in (III).Beneficial effect of the present invention comprises, and raw material is easy to get, and reaction conditions is gentle, simple to operate, can fast and synthesize the polysubstituted 4H-pyran derivate of 2-fluorine efficiently.The present invention has opened up a series of synthesis application of reaction product by other path, achieve the reduction of carbonyl, oxidation defluorinate, defluorinate nucleophilic substitution etc., the polysubstituted 4H-pyrylium compound of 2-fluorine prepared by the present invention, may be used for the enol lactone synthesizing multifunctional dough, a series of bioactive moleculess such as α-pyrone, have great importance in pharmacy, organic synthesis field.
The invention provides single fluorine pyrylium compound skeleton of various structures, not only significant to the synthesis of single fluorine substituted pyrane compounds, and to the synthesis screening of new drug and drug research, all there is extremely important meaning.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The preparation method of the polysubstituted 4H-pyran derivate of 2-fluorine that the present invention proposes, will such as formula the vinyl compound compound containing trifluoromethyl group shown in (I), such as formula 1 shown in (II), 3-dicarbonyl compound is dissolved in DMF respectively, wherein, vinyl compound containing trifluoromethyl group: 1, 3-dicarbonyl compound mol ratio=3.0:1.0, injected by syringe and molecular sieve and formula (II) 1 are housed, in the dry reaction pipe of the salt of wormwood of 3-dicarbonyl compound amount of substance 1.2 times, react under room temperature to 50 DEG C temperature condition, except desolventizing, obtain such as formula the polysubstituted 4H-pyran derivate of the 2-fluorine shown in (III) through column chromatography,
Wherein, R 1for ester group, carbonyl, aryl, alkynyl; R 2for aryl, heteroaryl, alkyl, hydrogen; R 3for aryl, alkyl, cycloalkyl, trifluoromethyl etc.; EWG is ester group, carbonyl.Wherein, described aryl comprise phenyl or neighbour, the substituted-phenyl of contraposition; Described heteroaryl is furans, thiophene substituting group.
Embodiment 1
By raw material 3-phenyl-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is dissolved in 1.0mLN respectively, dinethylformamide, injected by syringe and molecular sieve and formula (II) 1 are housed, in the dry reaction pipe of the salt of wormwood of 3-dicarbonyl compound amount of substance 1.2 times, fully react under 50 DEG C to room temperature, react 6 hours, by TLC detection reaction, to methyl ethyl diketone completely dissolve.5.0ml distilled water cancellation reaction is added after reaction terminates, extract by ether or ethyl acetate (3*5.0ml), merge organic relevant dry and revolve to boil off and desolventize, then directly used by thick product silica gel flash column chromatography (sherwood oil: ethyl acetate=20:1) to obtain single fluorine and replace 4H-pyran derivate sterling I II-1 (44mg, 73%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.53. 13c NMR (100MHz, CDCl 3) 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), 60.84,40.59 (d, J=2.0Hz), 29.97,18.15,14.08.MS (70eV): m/z (%): 304 (M +, 5.18), 84 (100) .HRMS calculate C 17h 17o 4f:304.1111, actual measurement: 304.1110.
Embodiment 2
By 3-(4-p-methoxy-phenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,7h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-2 (45mg, 68%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.73. 13c NMR (100MHz, CDCl 3) 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=6.2Hz), 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 C 18h 19o 5f:334.1217, actual measurement: 334.1219.
Embodiment 3
By 3-(4-chloro-phenyl-)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,7h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-3 (46mg, 68%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.00. 13c NMR (100MHz, CDCl 3) 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), 60.96,40.07 (d, J=2.0Hz), 30.04,18.23,14.09.MS (70eV): m/z (%): 338 (M +, 2.50), 84 (100) .HRMS calculate C 17h 16o 4fCl:338.0721, actual measurement: 338.0718.
Embodiment 4
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,5h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-4 (76mg, 99%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-77.97. 13c NMR (100MHz, CDCl 3) 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), 60.97,40.15 (d, J=2.0Hz), 30.05,18.24,14.10.MS (70eV): m/z (%): 382 (M +, 7.63), 384 (M ++ 2,7.56), 43 (100) .HRMS calculate C 17h 16o 4fBr:382.0216, actual measurement: 382.0219.
Embodiment 5
By 3-(4-nitrophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,5h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=5:1), obtain single fluorine and replace 4H-pyran derivate sterling III-5 (69mg, 99%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-77.07. 13c NMR (100MHz, CDCl 3) 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 C 17h 16nO 5f:349.0962, actual measurement: 349.0961.
Embodiment 6
By 3-(4-cyano-phenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,6h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=5:1), obtain single fluorine and replace 4H-pyran derivate sterling III-6 (45mg, 69%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-77.20. 13c NMR (100MHz, CDCl 3) 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=7.8Hz), 61.10,40.65,30.24,18.40,14.05.MS (70eV): m/z (%): 329 (M +, 34.40), 43 (100) .HRMS calculate C 18h 16nO 4f:329.1063, actual measurement: 329.1064.
Embodiment 7
By 3-(4-trifluoromethyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,5h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-7 (54mg, 73%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-62.59 (s, 3F) ,-77.62 (s, 1F). 13c NMR (100MHz, CDCl 3) 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 C 18h 16o 4f 4: 372.0985, actual measurement: 372.0982.
Embodiment 8
By 3-(2-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,3h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-8 (51mg, 67%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.78. 13c NMR (100MHz, CDCl 3) 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=6.9Hz), 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 calculate C 17h 16o 4fBr:382.0216, actual measurement: 382.0219.
Embodiment 9
By 3-(2-naphthyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,3h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-9 (55mg, 78%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.44. 13c NMR (100MHz, CDCl 3) δ 198.29 (d, J=1.1Hz), 163.99 (d, J=6.8Hz), 157.79 (d, J=279.9Hz), 155.13,140.13,133.24,132.69,128.56,127.93,127.57,127.26,126.21,126.12,126.05,117.18,86.97 (d, J=6.7Hz), 60.85,40.81,30.04,18.21,14.07.MS (70eV): m/z (%): 354 (M +, 100) and .HRMS calculates C 21h 19o 4f:354.1267, actual measurement: 354.1265.
Embodiment 10
By 3-(furans-2-base)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,3h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-10 (49mg, 84%).
1h NMR (400MHz, CDCl 3) 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=7.1Hz, 3H). 19f NMR (377MHz, CDCl 3) δ-76.69. 13c NMR (100MHz, CDCl 3) δ 197.81 (d, J=1.1Hz), 163.79 (d, J=6.9Hz), 158.36 (d, J=280.4Hz), 156.55,154.48 (d, J=1.6Hz), 142.16,114.50,110.51,106.80,84.35 (d, J=7.9Hz), 60.94,34.30,29.62,18.25,14.12.MS (70eV): m/z (%): 294 (M +, 51.71), 43 (100) .HRMS calculate C 15h 15o 5f:294.0904, actual measurement: 294.0902.
Embodiment 11
By 3-(thiophene-2-base)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,3h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-11 (46mg, 74%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-77.45. 13c NMR (100MHz, CDCl 3) 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 C 15h 15o 4fS:310.0675, actual measurement: 310.0676.
Embodiment 12
By 3-isobutyl--2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1,12h is stirred in reaction, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-12 (39mg, 68%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) 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 calculate C 15h 21o 4f:284.1424, actual measurement: 284.1426.
Embodiment 13
By (3,3,3-trifluoropropyl-1-alkene-2-base) benzene (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, 4h is stirred, silica gel chromatography (sherwood oil: ethyl acetate=15:1) at other operation reference examples 1,50 DEG C, obtain single fluorine and replace 4H-pyran derivate sterling III-13 (32mg, 70%).
1h NMR (400MHz, CDCl 3) δ 7.43-7.32 (m, 4H), 7.24 (t, J=7.2Hz, 1H), δ 3.42 (dd, J=5.0,1.0Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H). 19f NMR (377MHz, CDCl 3) δ-98.11. 13c NMR (100MHz, CDCl 3) 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 C 14h 13o 2f:232.0900, actual measurement: 232.0899.
Embodiment 14
By 1-methoxyl group-4-(3,3,3-trifluoropropyl-1-alkene-2-base) benzene (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, 10h is stirred, silica gel chromatography (sherwood oil: ethyl acetate=15:1) at other operation reference examples 1,50 DEG C, obtain single fluorine and replace 4H-pyran derivate sterling III-14 (20mg, 38%).
1h NMR (500MHz, CDCl 3) 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, CDCl 3) δ-99.66. 13cNMR (126MHz, CDCl 3) 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), 55.26,30.10,27.86 (d, J=3.5Hz), 18.72.MS (70eV): m/z (%): 262 (M +, 65.26), 180 (100) .HRMS calculate C 15h 15o 3f:262.1005, actual measurement: 262.1004.
Embodiment 15
By 1-ethoxycarbonyl-4-(3,3,3-trifluoropropyl-1-alkene-2-base) benzene (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 5h, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-15 (52mg, 86%).
Mp 119-121 DEG C. 1h NMR (400MHz, CDCl 3) 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=7.1Hz, 3H). 19f NMR (377MHz, CDCl 3) δ-94.78. 13c NMR (100MHz, CDCl 3) δ 198.01 (d, J=1.3Hz), 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 C 17h 17o 4f:304.1111, actual measurement: 304.1109.
Embodiment 16
By 1-nitro-3-(3,3,3-trifluoropropyl-1-alkene-2-base) benzene (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 7h, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-16 (44mg, 79%).
1h NMR (400MHz, CDCl 3) 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 (377MHz, CDCl 3) δ-94.72. 13c NMR (101MHz, CDCl 3) δ 197.78 (d, J=1.3Hz), 157.11 (d, J=3.1Hz), 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 C 14h 12nO 4f:277.0750, actual measurement: 277.0751.
Embodiment 17
By (3-(trifluoromethyl) fourth-3-alkene-1-alkynyl) benzene (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 5h, silica gel chromatography (sherwood oil: ethyl acetate=15:1), obtain single fluorine and replace 4H-pyran derivate sterling I II-17 (36mg, 70%).
Mp 88-90 DEG C. 1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-88.77. 13c NMR (100MHz, CDCl 3) 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), 29.98,28.04 (d, J=1.7Hz), 18.61.MS (70eV): m/z (%): 256 (M +, 48.31), 43 (100) .HRMS calculate C 16h 13o 2f:256.0900, actual measurement: 256.0901.
Embodiment 18
By (3-(trifluoromethyl) fourth-3-alkene-1-alkynyl) thiophene (0.6mmol), methyl ethyl diketone (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 7h, silica gel chromatography (sherwood oil: ethyl acetate=15:1), obtain single fluorine and replace 4H-pyran derivate sterling III-18 (25mg, 48%).
Mp 63-65 DEG C. 1h NMR (400MHz, CDCl 3) δ 7.27 (dd, J=5.0,1.0Hz, 1H), 7.21 (dd, J=3.6,1.0Hz, 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). 19fNMR (377MHz, CDCl 3) δ-87.85. 13c NMR (100MHz, CDCl 3) 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 C 14h 11o 2fS:262.0464, actual measurement: 262.0462.
Embodiment 19
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl acetoacetate (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 4h, silica gel chromatography (sherwood oil: ethyl acetate=15:1), obtain single fluorine and replace 4H-pyran derivate sterling III-19 (64mg, 81%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.91. 13c NMR (100MHz, CDCl 3) 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=1.6Hz), 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 C 17h 16o 5fBr:398.0165, actual measurement: 398.0167.
Embodiment 20
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl aceto acetate (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 5h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-20 (65mg, 79%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.90. 13c NMR (100MHz, CDCl 3) 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 C 18h 18o 5fBr:412.0322, actual measurement: 412.0324.
Embodiment 21
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), tert-butyl acetoacetate (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 7h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-21 (69mg, 78%).
Mp 78-79 DEG C. 1h NMR (400MHz, CDCl 3) 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). 19fNMR (377MHz, CDCl 3) δ-78.80. 13c NMR (100MHz, CDCl 3) 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), 131.18,130.21,120.89,110.90,86.30 (d, J=6.7Hz), 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 C 20h 22o 5fBr:440.0635, actual measurement: 440.0632.
Embodiment 22
3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), etheric acid to benzyl chloride ester (0.2mmol) as raw material, other operate reference example 1, stirred at ambient temperature 7h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-22 (61mg, 60%).
1h NMR (400MHz, CDCl 3) 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=6.2Hz, 1H), 4.22 – 3.99 (m, 2H), 2.40 (s, 3H), 1.20 (t, J=7.1Hz, 3H). 19f NMR (377MHz, CDCl 3) δ-78.87. 13c NMR (126MHz, CDCl 3) 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), 142.49,134.27,133.72,131.32,130.16,129.58,128.69,121.09,109.24,86.54 (d, J=6.7Hz), 65.85,60.90,39.56 (d, J=1.8Hz), 18.11,14.05.HRMS (ESI) calculate C 23h 19brClFNaO 5[M+Na +]: 530.9981, actual measurement: 531.0045.
Embodiment 23
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), diphenyl-methyl-3-oxobutanoic acid esters (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 3h, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-23 (79mg, 72%).
1h NMR (500MHz, CDCl 3) 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, CDCl 3) δ-78.63. 13c NMR (126MHz, CDCl 3) 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) calculates C 29h 24brFNaO 5[M+Na +]: 573.0683, actual measurement: 573.0747.
Embodiment 24
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), anthracene-9-ylmethyl-3-oxobutanoic acid esters (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 7h, silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtain single fluorine and replace 4H-pyran derivate sterling III-24 (72mg, 63%).
1h NMR (500MHz, CDCl 3) δ 8.54 (s, 1H), 8.08-8.04 (m, 4H), 7.69 – 7.42 (m, 4H), 6.95 (d, J=8.4Hz, 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, CDCl 3) δ-79.16. 13c NMR (126MHz, CDCl 3) 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 C 31h 24o 5fBr:574.0791, actual measurement: 574.0789.
Embodiment 25
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), Propionylacetic acid ethyl ester (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 4h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-25 (57mg, 67%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.74. 13c NMR (126MHz, CDCl 3) 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), 60.92,60.82,39.65 (d, J=1.8Hz), 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 C 19h 20o 5fBr:426.0478, actual measurement: 426.0474.
Embodiment 26
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), benzyl-3-oxo-caproate (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 7h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-26 (69mg, 69%).
1h NMR (500MHz, CDCl 3) 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, CDCl 3) δ-78.73. 13c NMR (126MHz, CDCl 3) 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) calculates C 25h 24brFNaO 5[M+Na +]: 525.0683, actual measurement: 525.0743.
Embodiment 27
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), methyl-4-methyl-3-oxopentanoic acid ester (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 7h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-27 (66mg, 78%).
Mp 95-96 DEG C. 1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.76. 13c NMR (100MHz, CDCl 3) δ 165.75 (d, J=2.1Hz), 164.16,163.71 (d, J=7.1Hz), 158.52 (d, J=280.6Hz), 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 C 19h 20o 5fBr:426.0478, actual measurement: 426.0480.
Embodiment 28
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), ethyl-4-methyl-3-oxopentanoic acid ester (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 10h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-28 (76mg, 86%).
Mp 109-111 DEG C. 1h NMR (500MHz, CDCl 3) 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, CDCl 3) δ-78.73. 13c NMR (126MHz, CDCl 3) 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), 60.93,60.79,39.74 (d, J=1.7Hz), 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 C 20h 22o 5fBr:440.0635, actual measurement: 440.0637.
Embodiment 29
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), 3-cyclohexyl-3-oxopropanoate (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 11h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-29 (55mg, 57%).
1h NMR (500MHz, CDCl 3) 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, CDCl 3) δ-78.68. 13c NMR (126MHz, CDCl 3) 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 (70eV): m/z (%): 480 (M +, 27.79), 482 (M ++ 2,27.85), 325 (100) .HRMS calculate C 23h 26o 5fBr:480.0948, actual measurement: 480.0944.
Embodiment 30
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), ethyl benzoylacetate (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 5h, silica gel chromatography (sherwood oil: ethyl acetate=20:1), obtain single fluorine and replace 4H-pyran derivate sterling III-30 (56mg, 59%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-78.10. 13c NMR (100MHz, CDCl 3) δ 165.46 (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 C 23h 20o 5fBr:474.0478, actual measurement: 474.0475.
Embodiment 31
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), trifluoroacetic ethyl acetoacetate (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 41h, silica gel chromatography (sherwood oil: ethyl acetate=15:1), obtain single fluorine and replace 4H-pyran derivate sterling III-31 (28mg, 30%).
1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-66.86 (s, 3F) ,-78.39 (s, 1F). 13c NMR (100MHz, CDCl 3) δ 163.06,162.69 (d, J=6.7Hz), 157.50 (d, J=282.4Hz), 139.09,137.57 (q, J=36.9Hz), 131.94,130.00,122.18 (d, J=28.9Hz), 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) calculates C 18h 15brF 4naO 5[M+Na +]: 488.9931, actual measurement: 489.0008.
Embodiment 32
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), 1,3-diphenyl propane-1,3-diketone (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 6h, silica gel chromatography (sherwood oil: ethyl acetate=15:1), obtain single fluorine and replace 4H-pyran derivate sterling III-32 (42mg, 42%).
Mp 144-146 DEG C. 1h NMR (400MHz, CDCl 3) 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). 19fNMR (377MHz, CDCl 3) δ-77.12. 13c NMR (126MHz, CDCl 3) 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 C 27h 20brFNaO 4[M+Na +]: 529.0421, actual measurement: 529.0424.
Embodiment 33
By 3-(4-bromophenyl)-2-(trifluoromethyl) ethyl propenoate (0.6mmol), 1-phenyl butane-1,3-diketone (0.2mmol) is as raw material, other operate reference example 1, stirred at ambient temperature 3h, silica gel chromatography (sherwood oil: 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 DEG C. 1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-77.94. 13c NMR (100MHz, CDCl 3) 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), 60.78,41.92 (d, J=2.0Hz), 17.66,14.02.MS (70eV): m/z (%): 444 (M +, 8.67), 446 (M ++ 2,4.91), 105 (100) .HRMS calculate C 22h 18o 4fBr:444.0372, actual measurement: 444.0373.
III-33-2Mp 95-97 DEG C. 1h NMR (500MHz, CDCl 3) δ 7.55 – 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, CDCl 3) δ-78.27. 13c NMR (126MHz, CDCl 3) 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 calculate C 22h 18o 4fBr:444.0372, actual measurement: 444.0377.
Embodiment 34
Under argon atmosphere, take 1H-indoles (0.31mmol) and be placed in dry reaction tubes, inject 2.0ml tetrahydrofuran (THF) and methyl-magnesium-bromide (0.29mmol) wherein, after stirred at ambient temperature 0.5h, single fluorine previous embodiment 1 prepared replaces 4H-pyran derivate sterling III-1 (0.26mmol) and is dissolved in a small amount of tetrahydrofuran (THF), dropwise inject above-mentioned mixed solution by syringe, continue to stir 1h.Reaction completes, and directly desolventizing is revolved in decompression, is directly used by thick product silica gel flash column chromatography (sherwood oil: ethyl acetate=10:1) to obtain indoles and replaces 4H-pyran derivate IV (58mg, 56%).
1h NMR (500MHz, CDCl 3) 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 (126MHz, CDCl 3) δ 198.34,165.07,157.07,148.14,143.74,136.27,129.10,128.86,127.98,127.44,127.07,123.12,121.41,121.08,117.20,111.00,105.48,102.59,60.80,40.34,29.95,18.64,13.26.HRMS (ESI) calculates C 25h 23nNaO 4[M+Na +]: 424.1519, actual measurement: 424.1532.
Embodiment 35
Under argon atmosphere, the N of 4-methylbenzene phenyl-sulfhydrate (0.24mmol) is injected in the dry reaction pipe that 4A molecular sieve (100mg) and salt of wormwood (0.4mmol) is housed, dinethylformamide solution (1.0mL), stirred at ambient temperature half hour, single fluorine previous embodiment 1 prepared replaces 4H-pyran derivate sterling III-1 (0.2mmol) and is dissolved in 1.0mLDMF, dropwise inject above-mentioned mixed solution by syringe, continue to stir 3h at 50 DEG C.Reaction completes, and goes out with 5.0mL shrend, and ethyl acetate (5.0mL*3 time) extracts.Organic phase is with after saturated common salt water washing, through dried over mgso, revolve desolventizing, directly used by thick product silica gel flash column chromatography (sherwood oil: methylene dichloride=1:2) to obtain replacing 4H-pyran derivate V (71mg, 87%) to methylbenzene phenyl-sulfhydrate.
Mp.133-134 DEG C. 1h NMR (500MHz, CDCl 3) 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, CDCl 3) δ 198.51,165.92,157.77,157.76,143.66,139.44,135.29,129.53,128.47,128.12,127.00,125.18,116.48,106.25,60.73,39.75,29.95,21.29,18.24,14.24.HRMS (ESI) calculates C 24h 24naO 4s [M+Na +]: 431.1288, actual measurement: 431.1292.
Embodiment 36
Under argon atmosphere, in-20 DEG C, tetrahydrofuran (THF) (1.0mL) solution of propyl carbinol (0.24mmol) is added successively in the reaction tubes of drying, n-Butyl Lithium (0.24mmol), after stirred at ambient temperature 0.5h, single fluorine previous embodiment 4 prepared replaces 4H-pyran derivate sterling III-4 (0.2mmol) and is dissolved in 1.0mL tetrahydrofuran (THF), dropwise injects above-mentioned mixed solution by syringe, continues to stir 3h.Reaction completes, and goes out with 5.0mL shrend, and ethyl acetate (5.0mL*3 time) extracts.Organic phase is with after saturated common salt water washing, through dried over mgso, revolve desolventizing, directly used by thick product silica gel flash column chromatography (sherwood oil: ethyl acetate=10:1) to obtain alkoxyl group and replace 4H-pyran derivate VI (48mg, 55%).
1h NMR (400MHz, CDCl 3) 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=7.1Hz, 3H), 0.95 (t, J=7.4Hz, 1H). 13c NMR (100MHz, CDCl 3) δ 198.61,165.99,158.92,155.94,143.45,131.50,129.79,120.74,117.26,86.68,69.55,60.13,39.73,31.24,29.97,18.89,18.36,14.24,13.66.HRMS (ESI) calculates C 21h 25brNaO 5[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) and is dissolved in DMF (2.0ml), add tetrabutylammonium acetate ammonium (0.3mmol) wherein, stirred at ambient temperature, until III-4 almost reacts completely, go out with 5.0mL shrend, ethyl acetate (5.0mL*3 time) extracts.Organic phase, with after saturated common salt water washing, through dried over mgso, revolves desolventizing, is directly used by thick product silica gel flash column chromatography (sherwood oil: ethyl acetate=5:1) to obtain enol lactone derivative VII (61mg, 80%).
1h NMR (400MHz, CDCl 3) 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). 13cNMR (100MHz, CDCl 3) δ 196.81,165.86,161.66,160.53,136.37,132.67,128.64,122.37,115.32,62.86,53.70,41.95,29.73,18.78,13.98.HRMS (ESI) calculates C 17h 17brNaO 5[M+Na +]: 403.0152, actual measurement: 403.0172.
Embodiment 38
Single fluorine previous embodiment 32 prepared replaces 4H-pyran derivate sterling III-32 (0.2mmol) as raw material, and other operate reference example 37, obtain enol lactone VIII (74mg, 74%).
Bai Gu (White solid.) Mp 135-136 DEG C. 1h NMR (400MHz, CDCl 3) δ 7.54 – 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, CDCl 3) δ 194.82,166.36,162.55,156.07,136.79,136.61,132.78,132.47,131.34,130.66,129.10,128.93,128.83,128.14,128.09,122.17,115.65,62.87,53.35,43.84,14.02.HRMS (ESI) calculates C 27h 21brNaO 5[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) and is dissolved in dry tetrahydrofuran (THF) (2.0ml), dropwise add ethylmagnesium bromide (0.24mmol) wherein, after reaction 3h, be slowly warming up to 0 DEG C, until III-4 almost reacts completely, go out with 5.0mL shrend, ethyl acetate (5.0mL*3 time) extracts.Organic phase, with after saturated common salt water washing, through dried over mgso, revolves desolventizing, is directly used by thick product silica gel flash column chromatography (sherwood oil: ethyl acetate=10:1) alkyl to replace 4H-pyran derivate IX (41mg, 52%).
1h NMR (500MHz, CDCl 3) 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, CDCl 3) δ 198.32,166.24,162.94,157.46,143.87,131.47,130.00,120.71,115.74,107.55,60.54,38.52,30.06,25.27,19.12,14.10,11.60.HRMS (ESI) calculates C 19h 21brNaO 4[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) and dissolves with a small amount of tetrahydrofuran (THF), inject 2.0mL ethanol wherein as solvent, sodium borohydride (0.2mmol) is as reductive agent, stirred at ambient temperature 0.5h, until III-4 reacts completely, desolventizing is revolved in direct decompression, silica gel flash column chromatography (sherwood oil: ethyl acetate=5:1) is directly used by thick product to obtain single fluorine 4H-pyran derivate X and X ' (76mg of a pair diastereoisomeric carbonyl reduction, 99%, dr=2:1).
Main isomer X 1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-76.81. 13c NMR (100MHz, CDCl 3) δ 164.38 (d, J=6.9Hz), 159.21 (d, J=279.2Hz), 144.18,143.98,131.58,129.92,120.89,117.94,85.88 (d, J=7.2Hz), 66.91,60.60,38.93 (d, J=2.1Hz), 21.63,15.22,14.10.HRMS (ESI) calculates C 17h 18brFNaO 4[M+Na +]: 407.0265, actual measurement: 407.0316.
Secondary isomer X ' 1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ-76.75. 13c NMR (100MHz, CDCl 3) 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 C 17h 18brFNaO 4[M+Na +]: 407.0265, actual measurement: 407.0316.
Embodiment 41
Under 50 DEG C of conditions, single fluorine previous embodiment 1 prepared replaces the mixed solvent (9:1 that 4H-pyran derivate sterling III-1 (0.2mmol) is dissolved in tetrahydrofuran (THF) and water, v/v, 5mL), add DDQ DDQ (1.2mmol) wherein as oxygenant, after stirring 5h, revolve desolventizing, in concentrated solution, add a small amount of methylene dichloride, filters solid suspended substance, rinse filtrate.After dried over sodium sulfate, revolve desolventizing, directly used by thick product silica gel flash column chromatography (sherwood oil: ethyl acetate=3:1) to obtain α-pyrone derivative XI (25mg, 42%).
Mp 128-130 DEG C. 1h NMR (400MHz, CDCl 3) 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, CDCl 3) δ 194.78,169.49,165.97,159.54,140.46,138.04,130.50,129.62,127.93,123.00,116.97,61.08,29.36,20.74,14.23.MS (70eV): m/z (%): 300 (M +, 24.22), 43 (100) .HRMS calculate C 17h 16o 5: 300.0998, actual measurement: 300.1001.
The present invention is not limited to above embodiment.Without prejudice under the spirit and scope of inventive concept, the change that those skilled in the art can expect and advantage all comprise in the present invention, and are protection domain with appending claims.

Claims (10)

1. the polysubstituted 4H-pyran derivate of 2-fluorine, is characterized in that, its structure such as formula shown in (III),
Wherein, R 1for ester group, carbonyl, aryl, alkynyl; R 2for aryl, heteroaryl, alkyl, hydrogen; R 3for aryl, alkyl, cycloalkyl, trifluoromethyl; EWG comprises ester group, carbonyl.
2. the polysubstituted 4H-pyran derivate of 2-fluorine as claimed in claim 1, is characterized in that, described aryl comprise phenyl or neighbour, the substituted-phenyl of contraposition; Described heteroaryl is furans, thiophene.
3. the polysubstituted 4H-pyran derivate of 2-fluorine as claimed in claim 1, it is characterized in that, described 2-fluorine polysubstituted 4H-pyran derivate comprises the fluoro-6-methyl 4-phenyl of 5-ethanoyl-2--4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-p-methoxy-phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-chloro-phenyl-)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-nitrophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-cyano-phenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-trifluoromethyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(2-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-6-methyl of 5-ethanoyl-2--4-(naphthalene-2-base)-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(furans-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(thiophene-2-base)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-isobutyl-of 5-ethanoyl-2--6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 1-(the fluoro-2-methyl of 6--5-phenyl-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-5-of 6-(4-p-methoxy-phenyl)-2-methyl-4H-pyrans-3-base) ethyl ketone, 4-(the fluoro-6-methyl of 5-ethanoyl-2--4H-pyrans-3-base) ethyl benzoate, 1-(the fluoro-2-methyl of 6--5-(3-nitrophenyl)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl of 6--5-(phenylene-ethynylene)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl of 6--5-(thiophene-2-ethyl-acetylene base)-4H-pyrans-3-base) ethyl ketone, 1-(the fluoro-2-methyl 4-phenyl of 5-benzoyl-6--4H-pyrans-3-base) ethyl ketone, the fluoro-4-of 5-methoxycarbonyl base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-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 the fluoro-4-of benzyloxycarbonylchloride base-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-hexichol methoxycarbonyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, 5-(naphthalene-9-methoxycarbonyl) the fluoro-4-of-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-ethyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-carbobenzoxy-(Cbz)-2-(4-bromophenyl)-6-propyl group-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-methoxycarbonyl-2-(4-bromophenyl)-6-sec.-propyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-sec.-propyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-cyclohexyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethoxycarbonyl-2-(4-bromophenyl)-6-trifluoromethyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-2-(4-bromophenyl)-6-methyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-benzoyl-2-(4-bromophenyl)-6-phenyl-4H-pyrans-3-carboxylic acid, ethyl ester, the fluoro-4-of 5-ethanoyl-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.
4. the preparation method of the polysubstituted 4H-pyran derivate of 2-fluorine, it is characterized in that, under the effect of alkali, containing trifluoromethyl vinyl compound and 1,3-dicarbonyl compound generation cyclization, obtains the polysubstituted 4H-pyran derivate of described 2-fluorine through extraction, concentrated, column chromatography; The reaction formula of described preparation method such as formula shown in (1),
Wherein, R 1for ester group, carbonyl, aryl, alkynyl; R 2for aryl, heteroaryl, alkyl, hydrogen; R 3for aryl, alkyl, cycloalkyl, trifluoromethyl; EWG comprises ester group, carbonyl.
5. preparation method as claimed in claim 4, it is characterized in that, described organic solvent is DMF.
6. preparation method as claimed in claim 4, it is characterized in that, the consumption of described organic solvent is 8.0 ~ 10.0mL/mmol1,3-dicarbonyl compound.
7. preparation method as claimed in claim 4, it is characterized in that, described alkali is mineral alkali, is selected from salt of wormwood, sodium carbonate.
8. preparation method as claimed in claim 4, it is characterized in that, described reaction is carried out under 50 DEG C to room temperature condition.
9. preparation method as claimed in claim 4, it is characterized in that, the reaction times is 3 ~ 41 hours.
10. preparation method as claimed in claim 4, is characterized in that, the described mol ratio containing trifluoromethyl vinyl compound, 1,3-dicarbonyl compound, alkali is trifluoromethyl vinyl compound: 1,3-dicarbonyl compound: alkali=3.0:1.0:1.2.
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