CN107011305A - A kind of synthetic method of medicine intermediate aryl ketones coumarin derivative - Google Patents

A kind of synthetic method of medicine intermediate aryl ketones coumarin derivative Download PDF

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CN107011305A
CN107011305A CN201710215204.0A CN201710215204A CN107011305A CN 107011305 A CN107011305 A CN 107011305A CN 201710215204 A CN201710215204 A CN 201710215204A CN 107011305 A CN107011305 A CN 107011305A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/842—Iron

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Abstract

The present invention relates to a kind of synthetic method of medicine intermediate aryl ketones coumarin derivative shown in lower formula (III), methods described includes：In organic solvent, in the presence of bicomponent catalyst, oxidant, reaction promoter and alkali, lower formula (I) compound and lower formula (II) compound react, so that the formula (III) compound is obtained, wherein,R1Selected from H, C1‑C6Alkyl, C1‑C6Alkoxy or halogen；R2For phenyl, naphthyl, the phenyl with substituent or the naphthyl with substituent, the substituent is, C1‑C6Alkyl or halogen；R3For H or, C1‑C6Alkyl；R4For, C1‑C6Alkyl.This method is by the comprehensive selection of bicomponent catalyst, oxidant, reaction promoter, alkali, organic solvent and reaction substrate structure with cooperateing with, purpose product is obtained so as to high yield, is had a good application prospect and extensive industrial production potential in organic chemical synthesis technical field.

Description

A kind of synthetic method of medicine intermediate aryl ketones coumarin derivative
Technical field
The present invention relates to a kind of synthetic method of ketone compounds, relate more particularly to a kind of aryl ketones coumarin derivative Synthetic method, belong to organic chemical synthesis especially medicine intermediate synthesis field.
Background technology
In organic chemistry filed, coumarin kind compound and its derivant structure are widely present in natural active compound Among medical compounds, it gets most of the attention as a kind of important heterocyclic compound.
Just because of the such important effect of coumarin kind compound and pharmaceutical potential, therefore, new cumarin is studied The synthetic method of analog derivative is always the important topic of synthesis chemical field.
The synthetic method of traditional coumarin kind compound is to be related to the condensation reaction of group compounds of aldehydes and ketones, but these sides Method causes the application of substrate to be extremely limited.It is simple to rely on condensation reaction not because coumarin derivatives species is various It disclosure satisfy that the demand of commercial Application.In recent years, a variety of perfume (or spice) are reported one by one to solve these problems in the prior art The synthetic method of legumin analog derivative, for example：
Wei We etc.（“Direct and metal-free arylsulfonylation o f alkynes with sulfonylhydrazides for the construction of 3-sulfonated coumarins ”,Chem. Commun .,2015,51,768-771）A kind of synthetic method nickel of 3- sulfonic acid butylcoumariii is reported, its reaction equation is as follows：
Li Yue wen etc.（“Copper-Catalyzed Direct Trifluoromethylation of Propiolates : Construction of Trifluoromethylated Coumarins”,Organic Letters, 2014,16（16）,4240-4243）A kind of synthesis technique of trifluoromethylation cumarin is reported, its reaction equation is as follows：
However, existing method often has some and is unfavorable for the production of scale, if desired for adding, synthetic yield is inadequate Ideal, process conditions more harshness etc..
In addition, carbonyl is also the common active group of a class in organic chemistry, it has good reactivity, so as to To change into a variety of other groups as starting group, therefore how carbonyl especially aromatic carbonyl is introduced on tonka bean camphor structure （Namely aryl ketones）, it is also the direction studied at present.But so far, such report is seldom.
In order to overcome problems, the present inventor proposes a kind of aryl ketones coumarin derivative by substantial amounts of research Synthetic method, comprehensive selection and combination by many factors such as catalyst obtain purpose product so as to high yield, Industrially there is good application value and productive potentialities.
The content of the invention
In order to overcome many defects as indicated above, present inventor has performed in-depth study and exploration, paying After enough creative works, so as to complete the present invention.
Specifically, technical scheme and content are related to a kind of following formula（III）Shown aryl ketones cumarin derives The synthetic method of thing, methods described includes：In organic solvent, exist in bicomponent catalyst, oxidant, reaction promoter and alkali Under, following formula（I）Compound and following formula（II）Compound reacts, so as to obtain the formula（III）Compound,
Wherein, R1Selected from H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
R2For phenyl, naphthyl, the phenyl with substituent or the naphthyl with substituent, the substituent is C1-C6Alkyl or halogen Element；
R3For H or C1-C6Alkyl；
R4For C1-C6Alkyl.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom Or branched alkyl, for example can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner Butyl, n-pentyl, isopentyl, tertiary pentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6The implication of alkoxy refers to C defined above1-C6Alkyl The group obtained after being connected with oxygen atom.
In the synthetic method of the present invention, the halogen is halogen atom, such as can be F, Cl, Br or I.
In the synthetic method of the present invention, R4For C defined above1-C6Alkyl, the preferably tert-butyl group or tertiary pentyl, Most preferably tertiary pentyl.
In the synthetic method of the present invention, the bicomponent catalyst is that copper compound and 1,1'- are double（Diphenyl Phosphine）The mixture of ferrocene, wherein copper compound and 1,1'- are double（Diphenylphosphine）The mol ratio of ferrocene is 3-4:1.
Wherein, the copper compound is copper acetate, trifluoroacetic acid copper, copper trifluoromethanesulfcomposite, copper nitrate, CuPc or lemon Any one in sour copper, most preferably trifluoroacetic acid copper.
In the synthetic method of the present invention, the oxidant is K2S2O8、（NH4）2S2O8Or Na2S2O8It is any one Kind, most preferably Na2S2O8。
In the synthetic method of the present invention, the reaction promoter is 1,3- double（1- adamantyls）Imidazoles tetrafluoro boric acid Salt, 1,3- are double（1- adamantyls）Any one in imidazole hydrochloride or 1,3- dicyclohexyl tetrafluoroborate, it is optimal Elect 1,3- as double（1- adamantyls）Tetrafluoroborate.
In the synthetic method of the present invention, the alkali is sodium carbonate, caustic alcohol, potassium tert-butoxide, NaOH, bicarbonate Any one in sodium, diisopropanolamine (DIPA) or triisopropanolamine, most preferably triisopropanolamine.
In the synthetic method of the present invention, the organic solvent is acetonitrile and DMF（N,N-dimethylformamide）'s Mixture.Wherein, acetonitrile and DMF volume ratio are 1:3.
In the synthetic method of the present invention, the consumption of the organic solvent is not particularly limited, this area skill Suitable consumption may be selected in art personnel, for example, reacting balance is carried out, or post processing is easy to the amount of progress, and this belongs to ability The conventional technical means in domain, this is no longer going to repeat them.
In the synthetic method of the present invention, the formula（I）Compound and formula（II）The mol ratio of compound is 1: 1.5-2, for example, can be 1:1.5、1:1.7、1:1.9 or 1:2.
In the synthetic method of the present invention, the formula（I）Compound and the mol ratio of bicomponent catalyst are 1: 0.04-0.08, i.e., described formula（I）The mole dosage of compound and the copper compound and 1,1'- for constituting the bicomponent catalyst It is double（Diphenylphosphine）The ratio of the total moles consumption of both ferrocene is 1:0.04-0.08, for example, can be 1:0.04、1:0.06 or 1: 0.08。
In the synthetic method of the present invention, the formula（I）Compound and the mol ratio of oxidant are 1:1-1.5, example Such as can be 1:1、1:1.2、1:1.4 or 1:1.5.
In the synthetic method of the present invention, the formula（I）Compound and the mol ratio of reaction promoter are 1:0.1- 0.2, for example can be 1:0.1、1:0.15 or 1:0.2.
In the synthetic method of the present invention, the formula（I）Compound and the mol ratio of alkali are 1:1-1.4, for example may be used For 1:1、1:1.2 or 1:1.4.
In the synthetic method of the present invention, reaction temperature is 60-80 DEG C, for example, can be 60 DEG C, 70 DEG C or 80 DEG C.
In the synthetic method of the present invention, the reaction time is 5-8 hours, for example, can be 5 hours, 6 hours, 7 hours Or 8 hours.
In the synthetic method of the present invention, the post processing terminated is reacted specific as follows：It is after reaction terminates, reaction is mixed Compound is filtered while hot, and filtrate is naturally cooled into room temperature, is then adjusted pH value to neutrality, is added deionized water and fully vibrate, It is eventually adding ethyl acetate to extract 2-3 times, merges organic phase, be concentrated under reduced pressure, gained residue is crossed into silica gel flash column chromatography, with Volume ratio is 1:2 acetone and the mixed solvent of petroleum ether are as eluent, so as to obtain the formula（III）Compound.
In summary, the invention provides a kind of synthetic method of aryl ketones coumarin derivative, this method is creatively Comprehensive selection and coordination using bicomponent catalyst, oxidant, reaction promoter, alkali and organic solvent, so as to achieve good Good products collection efficiency, has extensive industrial application value in organic synthesis field especially medicine intermediate synthesis field.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and Purpose only be used for enumerate the present invention, not to the present invention real protection scope constitute it is any type of it is any limit, it is more non-will Protection scope of the present invention is confined to this.
Embodiment 1
At room temperature, the appropriate organic solvent into reactor（For volume 1:3 acetonitrile and DMF mixture）In, add 100mmol above formulas（I）Compound, 150mmol above formulas（II）Compound, 4mmol catalyst（For 3mmol trifluoroacetic acids copper with 1mmol1,1'- is double（Diphenylphosphine）The mixture of ferrocene）, 100mmol oxidants Na2S2O8, 10mmol reaction promoters 1,3- It is double（1- adamantyls）Tetrafluoroborate and 100mmol alkali triisopropanolamines；60 DEG C are then heated to, and at such a temperature Stirring reaction 8 hours.
After reaction terminates, reactant mixture is filtered while hot, filtrate is naturally cooled into room temperature, then adjust pH value into Property, adding deionized water fully vibrates, and is eventually adding ethyl acetate and extracts 2-3 times, merges organic phase, is concentrated under reduced pressure, by institute Obtain residue and cross silica gel flash column chromatography, using volume ratio as 1:2 acetone and the mixed solvent of petroleum ether as eluent so that Obtain above formula（III）Compound（Wherein t-Bu is the tert-butyl group）, yield is 97.1%.
1HNMR（CDCl3,400MHz）:δ1.39（s,9H）,7.22-7.35（m,9H）,7.49-7.74（m,2H）,7.83 （D, J=8.4Hz, 2H）.
HRMS（ESI）（（M+H）+）:405.147.
Embodiment 2
At room temperature, the appropriate organic solvent into reactor（For volume 1:3 acetonitrile and DMF mixture）In, add 100mmol above formulas（I）Compound, 200mmol above formulas（II）Compound, 6mmol catalyst（For 4.8mmol trifluoroacetic acids copper with 1.2mmol1,1'- it is double（Diphenylphosphine）The mixture of ferrocene）, 120mmol oxidants Na2S2O8, 20mmol reaction promoters 1, 3- is double（1- adamantyls）Tetrafluoroborate and 120mmol alkali triisopropanolamines；80 DEG C are then heated to, and in the temperature Lower stirring reaction 5 hours.
After reaction terminates, reactant mixture is filtered while hot, filtrate is naturally cooled into room temperature, then adjust pH value into Property, adding deionized water fully vibrates, and is eventually adding ethyl acetate and extracts 2-3 times, merges organic phase, is concentrated under reduced pressure, by institute Obtain residue and cross silica gel flash column chromatography, using volume ratio as 1:2 acetone and the mixed solvent of petroleum ether as eluent so that Obtain above formula（III）Compound, yield is 97.4%.
1HNMR（CDCl3,400MHz）:δ6.95-7.04（m,1H）,7.22（D, J=8.8,1H）,7.18-7.38 （m, 8H）, 7.54（T, J=7.4Hz, 1H）,7.82（D, J=8.4Hz, 2H）.
HRMS（ESI）（（M+H）+）:367.074.
Embodiment 3
At room temperature, the appropriate organic solvent into reactor（For volume 1:3 acetonitrile and DMF mixture）In, add 100mmol above formulas（I）Compound, 180mmol above formulas（II）Compound, 8mmol catalyst（For 6mmol trifluoroacetic acids copper with 2mmol1,1'- is double（Diphenylphosphine）The mixture of ferrocene）, 150mmol oxidants Na2S2O8, 15mmol reaction promoters 1,3- It is double（1- adamantyls）Tetrafluoroborate and 140mmol alkali triisopropanolamines；70 DEG C are then heated to, and at such a temperature Stirring reaction 6 hours.
After reaction terminates, reactant mixture is filtered while hot, filtrate is naturally cooled into room temperature, then adjust pH value into Property, adding deionized water fully vibrates, and is eventually adding ethyl acetate and extracts 2-3 times, merges organic phase, is concentrated under reduced pressure, by institute Obtain residue and cross silica gel flash column chromatography, using volume ratio as 1:2 acetone and the mixed solvent of petroleum ether as eluent so that Obtain above formula（III）Compound, yield is 97.5%.
1HNMR（CDCl3,400MHz）:δ2.32（s,3H）,7.15-7.19（m,4H）,7.26（D, J=8.1Hz, 1H）, 7.34-7.41（m,3H）,7.47-7.55（m,2H）,7.62-7.66（m,1H）,7.83（D, J=8.4Hz, 2H）.
HRMS（ESI）（（M+H）+）:363.099.
Embodiment 4-24
Embodiment 4-6：In addition to the trifluoroacetic acid copper in catalyst is replaced with into copper acetate, other operations are constant, so as to repeat Embodiment 1-3 is carried out, embodiment 4-6 is obtained.
Embodiment 7-9：In addition to the trifluoroacetic acid copper in catalyst is replaced with into copper trifluoromethanesulfcomposite, other operations are not Become, so as to repeat embodiment 1-3, obtain embodiment 7-9.
Embodiment 10-12：In addition to the trifluoroacetic acid copper in catalyst is replaced with into copper nitrate, other operations are constant, from And repeat embodiment 1-3, obtain embodiment 10-12.
Embodiment 13-15：In addition to the trifluoroacetic acid copper in catalyst is replaced with into CuPc, other operations are constant, from And repeat embodiment 1-3, obtain embodiment 13-15.
Embodiment 16-18：In addition to the trifluoroacetic acid copper in catalyst is replaced with into copper citrate, other operations are constant, So as to repeat embodiment 1-3, embodiment 16-18 is obtained.
Embodiment 19-21：Except by catalyst replace with consumption be the total consumption of original two kinds of components one-component trifluoro second Outside sour copper, other operations are constant, so as to repeat embodiment 1-3, obtain embodiment 19-21.
Embodiment 22-24：It is double except catalyst is replaced with into the one-component 1,1'- that consumption is the total consumption of original two kinds of components （Diphenylphosphine）Outside ferrocene, other operations are constant, so as to repeat embodiment 1-3, obtain embodiment 22-24.
As a result it see the table below 1.
Table 1
" -- " represents to be not present.
From the data of table 1, in the bicomponent catalyst of the present invention, when copper compound is trifluoroacetic acid copper With best catalytic effect, even with its unusual similar copper acetate, also yield is caused to significantly reduce；It can also see Go out, when only with the best trifluoroacetic acid copper of effect as one-component catalyst, yield also has obvious reduction（See Embodiment 19-21）, and it is double only with 1,1'-（Diphenylphosphine）During ferrocene, yield is greatly lowered as 26.6-28.3%, Industrialized realistic meaning is lost.This proves only simultaneously double with 1,1'- using trifluoroacetic acid copper（Diphenylphosphine）Two The bicomponent catalyst of luxuriant iron, the unique concerted catalysis effect of competence exertion, could obtain the excellent skill of the present invention between the two Art effect.
Embodiment 25-30
Embodiment 25-27：Except oxidant is replaced with into K2S2O8Outside, other operations are constant, so that repeat embodiment 1-3, Obtain embodiment 25-27.
Embodiment 28-30：Except oxidant is replaced with（NH4）2S2O8Outside, other operations are constant, so as to repeat reality A 1-3 is applied, embodiment 28-30 is obtained.
As a result 2 be see the table below.
Table 2
As can be seen here, only Na2S2O8With best oxidation effectiveness, other oxidants are even very similar with it K2S2O8Also yield is caused to have certain reduction.
Embodiment 31-39
Embodiment 31-33：It is double except reaction promoter is replaced with into 1,3-（1- adamantyls）Outside imidazole hydrochloride, other operations are not Become, so as to repeat embodiment 1-3, obtain embodiment 31-33.
Embodiment 34-36：Except reaction promoter is replaced with outside 1,3- dicyclohexyl tetrafluoroborates, other operations are equal It is constant, so as to repeat embodiment 1-3, obtain embodiment 34-36.
Embodiment 37-39：In addition to reaction promoter is dispensed, other operations are constant, so that repeat embodiment 1-3, Obtain embodiment 37-39.
As a result 3 be see the table below.
Table 3
" -- " represents to be not present.
As seen from the data in Table 3, in all reaction promoters, 1,3- is double（1- adamantyls）Tetrafluoroborate has Best facilitation, and when without using auxiliary agent, yield, which has, significantly to be significantly reduced.
Embodiment 40-57
Embodiment 40-42：In addition to alkali is replaced with into sodium carbonate, other operations are constant, so as to repeat embodiment 1-3, obtain To embodiment 40-42.
Embodiment 43-45：In addition to alkali is replaced with into caustic alcohol, other operations are constant, so as to repeat embodiment 1- 3, obtain embodiment 43-45.
Embodiment 46-48：In addition to alkali is replaced with into potassium tert-butoxide, other operations are constant, so as to repeat embodiment 1-3, obtains embodiment 46-48.
Embodiment 49-51：In addition to alkali is replaced with into NaOH, other operations are constant, so that repeat embodiment 1-3, Obtain embodiment 49-51.
Embodiment 52-54：In addition to alkali is replaced with into sodium acid carbonate, other operations are constant, so as to repeat embodiment 1-3, obtains embodiment 52-54.
Embodiment 55-57：In addition to alkali is replaced with into diisopropanolamine (DIPA), other operations are constant, so as to repeat to implement Example 1-3, obtains embodiment 55-57.
As a result 4 be see the table below.
Table 4
As can be seen here, in all alkali, triisopropanolamine has best effect, and other alkali cause yield to have difference The reduction of degree, wherein even with triisopropanolamine very similar diisopropanolamine (DIPA), its yield also has obvious reduction, and The reduction degree of other alkali then becomes apparent.
Embodiment 58-63
Embodiment 58-60：In addition to the mixed organic solvents of acetonitrile and DMF are replaced with into single solvent acetonitrile, other operations are not Become, so as to repeat embodiment 1-3, obtain embodiment 58-60.
Embodiment 61-63：In addition to the mixed organic solvents of acetonitrile and DMF are replaced with into single solvent DMF, other operations are equal It is constant, so as to repeat embodiment 1-3, obtain embodiment 61-63.
As a result 5 be see the table below.
Table 5
As can be seen here, organic solvent also has a certain impact to reaction yield, can when the mixture using acetonitrile and DMF Best reaction effect is obtained, and when using single solvent component, yield decreases.
Embodiment 64-66
Will be in embodiment 1-3 corresponding to formula except respectively（II）Tertiary pentyl in compound replaces with the tert-butyl group（That is formula（II）Chemical combination Thing is benzoic acid t-butylperbenzoate）Outside, other operations are constant, so as to repeat embodiment 1-3, sequentially obtain embodiment 64-66。
As a result find, the yield of corresponding product is：Embodiment 64 is that 92.1%, embodiment 65 is 90.4% and embodiment 66 For 91.2%.
As can be seen here, formula（II）The group R4 of compound is most preferably tertiary pentyl, can now obtain very excellent production Produce rate, it was demonstrated that the selection of reaction substrate being capable of the final technique effect of significant impact.
Summary, the present inventor proposes a kind of synthetic method of aryl ketones coumarin derivative first, and this method is led to The comprehensive selection of bicomponent catalyst, oxidant, reaction promoter, alkali, organic solvent and reaction substrate structure is crossed with cooperateing with, so that Purpose product can be obtained with high yield, have a good application prospect and widely industrialize in organic chemical synthesis technical field Productive potentialities.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention Enclose.In addition, it will also be appreciated that after the technology contents of the present invention have been read, those skilled in the art can make each to the present invention Change, modification and/or variation are planted, all these equivalent form of values equally fall within the guarantor that the application appended claims are limited Within the scope of shield.

Claims (1)

1. a kind of synthetic method of aryl ketones coumarin derivative shown in lower formula (III), methods described includes：In organic solvent In, in the presence of bicomponent catalyst, oxidant, reaction promoter and alkali, lower formula (I) compound and lower formula (II) compound occur Reaction, after reaction terminates, reactant mixture is filtered while hot, filtrate is naturally cooled into room temperature, then adjusts pH value to neutrality, Add deionized water fully to vibrate, be eventually adding ethyl acetate and extract 2-3 times, merge organic phase, be concentrated under reduced pressure, gained is residual Thing is stayed to cross silica gel flash column chromatography, using volume ratio as 1:2 acetone and the mixed solvent of petroleum ether are as eluent, so as to obtain Formula (III) compound,
Wherein, R1Selected from H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
R2For phenyl, naphthyl, the phenyl with substituent or the naphthyl with substituent, the substituent is C1-C6Alkyl or halogen Element；
R3For H or C1-C6Alkyl；
R4For C1-C6Alkyl；
The bicomponent catalyst is the mixture of copper compound and double (diphenylphosphine) ferrocene of 1,1'-, wherein copper compound Mol ratio with double (diphenylphosphine) ferrocene of 1,1'- is 3-4:1；The copper compound is trifluoroacetic acid copper；
The oxidant is K2S2O8；
The reaction promoter is double (1- adamantyls) tetrafluoroborates of 1,3-；
The alkali is triisopropanolamine；
The organic solvent is the mixture of acetonitrile and DMF, and acetonitrile and DMF volume ratio are 1:3.
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