CN108329197A - A kind of preparation method of indanone compounds - Google Patents
A kind of preparation method of indanone compounds Download PDFInfo
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- CN108329197A CN108329197A CN201711362845.5A CN201711362845A CN108329197A CN 108329197 A CN108329197 A CN 108329197A CN 201711362845 A CN201711362845 A CN 201711362845A CN 108329197 A CN108329197 A CN 108329197A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
The present invention relates to organic synthesis fields, more particularly to a kind of preparation method of indanone compounds.The present invention provides a kind of preparation method of indanone compounds, including：1）Compound of formula I and Formula II compound are subjected to condensation reaction, prepare formula III compound；2）Formula III compound is hydrolyzed in the presence of a base, prepares formula IV compound；3）By formula IV compound acylation, cyclization, Formula V compound is prepared.The preparation method of indanone compounds provided by the present invention is compared with prior art, have many advantages, such as that cost of material is low, easy to operate, the three wastes are few, high income, it is more suitable for industrialized production, the preparation method of various indanone compounds in compared with the existing technology is with the obvious advantage, has good industrialization prospect.
Description
Technical field
The present invention relates to organic synthesis fields, more particularly to a kind of preparation method of indanone compounds.
Background technology
Indanone compounds are the important source materials for synthesizing polyene especially poly alpha olefin metallocene catalyst, are also simultaneously
The important intermediate of the fine chemicals such as synthetic pesticide, liquid crystal and active medicine component.
In existing document report, the synthetic method of some indanone compounds, such as European are had been disclosed for
Journal of Medicinal Chemistry, 2013,62,632-648, Molecules, 2014,19,5599-5610,
Organometallics 2006,25,1217-1229 and WO2007/070041, EP 0576970 A1, US4192888 A1,
US2002077507.The main method that indanone compounds are prepared in report has：
1, using benzaldehyde as the synthetic method of raw material：
Using substituted benzaldehyde as raw material, 3- substituted benzenes are obtained after condensation and decarboxylic reaction with substituted malonate
Base -2- substituent group acrylic acid, then hydrogenated, chloride, alchlor or polyphosphoric acid catalyzed Cyclization indanone compounds
(Organometallics 2006,25,1217-1229).
Using substituted benzaldehyde as raw material, perkin first occurs with acid anhydrides and reacts, right back end hydrogenation, chloride, alchlor
Fu Ke Cyclizations indanone compounds (European Journal of Medicinal Chemistry, 2013,62,632-
648)。
2, using substituted aroma hydrocarbon as raw material:
This method reacts in Aluminium Trichloride as Catalyst with 2- substitution propionyl chlorides using substituted aroma hydrocarbon as raw material, generates substituted benzene
Base ethyl ketone, then through bromination, Aluminium Trichloride as Catalyst cyclisation, hydrolysis obtain indanone compounds (US2002077507).
3, using substituted halogenation benzyl as raw material：
This method is mainly synthesized using substituted halogenation benzyl such as benzyl chloride as raw material, and halogenation benzyl is reacted with substituted malonate
The phenylpropyl alcohol acid compound of substitution is generated, then through chloride, alchlor or phosphorous acid compound for catalysis, further synthesizes indenes
Ketone compounds (US2007/0135595 A1).
In the method that above-mentioned document provides, cost of material is high, and reaction route is longer, complicated for operation, and prior art uses
Phosphorous raw material, will produce a large amount of phosphorus-containing wastewater, Removal of Phosphorus in Wastewater makes cost of goods manufactured greatly increase, otherwise to environment
Cause harmful effect.Therefore, exploitation is simple, the green synthesis method of low-cost suitable industrialization production indanone compounds
As one of the important goal of art technology worker.
Invention content
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide a kind of preparations of indanone compounds
Method, for solving the problems of the prior art.
In order to achieve the above objects and other related objects, the present invention provides a kind of preparation method of indanone compounds, packet
It includes：
1) compound of formula I and Formula II compound are subjected to condensation reaction, prepare formula III compound；
2) formula III compound is hydrolyzed in the presence of a base, prepares formula IV compound；
3) by formula IV compound acylation, cyclization, Formula V compound is prepared；
The structural formula of Formulas I-V compounds is as follows：
Wherein, R1, R2, R3, R4 are each independently selected from the C1-C18 alkyl of H, Cl, Br, I, F, linear chain or branched chain；
R5 is selected from the C1-C18 alkyl of H, Cl, Br, linear chain or branched chain；
R6 is selected from the C1-C18 alkyl of linear chain or branched chain.
X is selected from Cl or Br.
In some embodiments of the invention, R1, R2, R3, R4 are each independently selected from H, Cl, Br, F, linear chain or branched chain
C1-C8 alkyl.
In some of the invention embodiments, R1, R2, R3, R4 be each independently selected from H, Cl, linear chain or branched chain C1-
C4 alkyl.
In some embodiments of the invention, R5 is selected from the C1-C10 alkyl of linear chain or branched chain.
In some embodiments of the invention, R5 is selected from the C1-C4 alkyl of linear chain or branched chain.
In some embodiments of the invention, R6 is selected from the C1-C8 alkyl of linear chain or branched chain.
In some embodiments of the invention, R6 is selected from the C1-C4 alkyl of linear chain or branched chain.
In some embodiments of the invention, in the step 1), the molar ratio of compound of formula I and Formula II compound is 1
~6：1.
In some embodiments of the invention, in the step 1), the molar ratio of compound of formula I and Formula II compound is 1
~3：1.
In some embodiments of the invention, in the step 1), reaction carries out in the presence of a base.
In some embodiments of the invention, in the step 1), the alkali is selected from alkaline metal organic salt, alkali metal carbonic acid
One or more combinations in salt, Sodamide or sodium hydride.
In some embodiments of the invention, in the step 1), alkali is selected from sodium methoxide, potassium methoxide, sodium ethoxide, ethyl alcohol
It is one or more in potassium, sodium tert-butoxide, potassium tert-butoxide, n-BuLi, LDA, sodium hydride, Sodamide, sodium carbonate, potassium carbonate
Combination.
In some embodiments of the invention, in the step 1), the molar ratio of alkali and Formula II compound is 1~5：1.
In some embodiments of the invention, in the step 1), the molar ratio of alkali and Formula II compound is 1~3：1.
In some embodiments of the invention, in the step 1), reaction carries out in the presence of a solvent.
In some embodiments of the invention, in the step 1), solvent is selected from organic solvent.
In some embodiments of the invention, in the step 1), organic solvent is selected from ether solvent.
In some embodiments of the invention, in the step 1), the ether solvent is selected from ether, methyl tertbutyl
One or more combinations in ether, dioxane, tetrahydrofuran, 2- methyltetrahydrofurans.
In some embodiments of the invention, in the step 1), the temperature of reaction is 0-120 DEG C.
In some embodiments of the invention, in the step 1), the temperature of reaction is 20-50 DEG C.
In some embodiments of the invention, in the step 1), the post-processing of reaction includes：Water quenching is added to go out.
In some embodiments of the invention, in the step 2), alkali is selected from NaOH and/or KOH.
In some embodiments of the invention, in the step 2), the molar ratio of alkali and formula III compound is 1~6: 1,
Preferably 1~3: 1.
In some embodiments of the invention, in the step 2), the temperature of reaction is 0-100 DEG C.
In some embodiments of the invention, in the step 2), the temperature of reaction is 30-60 DEG C.
In some embodiments of the invention, in the step 2), the post-processing of reaction includes：Liquid separation, gained water phase tune
PH to 2.0-5.0 is saved, organic phase is collected.
In some embodiments of the invention, in the step 3), reaction carries out in the presence of a solvent.
In some embodiments of the invention, in the step 3), solvent is selected from organic solvent, and organic solvent is selected from dichloro
One or more combinations in methane, dichloroethanes, toluene, chlorobenzene, nitromethane, nitroethane.
In some of the invention embodiments, in the step 3), under the conditions of acylation reaction is existing for acylating reagent into
The molar ratio of row, acylating reagent and formula IV compound is 1~3: 1.
In some embodiments of the invention, in the step 3), the acylating reagent is selected from thionyl chloride and/or grass
Acyl chlorides.
In some embodiments of the invention, in the step 3), the reaction temperature of acylation reaction is 0-100 DEG C.
In some of the invention embodiments, in the step 3), under the conditions of ring closure reaction is existing for lewis acid into
Row.
In some embodiments of the invention, in the step 3), lewis acid is selected from alchlor, zinc chloride, trichlorine
Change one or more combinations in iron, butter of tin, alchlor.
In some embodiments of the invention, in the step 3), in the step 3), lewis acid and formula IV compound
Molar ratio be 1~3: 1.
In some embodiments of the invention, in the step 3), in the step 3), lewis acid and formula IV compound
Molar ratio be 1.2~2：1.
In some embodiments of the invention, in the step 3), the reaction temperature of ring closure reaction is 0-100 DEG C.
In some embodiments of the invention, in the step 3), the post-processing of reaction includes：It is quenched, liquid separation, organic phase
Precipitation purifies up to the indone compound.
In some embodiments of the invention, in the step 3), the method for purification is rectifying and/or recrystallization.
Specific implementation mode
Inventor passes through numerous studies, provides one kind and preparing indenes by condensation, hydrolysis, acylation, cyclization
The method of ketone compounds, the preparation method is of low cost, simple and practicable, completes the present invention on this basis.
One aspect of the present invention provides a kind of preparation method of indanone compounds, and the structural formula of the indanone compounds is such as
Shown in Formula V compound, the preparation method may include：
1) compound of formula I and Formula II compound are subjected to condensation reaction, prepare formula III compound；
2) formula III compound is hydrolyzed in the presence of a base, prepares formula IV compound；
3) by formula IV compound acylation, cyclization, Formula V compound is prepared；
The structural formula of Formulas I-V compounds is as follows：
In the preparation method of indanone compounds provided by the present invention, R1, R2, R3, R4 can be each independently selected from
H, the C1-C18 alkyl of Cl, Br, I, F, linear chain or branched chain is more preferably selected from the C1-C8 alkyl of H, Cl, Br, F, linear chain or branched chain,
The further preferably C1-C4 alkyl selected from H, Cl, linear chain or branched chain；R5 can be selected from the C1-C18 of H, Cl, Br, linear chain or branched chain
Alkyl is more preferably selected from the C1-C10 alkyl of linear chain or branched chain, is further preferably selected from the C1-C4 alkyl of linear chain or branched chain；R6
It can be more preferably selected from the C1-C8 alkyl of linear chain or branched chain selected from the alkyl of the linear chain or branched chain of C1-C18, further preferably selected
From the C1-C4 alkyl of linear chain or branched chain；X can be selected from Cl or Br..The C1-C4 alkyl can be specifically such as methyl, second
Base, n-propyl, isopropyl, normal-butyl, tertiary butyl, sec-butyl, isobutyl group etc..
In the preparation method of indanone compounds provided by the present invention, condensation reaction compounds of formula I is relative to Formula II
Compound by molar amount is typically basic equivalent or excessive, for example, the molar ratio of compound of formula I and Formula II compound can
Think 1~6：1, or 1~3：1.
In the preparation method of indanone compounds provided by the present invention, condensation reaction usually in the presence of a base into
Row, the alkali can be such as alkaline metal organic salt, alkali carbonate, Sodamide, sodium hydride in it is one or more
Combination, more specifically can be for example sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-BuLi,
One or more combinations in LDA, sodium hydride, Sodamide, sodium carbonate, potassium carbonate etc..The alkali is relative to Formula II compound
By molar amount it is typically basic equivalent or excessive, for example, the molar ratio of alkali and Formula II compound is 1~5：1, it can also
It is 1~3：1.
In the preparation method of indanone compounds provided by the present invention, condensation reaction is usually in the presence of a solvent
It carries out, solvent used in condensation reaction is usually organic solvent, and it is suitable that those skilled in the art can select according to reaction substrate
Organic solvent type and usage amount so that reaction substrate can fully disperse in the reaction system, for example, condensation is anti-
Solvent used in answering can be such as ether solvent, more specifically can be such as ether, methyl tertiary butyl ether(MTBE), dioxy six
One or more combinations in ring, tetrahydrofuran, 2- methyltetrahydrofurans etc., in a preferred embodiment of the invention, contracting
It is tetrahydrofuran to close the solvent used in reaction；For another example the dosage of solvent can be Formula II chemical combination substance in condensation reaction
1-20 times of amount.
In the preparation method of indanone compounds provided by the present invention, condensation reaction can usually be boiled not higher than solvent
It is carried out under point or room temperature to the temperature condition of solvent boiling point, for example, the temperature of condensation reaction can be 0-120 DEG C, or
20-50℃.Those skilled in the art can suitably adjust the reaction time of condensation reaction according to reaction process, monitor reaction process
Method should be known to those skilled in the art, such as can be the analysis methods such as chromatography, nuclear magnetic resonance method,
The specific reaction time can be such as 1-5 hours.
In the preparation method of indanone compounds provided by the present invention, suitable rear place may be selected in those skilled in the art
Reason method post-processes the product obtained by condensation reaction, for example, after the completion of reaction, the post-processing of condensation reaction can wrap
It includes：Into system plus water quenching is gone out.In a preferred embodiment of the invention, the reaction solution that water quenching is gone out is added to be used directly for
Subsequent reactions step.
In the preparation method of indanone compounds provided by the present invention, suitable species can be selected in those skilled in the art
Alkali is to provide the alkaline condition needed for hydrolysis, for example, the alkali can be NaOH and/or KOH, alkali is relative to formula in hydrolytic process
III compounds are typically basic equivalent or excessive according to the molar ratio, for example, the molar ratio of alkali and formula III compound can be with
It is 1~6: 1, or 1~3: 1.
In the preparation method of indanone compounds provided by the present invention, hydrolysis can usually be boiled not higher than solvent
It is carried out under point or room temperature to the temperature condition of solvent boiling point, for example, the temperature of hydrolysis can be 0-100 DEG C, or 30-60
℃.Those skilled in the art can suitably adjust the reaction time of hydrolysis according to reaction process, monitor the method for reaction process for
It should be known for those skilled in the art, such as can be the analysis methods such as chromatography, nuclear magnetic resonance method, it is specific anti-
It can be such as 1-5 hours between seasonable.
In the preparation method of indanone compounds provided by the present invention, suitable rear place may be selected in those skilled in the art
Reason method post-processes the product of hydrolysis gained, for example, after the completion of reaction, the post-processing of hydrolysis may include：Liquid separation,
Gained water phase adjusts pH to 2.0-5.0, collects organic phase, and suitable pH adjusting agent may be selected for adjusting in those skilled in the art
The pH value for saving reaction system, for example, applicable HCl, H3PO4、H2SO4、CH3COOH or their aqueous solution etc..
In the preparation method of indanone compounds provided by the present invention, acylation reaction and/or ring closure reaction can have
Carried out under the conditions of solvent is existing, those skilled in the art can be selected according to reaction substrate suitable organic solvent type and
Usage amount, so that reaction substrate can fully disperse in the reaction system, for example, in acylation reaction and/or ring closure reaction
Used organic solvent can be halogenated hydrocarbon solvent, nitro compound species solvent etc., more specifically can be such as dichloromethane
One or more combinations in alkane, dichloroethanes, toluene, chlorobenzene, nitromethane, nitroethane etc.；For another example acylation reaction
And/or the dosage of solvent can be 1-10 times of formula IV compound quality in ring closure reaction.
In the preparation method of indanone compounds provided by the present invention, the acylation reaction usually item existing for acylating reagent
It is carried out under part, the acylating reagent typically thionyl chloride and/oxalyl chloride, the acylating reagent is relative to formula IV compound
It is typically basic equivalent or excessive according to the molar ratio, for example, the molar ratio of the thionyl chloride and formula IV compound can be with
It is 1~3: 1.Acylating reagent is usually to be added by amount when reaction system is added, for example, it may be being added dropwise.
In the preparation method of indanone compounds provided by the present invention, acylation reaction can usually be boiled not higher than solvent
It is carried out under point or room temperature to the temperature condition of solvent boiling point, for example, the temperature of acylation reaction can be 0-100 DEG C.This field skill
Art personnel can suitably adjust the reaction time of acylation reaction according to reaction process, monitor the method for reaction process for this field skill
It should be known for art personnel, such as can be the analysis methods such as chromatography, nuclear magnetic resonance method, the specific reaction time can
To be such as 2-16 hours.
In the preparation method of indanone compounds provided by the present invention, the ring closure reaction usually item existing for lewis acid
Carried out under part, the lewis acid can be such as alchlor, zinc chloride, ferric trichloride, butter of tin, alchlor in
One or more combinations, the alchlor relative to formula IV compound according to the molar ratio be typically basic equivalent or mistake
Amount, for example, the alchlor and the molar ratio of formula IV compound can be 1~3: 1, can also be 1.2~2：1.Cyclization
When reaction, usually the corresponding chloride compounds obtained by acylation reaction can be added by amount in reaction system (can be in system
Including alchlor and solvent), for example, it may be being added dropwise.
In the preparation method of indanone compounds provided by the present invention, ring closure reaction can usually be boiled not higher than solvent
It is carried out under point or room temperature to the temperature condition of solvent boiling point, for example, the temperature of ring closure reaction can be 0-100 DEG C.This field skill
Art personnel can suitably adjust the reaction time of ring closure reaction according to reaction process, monitor the method for reaction process for this field skill
It should be known for art personnel, such as can be the analysis methods such as chromatography, nuclear magnetic resonance method, the specific reaction time can
To be such as 2-16 hours.
In the preparation method of indanone compounds provided by the present invention, suitable rear place may be selected in those skilled in the art
Reason method post-processes the product obtained by ring closure reaction, for example, after reaction, the post-processing of ring closure reaction can wrap
It includes：It is quenched, liquid separation, organic phase precipitation purifies up to the indone compound.It is described to be usually added into system when being quenched
Acid or their aqueous solution are quenched, for example, used acid can be able to be such as hydrochloric acid with HCl, corresponding aqueous solution
Deng.Those skilled in the art can be selected suitable method and be purified to the product after precipitation, for example, the method for purification can be
Rectifying, recrystallization etc..
The preparation method of indanone compounds provided by the present invention compared with prior art, have cost of material it is low, behaviour
Make the advantages that easy, the three wastes are few, high income, be more suitable for industrialized production, compared with the existing technology in various indone class chemical combination
The preparation method of object is with the obvious advantage, has good industrialization prospect.
Illustrate that embodiments of the present invention, those skilled in the art can be by this specification below by way of specific specific example
Disclosed content understands other advantages and effect of the present invention easily.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also be based on different viewpoints with application, without departing from
Various modifications or alterations are carried out under the spirit of the present invention.
It should be clear that in the following example not specifically dated process equipment or device be all made of conventional equipment in the art or
Device.
In addition, it should also be understood that, one or more method and step mentioned in the present invention does not repel before and after the combination step
It can also be inserted into other methods step there may also be other methods step or between these explicitly mentioned steps, unless separately
It is described；It should also be understood that the combination connection relation between one or more equipment/device mentioned in the present invention is not repelled
The front and back two equipment/devices specifically mentioned there may also be other equipment/device or at these of the unit equipment/device it
Between can also be inserted into other equipment/device, unless otherwise indicated.Moreover, unless otherwise indicated, the number of various method steps is only
Differentiate the convenient tool of various method steps, rather than to limit the ordering of various method steps or limiting the enforceable model of the present invention
It encloses, relativeness is altered or modified, and without material changes in technical content, when being also considered as, the present invention is enforceable
Scope.
Embodiment 1
The preparation of 2- methyl-1s-indone：
A.2L in four-hole boiling flask, it is separately added into 102.1g (1.0mol) ethyl propionates and 200g tetrahydrofurans at room temperature, and
102.0g (1.5mol) fresh ethanol sodium solid, interior temperature rises to 50-60 DEG C after charging, insulated and stirred 2h；Then start to control
Benzyl chloride 190.0g (1.5mol) is added dropwise at 55-60 DEG C processed, is dripped off in 2h, display is controlled in insulated and stirred 1h, GC and is reached home, it will be anti-
It answers liquid to be slowly added drop-wise in 500g water to be quenched, reaction solution is directly used in react in next step；
B. 2L four-hole boiling flasks will be poured into the reaction solution of step A, and 60.0g sodium hydrate solids, the complete molten rear liter of stirring is added
Temperature to 60-65 DEG C of insulation reaction about 3h, in GC control display reach home, then cool to 20 DEG C, stand liquid separation, the water phase separated
The HCl/water solution 190.1g for being added 30% adjusts pH about 3.0, and stratification is collected organic phase, then dried with anhydrous sodium sulfate
Organic phase obtains 136.3g, yield 83.1% (A, B two-step reaction)；
C. 200g dichloromethane is added in 136.3g organic phases step B obtained, then at 35-40 DEG C, is added dropwise
148.1g thionyl chlorides (1.24mol), keep the temperature 1h after dripping off, controlling display in GC reaches home, and precipitation obtains the concentrate of acyl chlorides；It takes
Another reaction bulb, is separately added into 166.1g alchlors (1.24mol) and 300g dichloromethane, then interior temperature drop is added dropwise to 0 DEG C
Acyl chlorides concentrate drips off in 3h, and interior temperature control system controls display in 0-10 DEG C, GC and reaches home, and 5% HCl/water solution is added dropwise
Reaction is quenched in 200g, stands liquid separation, for the organic layer separated through precipitation, rectifying obtains light yellow liquid 117.9g, GC purity
98.7%, yield 95.8%.1H NMR (300MHz, CDCl3)：δ=1.25-1.27 (d, 3H), δ=2.54-2.76 (d, 2H), δ
=3.34-3.46 (m, 1H), δ=7.31-7.40 (t, 1H), δ=7.43-7.48 (t, 1H), δ=7.51-7.60 (t, 1H), δ
=7.76-7.83 (t, 1H).
Embodiment 2
The preparation of 2,6- dimethyl -1- indones：
A.2L in four-hole boiling flask, it is separately added into 88.1g (1.0mol) methyl propionates and 200g tetrahydrofurans at room temperature, and
81.0g (1.5mol) fresh methanol sodium solid, interior temperature rises to 50-60 DEG C after charging, insulated and stirred 2h；Then start to control
Be added dropwise at 55-60 DEG C to methyl benzyl chloride 182.8g (1.3mol), dripped off in 2h, in insulated and stirred 1h, GC control display reach home,
Reaction solution is slowly added drop-wise in 500g water and is quenched, reaction solution is directly used in react in next step；
B. 2L four-hole boiling flasks will be poured into the reaction solution of step A, and 60.0g sodium hydrate solids, the complete molten rear liter of stirring is added
Temperature to 60-65 DEG C of insulation reaction about 3h, in GC control display reach home, then cool to 20 DEG C, stand liquid separation, the water phase separated
The HCl/water solution 190.1g for being added 30% adjusts pH about 3.0, and stratification is collected organic phase, then dried with anhydrous sodium sulfate
Organic phase obtains 142.7g, yield 80.1%；
C. 200g dichloromethane is added in 142.7g organic phases step B obtained, then at 35-40 DEG C, is added dropwise
150.1g (1.26mol) thionyl chloride, keeps the temperature 1h after dripping off, controlling display in GC reaches home, and precipitation obtains the concentrate of acyl chlorides；It takes
Another reaction bulb, is separately added into 172.1g (1.29mol) alchlors and 300g dichloromethane, then interior temperature drop is added dropwise to 0 DEG C
Acyl chlorides concentrate drips off in 3h, and interior temperature control system controls display in 0-10 DEG C, GC and reaches home, and 5% HCl/water solution is added dropwise
Reaction is quenched in 200g, stands liquid separation, for the organic layer separated through precipitation, rectifying obtains golden yellow liquid 122.6g, GC purity
99.0%, yield 94.6%.1H NMR (300MHz, CDCl3)：δ=1.25-1.27 (d, 3H), δ=2.35 (s, 3H), δ=
2.59-2.69 (m, 2H), δ=3.26-3.35 (m, 1H), δ=7.29-7.38 (m, 2H), δ=7.50 (s, 1H), GC/MS (m/z
=160).
Embodiment 3
The preparation of the fluoro- 1- indones of 2- methyl -6-：
A.2L in four-hole boiling flask, it is separately added into 88.1g methyl propionates (1.0mol) and 200g tetrahydrofurans at room temperature, and
The fresh sodium hydrides of 54.0g (2.25mol) solid, interior temperature rises to 40-50 DEG C after charging, insulated and stirred 2h；Then start to control
Be added dropwise at 55-60 DEG C processed to fluorine benzyl chloride 202.4g (1.4mol), dripped off in 2h, in insulated and stirred 1h, GC control display reach home,
Reaction solution is slowly added drop-wise in 500g water and is quenched, reaction solution is directly used in react in next step；
B. 2L four-hole boiling flasks will be poured into the reaction solution of step A, and 75.0g potassium hydroxide solids, the complete molten rear liter of stirring is added
Temperature to 60-65 DEG C of insulation reaction about 3h, in GC control display reach home, then cool to 20 DEG C, stand liquid separation, the water phase separated
The HCl/water solution 202.1g for being added 30% adjusts pH about 3.0, and stratification is collected organic phase, then dried with anhydrous sodium sulfate
Organic phase obtains 141.8g, yield 77.8%；
C. 200g dichloromethane is added in 141.8g organic phases step B obtained, then at 35-40 DEG C, is added dropwise
146.5g thionyl chlorides, keep the temperature 1h after dripping off, controlling display in GC reaches home, and precipitation obtains the concentrate of acyl chlorides；Take another reaction
Bottle, is separately added into 172.1g alchlors and 300g dichloromethane, then interior temperature drop is added dropwise acyl chlorides concentrate, is dripped in 3h to 0 DEG C
Complete, interior temperature control system controls display in 0-10 DEG C, GC and reaches home, and the HCl/water solution 200g for being added dropwise 5% is quenched reaction, stands and divides
Liquid, the organic layer separated are cooled to -20 DEG C of precipitation off-white powders, drying is weighed through precipitation after the dissolving of 100g ethyl alcohol is added
123.1g, GC purity 99.1%, yield 95.5%.1H NMR (300MHz, CDCl3)：δ=1.25-1.27 (d, 3H), δ=
2.55-2.77 (d, 2H), δ=3.33-3.46 (m, 1H), δ=7.05-7.25 (m, 2H), δ=7.51-7.65 (d, 1H).
Embodiment 4
The preparation of 6- methyl-1s-indone：
A.2L in four-hole boiling flask, it is separately added into 88.1g ethyl acetate and 200g tetrahydrofurans at room temperature and 102.0g is fresh
Sodium ethoxide solid, interior temperature rises to 50-60 DEG C after charging, insulated and stirred 2h；Then start to be added dropwise to first at 55-60 DEG C of control
It is dripped off in base benzyl chloride 182.8g, 2h, control shows and reaches home in insulated and stirred 1h, GC, and reaction solution is slowly added drop-wise to 500g water
In be quenched, reaction solution be directly used in next step react；
B. 2L four-hole boiling flasks will be poured into the reaction solution of step A, and 60.0g sodium hydrate solids, the complete molten rear liter of stirring is added
Temperature to 60-65 DEG C of insulation reaction about 3h, in GC control display reach home, then cool to 20 DEG C, stand liquid separation, the water phase separated
The HCl/water solution 190.1g for being added 30% adjusts pH about 3.0, and stratification is collected organic phase, then dried with anhydrous sodium sulfate
Organic phase obtains 137.8g, yield 83.9%；
C. 200g dichloromethane is added in 137.8g organic phases step B obtained, then at 35-40 DEG C, is added dropwise
160.1g oxalyl chlorides, keep the temperature 1h after dripping off, controlling display in GC reaches home, and precipitation obtains the concentrate of acyl chlorides；Another reaction bulb is taken,
It is separately added into 172.1g alchlors and 300g dichloromethane, then interior temperature drop is added dropwise acyl chlorides concentrate, is dripped off in 3h to 0 DEG C,
Interior temperature control system controls display in 0-10 DEG C, GC and reaches home, and the HCl/water solution 200g for being added dropwise 5% is quenched reaction, standing liquid separation,
For the organic layer separated through precipitation, rectifying obtains weak yellow liquid 117.6g, 60-62 DEG C of fusing point, purity 99.2%, yield
95.1%.1H NMR (300MHz, CDCl3)：δ=2.40 (s, 3H), δ=2.62-2.69 (m, 2H), δ=3.05-3.15 (m,
2H), δ=7.25-7.36 (m, 2H), δ=7.55 (s, 1H).
Embodiment 5
The preparation of the chloro- 1- indones of 5-：
A.2L in four-hole boiling flask, it is separately added into 88.1g ethyl acetate and 204.2g tetrahydrofurans at room temperature and 102.0g is new
Fresh sodium ethoxide solid, interior temperature rises to 50-60 DEG C after charging, insulated and stirred 2h；Then start between being added dropwise at 55-60 DEG C of control
It is dripped off in benzyl chloride chlorine 225.4g, 2h, control shows and reaches home in insulated and stirred 1h, GC, and reaction solution is slowly added drop-wise to 500g water
In be quenched, reaction solution be directly used in next step react；
B. 2L four-hole boiling flasks will be poured into the reaction solution of step A, and 60.0g sodium hydrate solids, the complete molten rear liter of stirring is added
Temperature to 60-65 DEG C of insulation reaction about 3h, in GC control display reach home, then cool to 20 DEG C, stand liquid separation, the water phase separated
The HCl/water solution 190.1g for being added 30% adjusts pH about 3.0, and stratification is collected organic phase, then dried with anhydrous sodium sulfate
Organic phase obtains 143.2g, yield 77.6%；
C. 200g dichloromethane is added in 143.2g organic phases step B obtained, then at 35-40 DEG C, is added dropwise
150.1g thionyl chlorides, keep the temperature 1h after dripping off, controlling display in GC reaches home, and precipitation obtains the concentrate of acyl chlorides；Take another reaction
Bottle, is separately added into 172.1g alchlors and 300g dichloromethane, then interior temperature drop is added dropwise acyl chlorides concentrate, is dripped in 3h to 0 DEG C
Complete, interior temperature control system controls display in 0-10 DEG C, GC and reaches home, and the HCl/water solution 200g for being added dropwise 5% is quenched reaction, stands and divides
Liquid, the organic layer separated are cooled to -20 DEG C of precipitation yellow solids after the dissolving of 100g ethyl alcohol is added, are separated by solid-liquid separation, are dry through precipitation
Weigh 121.5g, purity 98.5%, 91.5-96 DEG C of fusing point, yield 92.6%.1H NMR (300MHz, CDCl3)：δ=2.66-
2.71 (m, 2H), δ=2.95-3.09 (m, 2H), δ=7.14-7.26 (m, 2H), δ=7.75-7.80 (d, 1H).
In conclusion the present invention effectively overcomes various shortcoming in the prior art and has high industrial utilization.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology can all carry out modifications and changes to above-described embodiment without violating the spirit and scope of the present invention.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should by the present invention claim be covered.
Claims (10)
1. a kind of preparation method of indanone compounds, including：
1) compound of formula I and Formula II compound are subjected to condensation reaction, prepare formula III compound；
2) formula III compound is hydrolyzed in the presence of a base, prepares formula IV compound；
3) by formula IV compound acylation, cyclization, Formula V compound is prepared；
The structural formula of Formulas I-V compounds is as follows：
Wherein, R1, R2, R3, R4 are each independently selected from the C1-C18 alkyl of H, Cl, Br, I, F, linear chain or branched chain；
R5 is selected from the C1-C18 alkyl of H, Cl, Br, linear chain or branched chain；
R6 is selected from the C1-C18 alkyl of linear chain or branched chain；
X is selected from Cl or Br.
2. a kind of preparation method of indanone compounds as described in claim 1, which is characterized in that further include that following technology is special
It is one or more in sign：
A1) R1, R2, R3, R4 are each independently selected from the C1-C8 alkyl of H, Cl, Br, F, linear chain or branched chain；
A2) R5 is selected from the C1-C10 alkyl of linear chain or branched chain；
A3) R6 is selected from the C1-C8 alkyl of linear chain or branched chain.
3. a kind of preparation method of indanone compounds as claimed in claim 2, which is characterized in that further include that following technology is special
It is one or more in sign：
B1) R1, R2, R3, R4 be each independently selected from H, Cl, linear chain or branched chain C1-C4 alkyl；
B2) R5 is selected from the C1-C4 alkyl of linear chain or branched chain；
B3) R6 is selected from the C1-C4 alkyl of linear chain or branched chain.
4. a kind of preparation method of indanone compounds as described in claim 1, which is characterized in that further include that following technology is special
It is one or more in sign：
C1) in the step 1), the molar ratio of compound of formula I and Formula II compound is 1~6：1；
C2) in the step 1), reaction carries out in the presence of a base, and the molar ratio of alkali and Formula II compound is 1~5：1；
C3) in the step 1), reaction carries out in the presence of a solvent；
C4) in the step 1), the temperature of reaction is 0-120 DEG C；
C5) in the step 1), the post-processing of reaction includes：Water quenching is added to go out.
5. a kind of preparation method of indanone compounds as claimed in claim 4, which is characterized in that further include that following technology is special
It is one or more in sign：
D1) in the step 1), the molar ratio of compound of formula I and Formula II compound is 1~3：1；
D2) in the step 1), one kind in alkaline metal organic salt, alkali carbonate, Sodamide or sodium hydride of alkali or
A variety of combinations；
D3) in the step 1), the molar ratio of alkali and Formula II compound is 1~3：1；
D4) in the step 1), solvent is selected from organic solvent, and organic solvent is preferably selected from ether solvent, and organic solvent preferably selects
One or more combinations from ether, methyl tertiary butyl ether(MTBE), dioxane, tetrahydrofuran, 2- methyltetrahydrofurans；
D5) in the step 1), the temperature of reaction is 20-50 DEG C.
6. a kind of preparation method of indanone compounds as claimed in claim 5, which is characterized in that in the step 1), institute
It states alkali and is selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-BuLi, LDA, sodium hydride, ammonia
One or more combinations in base sodium, sodium carbonate, potassium carbonate.
7. a kind of preparation method of indanone compounds as described in claim 1, which is characterized in that further include that following technology is special
It is one or more in sign：
E1) in the step 2), alkali is selected from NaOH and/or KOH；
E2) in the step 2), the molar ratio of alkali and formula III compound is 1~6: 1；
E3) in the step 2), the temperature of reaction is 0-100 DEG C；
E4) in the step 2), the post-processing of reaction includes：Liquid separation, gained water phase adjust pH to 2.0-5.0, collect organic phase.
8. a kind of preparation method of indanone compounds as claimed in claim 7, which is characterized in that further include that following technology is special
It is one or more in sign：
F1) in the step 2), the molar ratio of alkali and formula III compound is 1~3: 1；
F2) in the step 2), the temperature of reaction is 30-60 DEG C.
9. a kind of preparation method of indanone compounds as described in claim 1, which is characterized in that further include that following technology is special
It is one or more in sign：
G1) in the step 3), reaction carries out in the presence of a solvent, and solvent is selected from organic solvent；
G2 it) in the step 3), is carried out under the conditions of acylation reaction is existing for acylating reagent, acylating reagent and formula IV compound
Molar ratio is 1~3: 1；
G3) in the step 3), the reaction temperature of acylation reaction is 0-100 DEG C；
G4 it) in the step 3), is carried out under the conditions of ring closure reaction is existing for lewis acid；
G5) in the step 3), the reaction temperature of ring closure reaction is 0-100 DEG C；
G6) in the step 3), the post-processing of reaction includes：It is quenched, liquid separation, organic phase precipitation purifies up to the indone
Close object.
10. a kind of preparation method of indanone compounds as claimed in claim 9, which is characterized in that further include following technology
It is one or more in feature：
H1) in the step 3), organic solvent is selected from dichloromethane, dichloroethanes, toluene, chlorobenzene, nitromethane, nitroethane
In one or more combinations；
H2) in the step 3), the acylating reagent is selected from thionyl chloride and/or oxalyl chloride；
H3) in the step 3), lewis acid is in alchlor, zinc chloride, ferric trichloride, butter of tin, alchlor
One or more combinations；
H4) in the step 3), the molar ratio of lewis acid and formula IV compound is 1~3: 1, preferably 1.2~2：1；
H5) in the step 3), the method for purification is rectifying and/or recrystallization.
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