CN107417594A - A kind of method of acid amides alcoholysis - Google Patents

A kind of method of acid amides alcoholysis Download PDF

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CN107417594A
CN107417594A CN201710317647.0A CN201710317647A CN107417594A CN 107417594 A CN107417594 A CN 107417594A CN 201710317647 A CN201710317647 A CN 201710317647A CN 107417594 A CN107417594 A CN 107417594A
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alcoholysis
alkyl
product
epoxide
amide compound
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CN107417594B (en
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卢江平
裴青蓝
余金权
张恩选
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Asymchem Laboratories Tianjin Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C07B41/12—Formation or introduction of functional groups containing oxygen of carboxylic acid ester groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
    • C07C67/20—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from amides or lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Epoxy Compounds (AREA)

Abstract

The invention provides a kind of method of acid amides alcoholysis.This method, as accelerator, carries out alcoholysis to amide compound in the basic conditions including the use of epoxide.The above method is not only easy to operation, and post-processing only needs simple conventional separation step to can obtain pure products, simultaneously because epoxide cost is cheap, therefore can greatly reduce the risk and cost of operation cost and three-protection design.And the above method is when in use, reaction condition is gentle, can compatible various different substituents and functional group, good yield, wide application range of substrates can be obtained to the acid amides of various different types of structure.I.e. the present invention is converted into more useful ester for acid amides and provides environment-friendly, an economical and practical high efficiency method.The above-mentioned alcoholysis reaction of the application will not be saved purification of intermediate step by the impurity effect in previous step C H priming reaction systems, can be activated with C H and acid amides alcoholysis two-step reaction is even thrown.

Description

A kind of method of acid amides alcoholysis
Technical field
The present invention relates to organic material to synthesize field, in particular to a kind of method of acid amides alcoholysis.
Background technology
Amido link is widely present in the natural products such as protein and synthesis compound as a kind of common functional groups.People It has been generally acknowledged that the resonance stability of amido link makes acid amides turn into a kind of weaker electrophilic reagent (The structure of proteins:two hydrogenbonded helical configurations of the polypeptide Chain.Proc.Natl.Acad.Sci.1951,37,205) so that be difficult the opening acyl with the method choice of chemical synthesis C-N keys (the Conversion of amides to esters by the nickel-catalysed activation of amine of amide C–N bonds.Nature 2015,524,79)。
-CONHArF(ArF=p-CF3C6F4) as a kind of excellent acid amides guiding base, in various types of β-C-H It is widely used in priming reaction, but its shortcoming is for some substrates, and the guiding base is difficult removing 4 (Ligand-Enabledβ-C-H Arylation ofα-Amino Acids Using a Simple and Practical Auxiliary.J.Am.Chem.Soc.2015,137,3338).Which greatly limits further turning for these C-H activation products Change and utilize, it is therefore necessary to develop a kind of pervasive method for removing the guiding base.
The existing method for removing the guiding base：1. being heated in strong alkali aqueous solution, make amide hydrolysis into carboxylic acid；2. strong Heated in acid, make amide hydrolysis into carboxylic acid；3. add NaNO2In Ac2O/AcOH in the mixed solvents obtain carboxylic acid；4. use BF3· Et2O heats to obtain in methyl alcohol；5.LiHMDS/MeOCOCl/MeONa stepwise reactions, which are realized, is hydrolyzed into ester.
It is above-mentioned to use BF3·Et2O reacts at 100 DEG C, realize be oriented to base alcoholysis, this method have reagent price compared with It is expensive, complex operation, the shortcomings that severe reaction conditions.Remaining above-mentioned method needs strong acid or basic conditions, and many functional groups are herein Under the conditions of and it is unstable.And above method is obvious by substrate steric influence, the substrate scope of application is small.
The content of the invention
It is a primary object of the present invention to provide a kind of method of acid amides alcoholysis, to solve acid amides alcoholysis of the prior art The problem of method complex operation, severe reaction conditions.
To achieve these goals, according to an aspect of the invention, there is provided a kind of method of acid amides alcoholysis, this method Including the use of epoxide as alcoholysis accelerator, alcoholysis is carried out to amide compound in the basic conditions.
Further, with epoxide and the molar ratio computing of amide compound, above-mentioned epoxide and amide compound The amount ratio of thing is 1~5：1.
Further, there is above-mentioned amide compound formula I, formula I to beR1, R2It is each independently selected from Alkyl, aryl, substitution alkyl and substituted aryl in any one, preferably alkyl is selected from C1~C18Alkyl in it is any one Kind, the backbone c atoms number for preferably substituting alkyl is C1~C18In any one, preferably substitute alkyl be monosubstituted alkyl or Polysubstituted alkyl, the substituent in alkyl is preferably substituted to be selected from aryl, aromatic heterocycle substituent, cycloalkane, heterocycloalkane, alkenyl With the combination substituent of any one or more in alkynyl.
Further, there is above-mentioned epoxide formula II, formula II to beR3And R4It is each independently selected from H, any of alkyl and aryl, preferably alkyl are selected from C1~C18Alkyl in any one.
Further, the above method includes：Amide compound, epoxide, pH value regulator and solvent are mixed, Alkaline reaction system is formed, the preferably pH value of alkaline reaction system is 7.5~9.5；Make alkaline reaction system at 50~150 DEG C Reaction is with to amide compound progress alcoholysis.
Further, above-mentioned pH value regulator is weak acid or weak base, and preferable ph conditioning agent is selected from CF3CO2K、 CF3CO2Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO3、KHCO3、NaHCO3、LiHCO3、CsF、KF、NaF、LiF、 Cs2CO3、K2CO3、Na2CO3、Li2CO3、K2HPO4、Na2HPO4、Li2HPO4、K3PO4、Na3PO4, sodium benzoate, tetramethyl second two Any one or more in amine, N-N diisopropylethylamine and triethylamine.
Further, above-mentioned solvent is selected from methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, n-amyl alcohol, different Amylalcohol, ethylene glycol, glycerine, 1,2- dimethoxy-ethanes, ethylene glycol diethyl ether, 2- methoxy ethyls ether, 2- ethoxyethyl groups Any one or more in ether and pyrroles.
Further, above-mentioned amide compound isEpoxide is methyl glycidyl Ether, pH value regulator KOAc, solvent are ethanol.
Further, above-mentioned alkaline reaction system is reacted at 80~100 DEG C to carry out alcoholysis to amide compound.
Further, after the completion of alcoholysis, the above method also includes：Decompression is carried out to alcoholysis product and removes solvent, is obtained residual Stay thing；Residue and water are mixed to form mixture；The pH value of mixture is adjusted to being extracted using n-hexane after 3.5~4.5 Take, obtain organic phase；And organic phase is dried, filtered.
Further, after the completion of alcoholysis, the above method also includes：Decompression is carried out to alcoholysis product and removes solvent, is obtained residual Stay thing；Residue is purified using silica gel column chromatography.
Apply the technical scheme of the present invention, the above method is not only easy to operation, and post processing only need to be simply normal Rule separating step can obtain pure products, simultaneously because epoxide cost is cheap, therefore can greatly reduce production exercise Make the risk and cost of cost and three-protection design.And the above method is when in use, reaction condition is gentle, being capable of compatible various differences Substituent and functional group, good yield, wide application range of substrates can be obtained to the acid amides of various different types of structure.I.e. originally Invent for acid amides-alcoholysis provide environment-friendly, an economical and practical high efficiency method.The above-mentioned alcoholysis reaction of the application is not Purification of intermediate step can be saved by the impurity effect in previous step C-H priming reaction systems, can be with C-H activation and acid amides Base alcoholysis two-step reaction is even thrown.
Embodiment
It should be noted that in the case where not conflicting, the feature in embodiment and embodiment in the application can phase Mutually combination.The present invention is described in detail below in conjunction with embodiment.
As the application background technology is analyzed, although there is the method for a variety of acid amides -ol solutions in the prior art, on State each method and be respectively provided with the defects of different, for example use BF3·Et2O reacts at 100 DEG C when realizing the alcoholysis of acid amides, this method More expensive with reagent price, complex operation, the shortcomings that severe reaction conditions, in order to solve the problem, this application provides one kind The method of acid amides alcoholysis, this method including the use of epoxide as accelerator, in the basic conditions to amide compound Carry out alcoholysis.
Present inventor has been surprisingly found that, in alkalescence condition when be oriented to the research of base removing to amide compound The lower alcoholic solution using epoxide can promote acid amides to be converted into ester, have certain acid acid amides N-H in alkalescence condition The alkylene oxide open loop that lower nucleophilic attack is activated, the transition state product of N- additions is formed, the transition state is unstable, is opened in alkylene oxide After ring after the carbonyl of generated in-situ negative oxygen ion nucleophilic attack amido link, the C-N keys of amide group disconnect, and complete acid amides alcoholysis Reaction.
The above method is not only easy to operation, and post-processing only needs simple conventional separation step to can obtain pure production Thing, simultaneously because epoxide cost is cheap, therefore the risk of operation cost and three-protection design can be greatly reduced And cost.And the above method is when in use, reaction condition is gentle, can compatible various different substituents and functional group, to various The acid amides of different types of structure can obtain good yield, wide application range of substrates.I.e. the present invention provides for the alcoholysis of acid amides One environment-friendly, economical and practical high efficiency method.The above-mentioned alcoholysis reaction of the application will not be activated anti-by previous step C-H The impurity effect in system is answered, saves purification of intermediate step, can be activated with C-H and acid amides alcoholysis two-step reaction is even thrown.
In order to improve the conversion ratio of acid amides as far as possible and ensure the utilization rate of epoxide, preferably with epoxide and The amount ratio of the molar ratio computing of amide compound, epoxide and amide compound is 1~5：1.Certainly, epoxy compound is worked as Thing and the amount ratio of amide compound are more than 5:When 1, alcoholysis can be also realized, only having more epoxide does not have Reaction is participated in, causes the waste of raw material.
The present processes reaction substrate universality is wide, is influenceed unobvious, the acid amides of nearly all structure by steric hindrance Substrate smoothly reaction can obtain good yield, and the preferably amide compound has formula I, and formula I is R1, R2Any one in alkyl, aryl, substitution alkyl and substituted aryl is each independently selected from, preferably alkyl is selected from C1~C18 Alkyl in any one, preferably substitute alkyl backbone c atoms number be C1~C18In any one, preferably substitute alkane Base is monosubstituted alkyl or polysubstituted alkyl, preferably substitutes the substituent in alkyl to be selected from aryl, aromatic heterocycle substituent, cycloalkanes The combination substituent of any one or more in hydrocarbon, heterocycloalkane, alkenyl and alkynyl, the substituent in above-mentioned substituted aryl can Think halogen, alkyl, substitution alkyl etc., such as R2ForWith above-mentioned Reaction temperature milder needed for the course of reaction of the amide compound of formula, reaction time are also shorter, are more suitable for work Industry large-scale application.
In order to further reduce the implementation cost of the above method, preferably above-mentioned epoxide has formula II, the formula II isR3And R4Any of H, alkyl and aryl are each independently selected from, preferably abovementioned alkyl is selected from C1~C18 Alkyl in any one.
It is above-mentioned using epoxide as accelerator carry out alcoholysis when, its specific implementation process may be referred to existing skill Alcoholysis process in art, the preferably above method include：Amide compound, epoxide, pH value regulator and solvent are mixed, Form alkaline reaction system；Alkaline reaction system is set to be reacted at 50~150 DEG C to carry out alcoholysis to amide compound.It is preferred that The pH value of the alkaline reaction system is 7.5~9.5.
After amide compound, epoxide are disperseed in a solvent, alkaline reaction body is adjusted using pH value regulator Be so that follow-up alcoholysis smoothly, is efficiently carried out, especially when the pH value of alkaline reaction system is 7.5~9.5, reaction rate It is even more ideal；Then reaction system can be carried out under 50~150 DEG C of cryogenic conditions.From said process, the application's Method does not need special expensive reagent, reaction condition gentle, and applicable substrate is wider, and the scope of application is larger.
PH value regulator needed for above-mentioned pH does not need strong acid and highly basic, preferably weak acid or weak base, further preferred pH Value conditioning agent is selected from CF3CO2K、CF3CO2Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO3、KHCO3、NaHCO3、LiHCO3、 CsF、KF、NaF、LiF、Cs2CO3、K2CO3、Na2CO3、Li2CO3、K2HPO4、Na2HPO4、Li2HPO4、K3PO4、Na3PO4, benzene first Any one or more in sour sodium, tetramethylethylenediamine, N-N diisopropylethylamine and triethylamine.Above-mentioned each material cost is low PH systems that are honest and clean and being formed are gentle.
The solvent of the application may be referred to the conventional solvent species of acid amides alcoholysis in the prior art, and preferably above-mentioned solvent is selected from Methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, glycerine, 1,2- dimethoxies Any one or more in base ethane, ethylene glycol diethyl ether, 2- methoxy ethyls ether, 2- ethoxyethyl groups ether and pyrroles.
Below using KOAc as pH value regulator, above-mentioned reaction principle is further illustrated so that ethanol is solvent as an example：With one The fixed acid acid amides N-H alkylene oxide open loops that nucleophilic attack potassium ion activated under KOAc effects, form the transition of N- additions State product, the transition state is unstable, after alkylene oxide open loop after the carbonyl of generated in-situ negative oxygen ion nucleophilic attack amido link, The C-N keys of amide group disconnect, and form esterification midbody product, are then esterified intermediate and alcohols solvent generation ester exchange is anti- Should, generate final acid amides alcoholysis product.It for details, reference can be made to following chemical reaction process：
In a kind of preferred embodiment of the application, above-mentioned amide compound isEpoxidation Compound is methyl glycidyl ether, and pH value regulator KOAc, solvent is ethanol.
When the present processes application first is stated in the alcoholysis of amide compound, the yield of final goal product compared with It is high.
In order to further speed up reaction rate, yield is improved, preferably above-mentioned alkaline reaction system is reacted at 80~100 DEG C To carry out alcoholysis to amide compound.
In order to reduce reaction consuming cost, it is preferred to use oil bath is heated to reaction system.
After the completion of above-mentioned alcoholysis, preferably the above method also includes：Decompression is carried out to alcoholysis product and removes solvent, is remained Thing；Residue and water are mixed to form mixture；The pH value of mixture is adjusted to being extracted using n-hexane after 3.5~4.5, Obtain organic phase；And organic phase is dried, filtered.Each material is conventional material used by said process, therefore The cost of the application method implementation will not be increased；Moreover, said process is the routine operation in purge process, it will not also increase this The complexity of application method；Further, in extraction, the pH value of mixture is controlled between 3.5~4.5, is advantageous to carry High extract and separate efficiency, for example adjust pH value the secondary amine knot on leaving group is formed salt for acidity, strengthen the water-soluble of leaving group Property, make leaving group accessory substance be easier to wash removing.If acid stronger other functional groups that may make on product go bad, together Shi Zaocheng reagent wastes.Or after the completion of above-mentioned alcoholysis, preferably the above method also includes：Decompression is carried out to alcoholysis product to go Solvent, obtain residue；Residue is purified using silica gel column chromatography, the process is adapted to the production of laboratory small lot experiment Thing separates.
Below with reference to embodiment and comparative example, the beneficial effect of the application is further illustrated.
Employed in following embodiment, amide compound is as follows：
Epoxide is as follows：
Product structure is as follows：
The reactant such as following table that following embodiment uses：
Embodiment 1
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (87.5mg, 0.2mmol), Potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, it is aqueous<0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), reaction system is formed.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC displays are former Material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains residue, 2.0mL purified waters are added into residue and form mixture, and it is 4 to stir the lower pH for using 3M hydrochloric acid to adjust mixture, then with just Organic phase is obtained by extraction in hexane (3mL × 3), and the organic phase after merging is dried using anhydrous sodium sulfate, after the completion of drying Filtering, pure product 45.5mg, yield 92% are obtained after filtrate concentration.
The chemical reaction of above-mentioned alcoholysis process sees below formula：
Product c1 (Ethyl 2- (1,3-dioxoisoindolin-2-yl) propanoate) nuclear-magnetism test result：
1NMR(400MHz,CDCl3) δ 7.92-7.79 (m, 2H), 7.77-7.60 (m, 2H), 4.95 (q, J=7.5Hz, 1H), 4.19 (td, J=7.0,3.5Hz, 2H), 1.69 (d, J=7.5Hz, 3H), 1.22 (t, J=7.0Hz, 3H).13C NMR (125MHz,CDCl3)δ169.75,167.47,134.20,131.99,123.49,61.90,47.66,15.28,14.12.
Embodiment 2
Difference with embodiment 1 is, after the dosage of each material of embodiment 1 is expanded into 100 times, using 500mL pressure Reactor carries out alcoholysis reaction, pure product 4.648g is obtained after filtrate concentration, yield 94%, the yield of embodiment 2, which is more than, to be implemented The yield of example 1, adhesion loss is big when being due to 1 a small amount of operations of embodiment, and yield is more accurate during big quantitative response.
Embodiment 3
Difference with embodiment 1 is that wherein methyl glycidyl ether b1 and a1 mol ratio is 5:1, yield 93%.
Embodiment 4
Difference with embodiment 1 is that wherein methyl glycidyl ether b1 and a1 mol ratio is 1:1, yield 69%.
Embodiment 5
Difference with embodiment 1 is that wherein methyl glycidyl ether b1 and a1 mol ratio is 8:1, yield 94%.
Embodiment 6
Difference with embodiment 1 is, above-mentioned Schlenck pipes are placed in into heating response 35 hours, product in 80 DEG C of oil baths Yield is 84%.
Embodiment 7
Difference with embodiment 1 is, above-mentioned Schlenck pipes are placed in into heating response 35 hours in 100 DEG C of oil baths, production Thing yield is 91%.
Embodiment 8
Difference with embodiment 1 is, above-mentioned Schlenck pipes are placed in into heating response 35 hours in 150 DEG C of oil baths, production Thing yield is 82%.
Embodiment 9
Difference with embodiment 1 is, above-mentioned Schlenck pipes are placed in into heating response 35 hours, product in 50 DEG C of oil baths Yield is 48%.
Embodiment 10
Difference with embodiment 1 is, above-mentioned Schlenck pipes are placed in into heating response 35 hours in 165 DEG C of oil baths, production Thing yield is 74%.
Embodiment 11
Difference with embodiment 1 is that used pH value regulator is CF3CO2K, product yield 93%.
Embodiment 12
Difference with embodiment 1 is that used pH value regulator is KHCO3, product yield 74%.
Embodiment 13
Difference with embodiment 1 is that used pH value regulator is K2HPO4, product yield 51%.
Embodiment 14
Difference with embodiment 1 is that used pH value regulator is K2CO3, product yield 22%.
Embodiment 15
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (87.5mg, 0.2mmol), NaHCO3(16.8mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 36.1mg, yield 73%.
Embodiment 16
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), LiOH (4.8mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), reaction system is formed.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC displays are former Material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains residue, Residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 32.1mg, yield 65%.The present embodiment is adopted The LiOH that pH value regulator uses, the material is highly basic, has not only acted as the effect of regulation pH value in the reaction, it is also possible to Play complex activation as metal ion.
Embodiment 17
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), NaOAc (16.4mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), reaction system is formed.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC displays are former Material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains residue, Residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 43.0mg, yield 87%.
Embodiment 18
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), KCl (14.9mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), reaction system is formed.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC displays are former Material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains residue, Residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 15.3mg, yield 31%.
Embodiment 19
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), Sodium trifluoroacetate (27.2mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 45 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 46.0mg, yield 93%.
Embodiment 20
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), Trifluoroacetic acid potassium (30.4mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 45 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 47.0mg, yield 95%.Though Yield slightly improves, but the reaction time extends, while with potassium acetate to compare cost higher for trifluoroacetic acid potassium.
Embodiment 21
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), Triethylamine (20.2mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 35.6mg, yield 72%.
Embodiment 22
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), Potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (1.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 38.6mg, yield 78%.
Embodiment 23
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), Potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (3.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 44.0mg, yield 89%.
Embodiment 24
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a1 (86.8mg, 0.2mmol), Potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (4.0mL, aqueous≤0.01wt%), methyl glycidyl ether b1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product 20.3mg, yield 41%.
Embodiment 25
Difference with embodiment 1 is that the solvent used is methanol, product yield 91%.
Product c2 (Methyl 2- (1,3-dioxoisoindolin-2-yl) propanoate) nuclear-magnetism test result：
1NMR(400MHz,CDCl3) δ 7.82-7.75 (m, 2H), 7.72-7.65 (m, 2H), 4.91 (q, J=7.5Hz, 1H), 3.67 (s, 3H), 1.63 (d, J=7.5Hz, 3H)
Embodiment 26
Difference with embodiment 1 is that the solvent used is isopropanol, product yield 95%.
Product c3 (Isopropyl 2- (1,3-dioxoisoindolin-2-yl) propanoate) nuclear-magnetism test knot Fruit：
1NMR(400MHz,CDCl3)δ7.83–7.76(m,2H),7.72–7.66(m,2H),5.09–4.95(m,1H), 4.87 (q, J=7.5Hz, 1H), 1.63 (d, J=7.5Hz, 1H), 1.16 (dd, J=20.0,6.5Hz, 6H)
Embodiment 27
Difference with embodiment 1 is that the solvent used is isobutanol, product yield 92%.
Product c4 (Isobutyl 2- (1,3-dioxoisoindolin-2-yl) propanoate) nuclear-magnetism test knot Fruit：
1NMR(400MHz,CDCl3) δ 7.83-7.76 (m, 2H), 7.73-7.65 (m, 2H), 4.94 (q, J=7.5Hz, 1H), 3.93-3.83 (m, 2H), 1.90-1.77 (m, 1H), 1.67 (d, J=7.5Hz, 3H), 0.81 (d, J=7.0Hz, 6H)
Embodiment 28
Difference with embodiment 1 is that the solvent used is isoamyl alcohol, product yield 87%.
Product c5 (Isopentyl 2- (1,3-dioxoisoindolin-2-yl) propanoate) nuclear-magnetism test knot Fruit：
1NMR(400MHz,CDCl3)δ7.85–7.80(m,2H),7.74–7.67(m,2H),4.98–4.89(m,1H), 4.14 (t, J=7.0Hz, 2H), 1.67 (d, J=7.5Hz, 3H), 1.59-7.50 (m, 1H), 1.49-1.37 (m, 2H), 0.84- 0.75(m,6H).
Embodiment 29
Difference with embodiment 1 is, product system stopping heating being cooled into room temperature, and removal of solvent under reduced pressure is remained Thing, 2.0mL purified waters are added into residue and form mixture, and it is 3.5 to stir the lower pH for using 3M hydrochloric acid to adjust mixture, then Organic phase is obtained by extraction with n-hexane (3mL × 3), the organic phase after merging is dried using anhydrous sodium sulfate, dried Into rear filtering, yield 91%.
Embodiment 30
Difference with embodiment 1 is, product system stopping heating being cooled into room temperature, and removal of solvent under reduced pressure is remained Thing, 2.0mL purified waters are added into residue and form mixture, and it is 4.5 to stir the lower pH for using 3M hydrochloric acid to adjust mixture, then Organic phase is obtained by extraction with n-hexane (3mL × 3), the organic phase after merging is dried using anhydrous sodium sulfate, dried Into rear filtering, yield 89%.
Embodiment 31
Difference with embodiment 1 is, product system stopping heating being cooled into room temperature, and removal of solvent under reduced pressure is remained Thing, 2.0mL purified waters are added into residue and form mixture, and it is 5, Ran Houyong to stir the lower pH for using 3M hydrochloric acid to adjust mixture Organic phase is obtained by extraction in n-hexane (3mL × 3), and the organic phase after merging is dried using anhydrous sodium sulfate, is dried and is completed After filter, yield 84%.
Embodiment 32
Difference with embodiment 1 is that the amide compound used is a2, yield 96.
Product c6 (Ethyl 3-phenylpropanoate) nuclear-magnetism test result：
a8NMR(500MHz,CDCl3) δ 7.32-7.26 (m, 2H), 7.24-7.17 (m, 3H), 4.13 (q, J=7.0Hz, 2H), 2.96 (t, J=8.0Hz, 2H), 2.63 (t, J=8.0Hz, 2H), 1.24 (t, J=7.0Hz, 3H).
Embodiment 33
Difference with embodiment 1 is that the amide compound used is a3, yield 41%.
Embodiment 34
Difference with embodiment 1 is that the amide compound used is a4, yield 97%.
Embodiment 35
Difference with embodiment 1 is that the amide compound used is a5, yield 96%.
Embodiment 36
Difference with embodiment 1 is that the amide compound used is a6, yield 93%.
Embodiment 37
Difference with embodiment 1 is that the amide compound used is a7, yield 90%.
Embodiment 38
Difference with embodiment 1 is that the amide compound used is a8, yield 62%.
Product c7 (Ethyl benzoate) nuclear-magnetism test result：
1H NMR(500MHz,CDCl3)δ8.13–7.97(m,2H),7.58–7.53(m,1H),7.47–7.38(m,2H), 4.39 (q, J=7.0Hz, 2H), 1.42 (t, J=7.0Hz, 3H).
Embodiment 39
Difference with embodiment 1 is that the amide compound used is a9, yield 91%.
Product c8 (Ethyl 2-methyl-3-phenylacrylate) nuclear-magnetism test result：
1H NMR(500MHz,CDCl3)δ7.70(s,1H),7.43–7.36(m,4H),7.35–7.29(m,1H),4.28 (q, J=7.0Hz, 2H), 2.13 (s, 3H), 1.36 (t, J=7.0Hz, 3H)
Embodiment 40
Difference with embodiment 1 is that the amide compound used is a10, yield 97%.
Embodiment 41
Difference with embodiment 1 is that the amide compound used is a11, yield 94%.
Product c9 (Ethyl 2,2-dimethyl-3-phenylpropanoate) nuclear-magnetism test result：
1H NMR(500MHz,CDCl3) δ 7.30-7.27 (m, 2H), 7.25-7.20 (m, a8), 7.13 (d, J=7.0Hz, 2H), 4.13 (q, J=7.0Hz, 2H), 2.87 (s, 2H), 1.25 (t, J=7.0Hz, 4H), 1.19 (s, 6H)13C NMR (125MHz,CDCl3)δ177.62,138.10,130.30,128.06,126.52,60.52,46.41,43.61,25.09, 14.31。
Embodiment 42
Difference with embodiment 1 is that the amide compound used is a12, yield 90%.
Product c10 (Ethyl 2,2-dimethyl-3-phenylpropanoate) nuclear-magnetism test result：
1NMR(400MHz,CDCl3) δ 7.85-7.75 (m, 2H), 7.74-7.67 (m, 2H), 4.22 (q, J=7.0Hz, 2H), 1.83 (s, 6H), 1.25 (t, J=7.0Hz, 3H).
Embodiment 43
Difference with embodiment 1 is that the amide compound used is 1m, yield 89%.
Product c11 (Ethyl 1-benzoylpyrrolidine-2-carboxylate) nuclear-magnetism test result：
1H NMR(500MHz,CDCl3) δ 7.55 (d, J=6.5Hz, 2H), 7.43-7.35 (m, 3H), 4.69-4.59 (m, 1H), 4.22 (q, J=7.0Hz, 2H), 3.64 (dt, J=14.0,7.0Hz, 1H), 3.56-3.47 (m, 1H), 2.31 (dd, J= 14.0,7.0Hz, 1H), 2.04-1.97 (m, 2H), 1.92-1.82 (m, 1H), 1.29 (t, J=7.0Hz, 3H).
Ar in the structural formula of example 4 below 4 to 59FFor p-CF3C5F4, and each amide compound can use now There are existing commodity in technology or corresponding substrate progress C-H is activated to obtain, while can also be used what is obtained after C-H is activated Product system need not be purified the amide groups alcoholysis that can directly carry out following embodiment.
Embodiment 44
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a14 (87.06mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute methanol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=10/1) through silica gel column chromatography, obtains pure product 42.3mg, yield 90%.
Product c12 (Methyl 4- (2- (methoxycarbonyl) cyclopropyl) benzoate) nuclear-magnetism test As a result：
1NMR(400MHz,CDCl3) δ 7.94 (d, J=8.0Hz, 2H), 7.33 (d, J=8.0Hz, 2H), 3.89 (s, 3H), 3.43 (s, 3H), 2.60 (q, J=8.0Hz, 1H), 2.18-2.13 (m, 1H), 1.77-1.72 (m, 1H), 1.43-1.37 (m, 1H)。
Embodiment 45
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a15 (89.86mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute methanol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=10/1) through silica gel column chromatography, obtains pure product, yield 93%.
Product c13 (Methyl 4- (2- (methoxycarbonyl) cyclobutyl) benzoate) nuclear-magnetism test knot Fruit：
1H NMR(400MHz,CDCl3) δ 7.98 (d, J=8.0Hz, 2H), 7.31 (d, J=8.0Hz, 2H), 3.91 (s, 3H), 3.88-3.81 (m, 1H), 3.71 (s, 3H), 3.22 (q, J=8.0Hz, 1H), 2.38-2.31 (m, 2H), 2.29-2.12 (m,2H).13C NMR(125MHz,CDCl3)δ174.66,167.13,148.93,129.86,128.39,126.50,52.16, 51.94,45.07,43.10,25.33,21.90。
Embodiment 46
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a16 (105.08mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute methanol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=10/1) through silica gel column chromatography, obtains pure product, yield 95%.
Product c14 (Dimethyl 4,4'- (2- (methoxycarbonyl) cyclobutane-1,3-diyl) Dibenzoate nuclear-magnetism test result)：
1H NMR(400MHz,CDCl3) δ 8.00 (d, J=8.0Hz, 4H), 7.34 (d, J=8.0Hz, 4H), 3.91 (s, 6H), 3.84 (q, J=8.0Hz, 2H), 3.75 (s, 3H), 3.32-3.28 (m, 1H), 2.87-2.81 (m, 1H), 2.34-2.26 (m,1H).13C NMR(125MHz,CDCl3)δ173.61,167.04,147.96,130.01,128.73,126.67,52.26, 52.23,51.98,39.53,32.49,29.85。
Embodiment 47
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a17 (95.47mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=10/1) through silica gel column chromatography, obtains pure product 53.8mg, yield 93%.
Product c15 (Ethyl 4- (2- (ethoxycarbonyl) cyclopentyl) benzoate) nuclear-magnetism test knot Fruit：
1H NMR(500MHz,CDCl3) δ 7.96 (t, J=8.0Hz, 2H), 7.29 (d, J=8.0Hz, 2H), 4.35 (q, J =7.0Hz, 2H), 4.05 (q, J=7.0Hz, 2H), 3.37 (q, J=9.0Hz, 1H), 2.81 (q, J=9.0Hz, 1H), 2.24- 2.10 (m, 2H), 2.02-1.93 (m, 1H), 1.91-1.79 (m, 2H), 1.79-1.69 (m, 1H), 1.37 (t, J=7.0Hz, 3H), 1.14 (t, J=7.0Hz, 3H)13C NMR(125MHz,CDCl3)δ175.54,166.67,149.47,129.83, 128.74,127.34,60.90,60.50,52.18,49.86,35.08,30.84,25.16,14.47,14.31。
Embodiment 48
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a18 (98.28mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=10/1) through silica gel column chromatography, obtains pure product 54.1mg, yield 89%.
Product c16 (Ethyl 4- (2- (ethoxycarbonyl) cyclohexyl) benzoate nuclear-magnetism test results：
1H NMR(500MHz,CDCl3) δ 7.94 (d, J=8.0Hz, 2H), 7.26 (d, J=8.0Hz, 2H), 4.35 (q, J =7.0Hz, 2H), 3.90-3.80 (m, 2H), 2.89-2.76 (m, 1H), 2.63-2.53 (m, 1H), 2.08-1.99 (m, 1H), 1.92-1.78 (m, 3H), 1.62-1.56 (m, 1H), 1.50-1.42 (m, 2H), 1.42-1.34 (m, 4H), 0.94 (t, J= 7.0Hz,3H).13C NMR(125MHz,CDCl3)δ174.95,166.72,150.21,129.75,128.74,127.49, 60.90,60.09,49.97,46.82,34.18,30.17,26.19,25.42,14.47,14.10.
Embodiment 49
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a19 (113.90mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=25/1) through silica gel column chromatography, obtains pure product, yield 95%.
Product c17 (Ethyl 4- (3-ethoxy-2- (4-isobutylphenyl) -3-oxopropyl) benzoate) Nuclear-magnetism test result：
1H NMR(400MHz,CDCl3) δ 7.91 (d, J=8.0Hz, 2H), 7.21-7.17 (m, 4H), 7.08 (d, J= 8.0Hz, 2H), 4.35 (q, J=8.0Hz, 2H), 4.15-3.96 (m, 2H), 3.83-3.76 (m, 1H), 3.46-3.41 (m, 1H), 3.08-3.03 (m, 1H), 2.44 (d, J=8.0Hz, 2H), 1.89-1.79 (m, 1H), 1.38 (t, J=8.0Hz, 3H), 1.12 (t, J=8.0Hz, 3H), 0.89 (d, J=8.0Hz, 6H)13C NMR(125MHz,CDCl3)δ173.30,166.65, 144.65,141.00,135.66,129.63,129.47,129.08,128.70,127.65,60.91,53.05,45.11, 39.95,30.26,22.44,14.42,14.14。
Embodiment 50
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a20 (143.53mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=25/1) through silica gel column chromatography, obtains pure product, yield 96%.
Product c18 (Diethyl 4,4'- (3-ethoxy-2- (4-isobutylphenyl) -3-oxopropane-1,1- Diyl) dibenzoate) nuclear-magnetism test result：
1H NMR(500MHz,CDCl3) δ 7.99 (d, J=8.0Hz, 2H), 7.73 (d, J=8.0Hz, 2H), 7.48 (d, J =8.0Hz, 2H), 7.15 (d, J=8.0Hz, 2H), 7.06 (d, J=8.0Hz, 2H), 6.94 (d, J=8.0Hz, 2H), 4.79 (d, J=12.0Hz, 1H), 4.40-4.33 (m, 3H), 4.27 (q, J=7.0Hz, 2H), 4.02-3.96 (m, 1H), 3.94- 3.88 (m, 1H), 2.35 (d, J=7.0Hz, 2H), 1.79-1.73 (m, 1H), 1.37 (t, J=7.0Hz, 3H), 1.31 (t, J= 7.0Hz, 3H), 1.01 (t, J=7.0Hz, 3H), 0.82-0.80 (m, 6H).
Embodiment 51
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a21 (99.49mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=50/1) through silica gel column chromatography, obtains pure product, yield 96%.
Product c19 (Ehyl 2- (5-isobutylbiphenyl-2-yl) propanoate) nuclear-magnetism test result：
1H NMR(500MHz,CDCl3) δ 7.47-7.40 (m, 2H), 7.36 (m, 4H), 7.15 (d, J=8.0Hz, 1H), 7.04 (s, 1H), 4.17-4.05 (m, 2H), 3.87 (q, J=7.0Hz, 1H), 2.49 (d, J=7.0Hz, 2H), 1.94-1.86 (m, 1H), 1.37 (d, J=7.0Hz, 3H), 1.20 (t, J=7.0Hz, 3H), 0.94 (d, J=6.5Hz, 6H)13C NMR (125MHz,CDCl3)δ175.21,141.65,141.51,140.05,136.04,130.96,129.59,128.68, 128.16,127.04,126.62,60.63,45.12,41.02,30.23,22.57,22.55,19.39,14.20。
Embodiment 52
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a22 (104.88mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product, yield 93%.
Product c20 (Ethyl 2- (1,3-dioxoisoindolin-2-yl) -3-p-tolylpropanoate) nuclear-magnetism Test result：
1H NMR(500MHz,CDCl3) δ 7.82-7.74 (m, 2H), 7.71-7.63 (m, 2H), 7.04 (d, J=8.0Hz, 2H), 6.98 (d, J=8.0Hz, 2H), 5.15-5.08 (m, 1H), 4.27-4.20 (m, 2H), 3.58-3.46 (m, 2H), 2.22 (s, 3H), 1.25 (t, J=7.0Hz, 3H).
Embodiment 53
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a23 (82.46mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=15/1) through silica gel column chromatography, obtains pure product, yield 94%.
Product c21 (Ethyl 2- ((2-fluoropyridin-4-yl) methyl) butanoate) nuclear-magnetism test knot Fruit：
1H NMR(500MHz,CDCl3) δ 8.09 (d, J=5.0Hz, 1H), 6.99 (d, J=5.0Hz, 1H), 6.74 (s, 1H), 4.15-4.01 (m, 2H), 2.96 (dd, J=14.0,9.5Hz, 1H), 2.77 (dd, J=14.0,6.0Hz, 1H), 2.65- 2.55 (m, 1H), 1.72-1.65 (m, 1H), 1.63-1.53 (m, 1H), 1.16 (t, J=7.0Hz, 3H), 0.94 (t, J= 7.5Hz,3H).13CNMR(125MHz,CDCl3) δ 174.66,164.15 (d, J=237.5Hz, 1H), 154.76 (d, J= 7.5Hz, 1H), 147.57 (d, J=15.0Hz, 1H), 122.07 (d, J=3.8Hz, 1H), 109.75 (d, J=36.3Hz, 1H), 60.65,48.01,37.14 (d, J=2.5Hz, 1H), 25.63,14.33,11.66.19F NMR(400MHz,CDCl3)δ- 69.29(S)。
Embodiment 54
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a24 (120.10mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=20/1) through silica gel column chromatography, obtains pure product 62.3mg, yield 75%.
Product c22 (Ethyl 2- (1,3-dioxoisoindolin-2-yl) -3-phenyl-3-p- Tolylpropanoate nuclear-magnetism test result)：
1H NMR(500MHz,CDCl3) δ 7.83-7.69 (m, 2H), 7.69-7.62 (m, 2H), 7.50 (d, J=7.5Hz, 1H), 7.41 (d, J=7.5Hz, 1H), 7.33 (t, J=7.5Hz, 1H), 7.27 (d, J=9.0Hz, 1H), 7.22 (t, J= 7.5Hz, 0.5H), 7.17 (t, J=7.0Hz, 1H), 7.11 (t, J=7.5Hz, 1H), 6.99 (t, J=7.5Hz, 0.5H), 6.93 (d, J=7.5Hz, 1H), 5.78-5.71 (m, 1H), 5.33-5.23 (m, 1H), 4.13-3.98 (m, 2H), 2.32 (s, 1.5H),2.13(s,1.5H),1.06–0.98(m,3H).13C NMR(125MHz,CDCl3)δ168.43,168.37,167.49, 167.44,142.03,140.84,138.75,137.61,136.46,136.44,134.11,131.52,131.45,129.47, 129.32,128.73,128.57,127.98,127.83,127.81,127.70,126.85,123.50,123.45,77.41, 77.16,76.91,61.75,61.71,55.40,55.26,50.33,50.29,29.81,21.14,20.99,13.83。
Embodiment 55
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a25 (118.89mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=10/1) through silica gel column chromatography, obtains pure product, yield 91%.
Product c23 (Ethyl 4- (2- (1,3-dioxoisoindolin-2-yl) -2- (ethoxycarbonyl) Cyclopropyl) benzoate) nuclear-magnetism test result：
1H NMR(500MHz,CDCl3) δ 8.02 (d, J=8.0Hz, 2H), 7.92-7.91 (m, 2H), 7.79-7.77 (m, 2H), 7.68 (d, J=8.0Hz, 2H), 4.38 (q, J=7.0Hz, 1H), 3.84-3.76 (m, 2H), 3.17 (t, J=9.5Hz, 1H),2.51(dd,J1=6.5Hz, J2=9.0Hz, 1H), 1.94 (dd, J1=6.5Hz, J2=9.0Hz, 1H), 1.40 (t, J= 7.0Hz, 3H), 0.78 (t, J=7.0Hz, 3H)13C NMR(125MHz,CDCl3)δ168.22,167.65,166.66, 140.20,134.56,131.87,129.91,129.46,123.76,61.74,61.07,38.21,33.48,19.24, 14.50,13.84。
Embodiment 56
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a26 (107.64mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=20/1) through silica gel column chromatography, obtains pure product, yield 89%.
Product c24 (Ethyl 1-benzoyl-4-p-tolylpiperidine-3-carboxylate) nuclear-magnetism test As a result：
1H NMR(500MHz,CDCl3)δ7.51–7.33(m,5H),7.18–7.01(m,2H),5.12–4.77(m,1H), 4.08–3.70(m,3H),3.37–3.08(m,1H),3.04–2.55(m,3H),2.31(s,3H),1.89–1.60(m,2H), 1.00–0.84(m,3H).
Embodiment 57
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a27 (78.26mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=30/1) through silica gel column chromatography, obtains pure product 38.7mg, yield 95%.
Product c25 (Ethyl 2-methyl-3-phenylbut-2-enoate) nuclear-magnetism test result：
1H NMR(500MHz,CDCl3) δ 7.42-7.35 (m, 2H), 7.32-7.28 (m, 1H), 7.17 (d, J=7.0Hz, 2H), 4.34-4.24 (m, 2H), 2.28 (d, J=1.5Hz, 3H), 1.78 (d, J=1.5Hz, 3H), 1.38 (t, J=7.0Hz, 3H).
Embodiment 58
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a28 (122.93mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=20/1) through silica gel column chromatography, obtains pure product, yield 85%.
Product c26 (Ethyl 2- (1,3-dioxoisoindolin-2-yl) -5- (triisopropylsilyl) pent- Nuclear-magnetism test result 4-ynoate)：
1H NMR(500MHz,CDCl3) δ 7.88-7.81 (m, 2H), 7.76-7.69 (m, 2H), 5.08 (dd, J=12.0, 5.0Hz, 1H), 4.29-4.15 (m, 2H), 3.36 (dd, J=17.5,12.0Hz, 1H), 3.11 (dd, J=17.5,5.0Hz, 1H), 1.23 (t, J=7.0Hz, 3H), 0.88-0.76 (m, 21H)13C NMR(125MHz,CDCl3)δ168.05,167.31, 134.21,132.02,123.59,102.79,83.66,62.28,50.91,20.86,18.43,18.42,14.19,11.11。
Embodiment 59
Sequentially added into the 25mL dried and clean Schlenck pipes with magnetic stir bar a29 (120.34mg, 0.2mmol), potassium acetate (19.6mg, 0.2mmol), absolute ethyl alcohol (2.0mL, aqueous≤0.01wt%), methyl glycidyl ether B1 (52.9mg, 0.6mmol), form reaction system.Above-mentioned Schlenck pipes are placed in heating response 35 hours in 90 DEG C of oil baths, TLC shows that raw material reaction is complete, obtains product system.Product system stopping heating being cooled to room temperature, and removal of solvent under reduced pressure obtains To residue, residue purifies (hexane/EA=50/1) through silica gel column chromatography, obtains pure product, yield 93%.
Product c27 (Ethyl 2- (4-isobutyl-2- ((triisopropylsilyl) ethynyl) phenyl) Propanoate nuclear-magnetism test result)：
1H NMR(500MHz,CDCl3) δ 7.27-7.25 (m, 1H), 7.21 (d, J=8.0Hz, 1H), 7.11-7.04 (m, 1H), 4.37 (q, J=7.0Hz, 1H), 4.21-4.03 (m, 2H), 2.41 (d, J=7.0Hz, 2H), 1.85 (dp, J=14.0, 7.0Hz, 1H), 1.47 (d, J=7.0Hz, 3H), 1.20 (t, J=7.0Hz, 3H), 1.14 (s, 18H), 0.90 (d, J= 7.0Hz,6H)。
Embodiment 60
Difference with embodiment 1 is that the epoxide used is b2, yield 92%.
Embodiment 61
Difference with embodiment 1 is that the epoxide used is b3, yield 69%.
Embodiment 62
Difference with embodiment 1 is that the epoxide used is b4, yield 21%.
Embodiment 63
Difference with embodiment 1 is that the epoxide used is b5, yield 68%.
Embodiment 64
Difference with embodiment 1 is that the epoxide used is b6, yield 87%.
Embodiment 65
Difference with embodiment 1 is that the epoxide used is b7, yield 89%.
Embodiment 66
Difference with embodiment 1 is that the epoxide used is b8, yield 47%.
It is can be seen that according to the result of the various embodiments described above using the present processes suitable substrates scope is relatively wide, reaction Mild condition.The yield of some embodiments is slightly lower, it is possible the reason for be reaction condition also need to adjustment or use solvent It is adjusted Deng needs.
As can be seen from the above description, the above embodiments of the present invention realize following technique effect：
Method provided herein, it is not only easy to operation, and also post processing only needs simple conventional separation step Pure products are can obtain, simultaneously because epoxide cost is cheap, therefore operation cost and three can be greatly reduced The risk and cost of useless processing.And the above method is when in use, reaction condition is gentle, being capable of compatible various different substituents and official It can roll into a ball, good yield, wide application range of substrates can be obtained to the acid amides of various different types of structure.I.e. the present invention is acid amides Alcoholysis provides environment-friendly, an economical and practical high efficiency method.The above-mentioned alcoholysis reaction of the application will not be by previous step Impurity effect in C-H priming reaction systems, purification of intermediate step is saved, can be activated and acid amides alcoholysis two-step reaction with C-H Even throw.
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area For art personnel, the present invention can have various modifications and variations.Within the spirit and principles of the invention, that is made any repaiies Change, equivalent substitution, improvement etc., should be included in the scope of the protection.

Claims (11)

  1. A kind of 1. method of acid amides alcoholysis, it is characterised in that methods described including the use of epoxide as accelerator, in alkali Property under the conditions of to amide compound carry out alcoholysis.
  2. 2. according to the method for claim 1, it is characterised in that with epoxide and the molar ratio computing of amide compound, The epoxide and the amount ratio of the amide compound are 1~5：1.
  3. 3. according to the method for claim 1, it is characterised in that the amide compound has formula I, the formula I ForR1, R2Any one in alkyl, aryl, substitution alkyl and substituted aryl is each independently selected from, it is preferably described Alkyl is selected from C1~C18Alkyl in any one, preferably it is described substitution alkyl backbone c atoms number be C1~C18In appoint Meaning is a kind of, and preferably described substitution alkyl is monosubstituted alkyl or polysubstituted alkyl, and the preferably described substituent substituted in alkyl selects From the combination of any one or more substitution in aryl, aromatic heterocycle substituent, cycloalkane, heterocycloalkane, alkenyl and alkynyl Base.
  4. 4. according to the method for claim 1, it is characterised in that the epoxide has formula II, the formula II ForThe R3With the R4Any of H, alkyl and aryl are each independently selected from, preferably described alkyl is selected from C1~C18Alkyl in any one.
  5. 5. method according to any one of claim 1 to 4, it is characterised in that methods described includes：
    The amide compound, the epoxide, pH value regulator and solvent are mixed, form alkaline reaction system, It is preferred that the pH value of the alkaline reaction system is 7.5~9.5；
    The alkaline reaction system is set to be reacted at 50~150 DEG C to carry out alcoholysis to the amide compound.
  6. 6. according to the method for claim 5, it is characterised in that the pH value regulator is weak acid or weak base, preferably described PH value regulator is selected from CF3CO2K、CF3CO2Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO3、KHCO3、NaHCO3、 LiHCO3、CsF、KF、NaF、LiF、Cs2CO3、K2CO3、Na2CO3、Li2CO3、K2HPO4、Na2HPO4、Li2HPO4、K3PO4、 Na3PO4, sodium benzoate, tetramethylethylenediamine, any one or more in N-N diisopropylethylamine and triethylamine.
  7. 7. according to the method for claim 5, it is characterised in that the solvent be selected from methanol, ethanol, normal propyl alcohol, isopropanol, N-butanol, isobutanol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, glycerine, 1,2- dimethoxy-ethanes, ethylene glycol diethyl ether, 2- first Any one or more in epoxide ethylether, 2- ethoxyethyl groups ether and pyrroles.
  8. 8. according to the method for claim 5, it is characterised in that the amide compound is The epoxide is methyl glycidyl ether, and the pH value regulator is KOAc, and the solvent is ethanol.
  9. 9. according to the method for claim 8, it is characterised in that the alkaline reaction system reacted at 80~100 DEG C with Alcoholysis is carried out to the amide compound.
  10. 10. according to the method for claim 8, it is characterised in that after the completion of the alcoholysis, methods described also includes：
    Decompression is carried out to the alcoholysis product and removes solvent, obtains residue；
    The residue and water are mixed to form mixture；
    The pH value of the mixture is adjusted to being extracted using n-hexane after 3.5~4.5, obtains organic phase；And
    The organic phase is dried, filtered.
  11. 11. according to the method for claim 8, it is characterised in that after the completion of the alcoholysis, methods described also includes：
    Decompression is carried out to the alcoholysis product and removes solvent, obtains residue；
    The residue is purified using silica gel column chromatography.
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WO2023182522A1 (en) * 2022-03-24 2023-09-28 積水化学工業株式会社 Epoxy resin, cured body of same and method for producing epoxy resin

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Publication number Priority date Publication date Assignee Title
CN106831285A (en) * 2017-03-08 2017-06-13 湖北科技学院 The method that acid amides, urea are converted into ester
CN106831285B (en) * 2017-03-08 2020-08-11 湖北科技学院 Method for converting amide and urea into ester
WO2023182522A1 (en) * 2022-03-24 2023-09-28 積水化学工業株式会社 Epoxy resin, cured body of same and method for producing epoxy resin
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