CN103922934A - Alkylation method of active methylene compound - Google Patents
Alkylation method of active methylene compound Download PDFInfo
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- CN103922934A CN103922934A CN201410148592.1A CN201410148592A CN103922934A CN 103922934 A CN103922934 A CN 103922934A CN 201410148592 A CN201410148592 A CN 201410148592A CN 103922934 A CN103922934 A CN 103922934A
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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
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Abstract
The invention discloses an alkylation method of an active methylene compound. The method comprises the following steps: A, adding the active methylene compound to an inorganic alkali-first polar organic solvent mixing system to form a to-be-reacted mixture; B, adding an alkylating agent to the to-be-reacted mixture, filtering after reacting to obtain filtrate, and removing a solvent in the filtrate to obtain the alkylated active methylene compound. According to the method, the inorganic alkali is adopted as a proton abstraction reagent of the active methylene compound, so that the removal effect on alpha-hydrogen in the active methylene compound can be ensured, the alkylation reaction of the active methylene compound can be carried out under a mild condition, and the reaction safety is improved. Meanwhile, the inorganic alkali is low in price, so that the production cost of the alkylation reaction is reduced.
Description
Technical field
The present invention relates to compound preparation field, in particular to a kind of alkylation of active methylene compound.
Background technology
While being connected with the electron-withdrawing groups such as carbonyl, ester group, phenyl, nitro or cyano group on a saturated carbon atom, the hydrogen atom (α-hydrogen) being connected with this carbon atom has just had certain acidity, be equivalent to this carbon atom by activation, this compounds is also referred to as active methylene compound.Common active methylene compound has straight chain ketone, aldehyde compound, propanedioic acid and derivative thereof, acetonitrile and derivative thereof, nitroparaffins compounds and has single, double carbonyl compound of ring texture etc.
In the chemical reaction relevant to above-mentioned active methylene compound, the most important alkylated reaction when number active methylene compounds, its product is widely used in the fields such as medicine is synthetic.For example: by alkylation, synthesize 2,2-dimethyl methyl acetoacetate can be used for that sterilant is synthetic, antimalarial agent synthetic, is also for the synthesis of the antibiotic important intermediate of cephalo element class.2,2-dimethyl methyl acetoacetate can also be as the solvent of cellulose ester solvent and spices and coating.In addition,, as polymerizing catalyst, 2,2-dimethyl methyl acetoacetate can be used for preparing metal complex.By alkylation, synthesize 2,2-dimethyl malonic ester compound is also some medicines and the synthetic important intermediate of natural product, has also been widely used in dyestuff, spices, agricultural chemicals and medicine and other fields.Therefore the alkylation process that, builds active methylene compound is produced significant.
At present, the alkylation process of active methylene compound has a lot, more typically has following several:
Method 1: Maxwell acid and methyl iodide are reacted and obtain pair methyl substituted target compounds under the effect of silver suboxide:
In the method, the toxicity of acetonitrile is larger, and silver suboxide cost is higher, is not suitable for industrial a large amount of production.
Method 2: use potassium tert.-butoxide (t-BuOK) to do alkali, methyl iodide is done methylating reagent, obtains 2,2-dimethyl methyl acetoacetate.
In the method, because t-BuOK can generate corresponding ether when running into haloalkane, in alkylating process, need to add at twice t-BuOK and methyl iodide.Meanwhile, the easy moisture absorption of t-BuOK, causes its activity decreased.In addition, the production cost of t-BuOK is higher.
Method 3: utilize the alpha-brominated isopropylformic acid of zinc and methyl to make Grignard reagent, take mercury chloride as catalyzer, synthesized 2,2-dimethyl methyl acetoacetate in the mixed solvent of ether and benzene.
In the method, require the particle diameter of zinc to be made as 20 orders, with heating gun, heat and cause backflow, technology difficulty is larger, and mercury chloride heating has mercury vapour volatilization.
Method 4: utilize sodium hydride as deprotonation reagent, dimethyl sulfoxide (DMSO) is done methylating reagent and synthesized 2,2-dimethyl methyl acetoacetate.The productive rate of target compound is 55%.
In this process, use NaH comparatively dangerous, be heated or contacting and emit heat and hydrogen with moisture, acids, cause burning and blast.In addition, dimethyl sulfoxide (DMSO) damage ratio is more serious, and skin is had to strong penetrating power.In last handling process, need this reaction of water cancellation.Product is under strong alkaline condition, and meeting fishery products can be hydrolyzed, and productive rate is declined.
Method 5: use sodium methylate as deprotonation reagent, do synthetic 2, the 2-dimethyl methyl acetoacetate of methylating reagent with methyl iodide.
Preparation method is easy for this method, but needs sodium alkoxide to do alkali, and its production cost is relatively high.
Method 6: cook phase-transfer catalyst with Tetrabutyl amonium bromide, butyl bromide or benzyl bromine are methylating reagent, the methylation reaction to propane dinitrile under inorganic or organic bases effect, the yield of target compound is between 60%～70%.
This reaction needed promotes the reaction between solid liquid phase with phase-transfer catalyst, has increased cost, and reaction yield is also relatively low.
Method 7: form carbon-to-carbon singly-bound with InCl3 catalysis vinyl carbinol and diethyl malonate reaction.Reaction is reacted 3h and is obtained 52% target product under 80 ℃ of conditions.
The defect of this reaction is reaction under reaction needed comparatively high temps (80 ℃), uses rare-earth metal catalyst, and industrial production cost is higher.In addition, reaction yield is also relatively low.
Method 8: use Yb (OTf)
3make catalyzer, CH
3nO
2making solvent at room temperature reacts 0.5h and can obtain 93% target product.
The defect of this reaction is agents useful for same Yb (OTf)
3expensive, and reaction solvent CH
3nO
2there is certain toxicity.
As shown in the above, while at present active methylene compound being carried out to alkylation processing, generally select the mixture of alkali-metal alcohol compound, sodium hydride, ionic liquid or inorganic weak bases and phase-transfer catalyst as deprotonation reagent.These reaction product purity are lower, reaction raw materials too costliness or reaction safety poor, production cost is increased or is unfavorable for safety in production, unsuitable large-scale industrial production.Therefore, be badly in need of the alkylation that a kind of reaction conditions is gentle, production cost is lower method completes active methylene compound.
Summary of the invention
The present invention aims to provide a kind of alkylation of active methylene compound, to solve the high problem of alkylation cost of active methylene compound in prior art.
To achieve these goals, according to an aspect of the present invention, the alkylation that a kind of active methylene compound is provided, it comprises the following steps: steps A: active methylene compound is added in inorganic strong alkali-the first polar organic solvent mixed system, form question response mixture; Step B: add alkylating reagent in question response mixture, filter and obtain filtrate after reaction, the solvent of removing in filtrate obtains alkylation active methylene compound.
Further, above-mentioned steps A comprises: steps A 1: active methylene compound is added to the second polar organic solvent, form substrate solution; Steps A 2: substrate solution is added in described inorganic strong alkali-the first polar organic solvent mixed system, form question response mixture; Wherein, the first polar organic solvent and the second polar organic solvent are identical or different.
Further, in above-mentioned steps A1, at the temperature of-20～70 ℃, active methylene compound is added to the second polar organic solvent, form the substrate solution that active methylene compound concentration is 0.3～0.8g/ml; In steps A 2, at the temperature of-20～70 ℃, substrate solution is added in inorganic strong alkali-the first polar organic solvent mixed system, form the question response mixture that active methylene compound concentration is 0.1～0.3g/ml.
Further, in above-mentioned steps A, according to the mol ratio of inorganic strong alkali and active methylene compound, be 2.0～25:1, be preferably 2.5～5:1, active methylene compound or substrate solution are added in inorganic strong alkali-the first polar organic solvent mixed system.
Further, in above-mentioned steps B, at the first temperature, the mode adopt dripping adds to alkylating reagent in question response mixture, drips after finishing and react 2～15h at the second temperature; The speed preferably dripping is 0.2～0.3g/min, and temperature of reaction is 0～70 ℃, and the first temperature is-20～70 ℃, and the second temperature is-20～70 ℃, and the second temperature is higher than equaling the first temperature.
Further, in above-mentioned steps B, according to the mol ratio of alkylating reagent and active methylene compound, be 2.0～4.8:1, in question response mixture, add alkylating reagent.
Further, in above-mentioned inorganic strong alkali-the first polar organic solvent mixed system, inorganic strong alkali is KOH, NaOH, LiOH, and the first polar organic solvent and the second polar organic solvent are respectively one or more in the alcoholic solvent of polar ether kind solvent and C1～C6; Preferably polar ether kind solvent is ether, propyl ether, isopropyl ether, tetrahydrofuran (THF), propylene oxide or methyl tertiary butyl ether, more preferably tetrahydrofuran (THF); Preferably the alcoholic solvent of C1～C6 is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, Pentyl alcohol, sec.-amyl alcohol, primary isoamyl alcohol, n-hexyl alcohol or hexalin, more preferably methyl alcohol or Virahol, then be preferably methyl alcohol; Preferably the first polar organic solvent is identical with the second polar organic solvent.
Further, active methylene compound is the compound with formula I structure, and the structure of its Chinese style I is as follows:
Wherein, R
1and R
2for electron-withdrawing group; Preferred R
1and R
2respectively independently selected from by
and the group that forms of aryl, R ' and R ' ' are respectively independently selected from the group being comprised of alkyl, alkoxyl group and thiazolinyl.More preferably R
1and R
2respectively independently selected from by
and
the group forming, R ' and R ' ' are respectively methyl or ethyl.
Further, alkylating reagent is the alkyl halide class alkylating reagent of ester class alkylating reagent or C1～C2; Preferably ester class alkylating reagent is ethyl sulfate, trimethyl phosphite 99, methyl tosylate or methyl-sulfate, more preferably methyl-sulfate; Preferably the alkyl halide class alkylating reagent of C1～C2 is monobromethane, methyl chloride, methyl iodide, monochloroethane, monobromethane, iodoethane, Mono Chloro Acetic Acid or chloroethanol, more preferably monobromethane or methyl iodide.
Further, above-mentioned the first polar organic solvent and the second polar organic solvent are tetrahydrofuran (THF), inorganic strong alkali is KOH, NaOH or LiOH, the alkylation of active methylene compound comprises the following steps: at 0～40 ℃ of temperature, the KOH that is 2.5～5:1 by the mol ratio with active methylene compound, NaOH, LiOH add in tetrahydrofuran (THF), after stirring, form inorganic strong alkali-the first polar organic solvent mixed system; At 0～40 ℃ of temperature, active methylene compound is added in tetrahydrofuran (THF) to the substrate solution that formation concentration is 0.3～0.8g/mL; Substrate solution is dropped to inorganic strong alkali-the first polar organic solvent mixed system with 0.5～1g/min, the question response mixture that formation concentration is 0.1～0.3g/ml; Holding temperature is at 0～40 ℃, according to the mol ratio of alkylating reagent and active methylene compound, be 2.0～4.8:1, alkylating reagent is dropped to question response mixture with 0.2～0.3g/min, after insulation reaction 2～4h, filtration obtains filtrate, after concentrated filtrate, distill, obtain alkylating active methylene compound.
Further, above-mentioned the first polar organic solvent and the second polar organic solvent are methyl alcohol, inorganic strong alkali is KOH, NaOH, LiOH, the alkylation of active methylene compound comprises the following steps: at 0～20 ℃ of temperature, the KOH that is 2.5～5:1 by the mol ratio with active methylene compound, NaOH, LiOH add in methyl alcohol, after stirring, form inorganic strong alkali-the first polar organic solvent mixed system; At 0～20 ℃ of temperature, active methylene compound is added in methyl alcohol to the substrate solution that formation concentration is 0.2～0.25g/mL; Substrate solution is dropped to inorganic strong alkali-the first polar organic solvent mixed system with 0.5～1g/min, the question response mixture that formation concentration is 0.05～0.1g/ml; Holding temperature is at-2～20 ℃, according to the mol ratio of alkylating reagent and active methylene compound, be 4～4.5:1, alkylating reagent is dropped to question response mixture with 0.2～0.3g/min, after insulation reaction 2～19h, filtration obtains filtrate, after concentrated filtrate, distill, obtain alkylating active methylene compound.
Apply the alkylation of active methylene compound of the present invention, using inorganic strong alkali as the deprotonation reagent of active methylene compound, its to α-hydrogen in active methylene compound to remove effect stronger.The alkylated reaction of active methylene compound can be carried out under relatively mild temperature condition, and this just can effectively improve the security of reaction.Meanwhile, with respect to organic bases, the price of mineral alkali is lower, and the production cost of alkylated reaction is reduced.In addition, because inorganic strong alkali is polar compound, added in polar organic solvent, can be increased the consistency of the two, improved the solubleness of inorganic strong alkali.Thereby make inorganic strong alkali more effectively act on active methylene compound, improve alkylating speed.
Embodiment
It should be noted that, in the situation that not conflicting, embodiment and the feature in embodiment in the application can combine mutually.Below in conjunction with embodiment, describe the present invention in detail.
As background technology part, introducing, there is the problem that cost is high in the alkylation of active methylene compound.In order to address this problem, inventor provides a kind of alkylation of active methylene compound, it comprises the following steps: steps A: active methylene compound is added in inorganic strong alkali-the first polar organic solvent mixed system, form question response mixture; Step B: add alkylating reagent in question response mixture, filter and obtain filtrate after reaction, the solvent of removing in filtrate obtains alkylation active methylene compound.
In aforesaid method provided by the present invention, using the deprotonation reagent of inorganic strong alkali as active methylene compound, can guarantee its effect that removes to α-hydrogen in active methylene compound, can make again the alkylated reaction of active methylene compound carry out under relatively mild condition, improve the security of reaction.Meanwhile, the price of mineral alkali is lower, and the production cost of alkylated reaction is reduced.In addition, the solvent borne of inorganic strong alkali in polar organic solvent is better, based on this, using the solvent of polar organic solvent as alkylated reaction, be conducive to make more inorganic strong alkali and active methylene compound for same homogeneous system, thereby make inorganic strong alkali act on more fully active methylene compound, and then be conducive to improve the speed of alkylated reaction.
As long as according to the method described above, just can access alkylation active methylene compound.A kind of preferred embodiment in, above-mentioned steps A comprises: steps A 1: active methylene compound is added to the second polar organic solvent, form substrate solution; Steps A 2: substrate solution is added in inorganic strong alkali-the first polar organic solvent mixed system, form question response mixture; Wherein, the first polar organic solvent and the second polar organic solvent are identical or different.Than directly alkylation active methylene compound being added in inorganic strong alkali-the first polar organic solvent mixed system, first configure the substrate solution of active methylene compound, substrate solution is added in inorganic strong alkali-the first polar organic solvent mixed system again, can make the dispersion of active methylene compound more even.And then can make alkylated reaction speed improve.Adopt the more enough reaction system homogeneous more that makes of identical polar organic solvent, thereby can further improve speed and the transformation efficiency of alkylated reaction.
According to instruction of the present invention, those skilled in the art have the ability to select applicable processing parameter, with the α-hydrogen in active methylene compound, remove processing, obtain question response mixture.A kind of preferred embodiment in, in above-mentioned steps A1, at-20～70 ℃ of temperature, active methylene compound is added to the second polar organic solvent, form the substrate solution that active methylene compound concentration is 0.3～0.8g/ml; In steps A 2, at-20～70 ℃ of temperature, substrate solution is added in inorganic strong alkali-the first polar organic solvent mixed system, form the question response mixture that active methylene compound concentration is 0.1～0.3g/ml.In the alkylation of active methylene compound of the present invention, steps A is not limited to and adopts above-mentioned steps and processing parameter, yet under above-mentioned processing condition, transformation efficiency that the speed of reaction of alkylated reaction can access relative raising and prepared product is higher, purity is higher.
In the above-mentioned method of the present invention, the add-on of inorganic strong alkali is not had to special requirement, as long as carry out according to inorganic strong alkali and active methylene compound the theoretical molar ratio that deprotonation reacts, add.A kind of preferred embodiment in, in above-mentioned steps A, according to the mol ratio of inorganic strong alkali and active methylene compound, be 2.0～25:1, be preferably 2.5～5:1, active methylene compound or substrate solution are added in inorganic strong alkali-the first polar organic solvent mixed system.Within the scope of aforementioned proportion, the consumption of inorganic strong alkali is apparently higher than theoretical consumption, the inorganic strong alkali that now added, and a part can, as the deprotonation reagent of active methylene compound, participate in alkylated reaction; A part can provide alkaline environment to alkylated reaction, impels the alkylated reaction in running balance to carry out to the forward that generates alkylate.The factor of above two aspects can further improve product production rate and the speed of reaction of alkylated reaction.
According to instruction of the present invention, those skilled in the art have the ability to select concrete processing condition, to impel the carrying out of alkylated reaction.A kind of preferred embodiment in, above-mentioned steps B comprises, at the first temperature, adopts the mode dripping that alkylating reagent is added in question response mixture, drips after finishing and react 2～15h at the second temperature; The speed preferably dripping is 0.2～0.3g/min, and temperature of reaction is 0～70 ℃, and the second temperature is higher than equaling described the first temperature, and the first temperature and described the second temperature are respectively-20～70 ℃.In invention, above-mentioned steps B is not limited to above-mentioned processing method and processing parameter.By the mode dripping, alkylating reagent is added in question response mixture, be conducive to the dispersion of alkylating reagent in question response mixture more even, thereby improve the speed of reaction of alkylated reaction.Abovementioned alkylization reaction, for thermopositive reaction, can spontaneously heat up reaction system.It is 0.2～0.3g/min that rate of addition is controlled, and can make alkylated reaction more abundant, can also avoid dripping the too fast problem of too fast the caused local heating of speed., temperature of reaction is controlled in above-mentioned scope, the speed of reaction causing in the time of can avoiding low temperature is too low meanwhile, and the byproduct of reaction causing in the time of can avoiding excess Temperature increases simultaneously, thereby affects the production rate of alkylate.
In the above-mentioned method of the present invention, the add-on of alkylating reagent can be adjusted according to the add-on of the active methylene compound of question response.Preferably, in above-mentioned steps B, according to the mol ratio of alkylating reagent and active methylene compound, be 2.0～4.8:1, in question response mixture, add alkylating reagent.The alkylating reagent that adopts aforementioned proportion, can impel alkylated reaction more abundant, and then improves the transformation efficiency of alkylated reaction.
In the above-mentioned method of the present invention, in inorganic strong alkali-the first polar organic solvent mixed system, inorganic strong alkali adopts the common middle highly basic raw material hydroxy that contains, and includes but not limited to KOH, NaOH, LiOH.These several inorganic strong alkalis, can effectively deviate from the α-hydrogen of active methylene compound, promote the carrying out of alkylated reaction.And the cost of these inorganic strong alkalis is lower, can effectively reduce the cost of alkylated reaction.Meanwhile, adopt these several inorganic strong alkalis to carry out alkylated reaction, mild condition, easily control, and security is higher.The impact of the high-boiling-point impurity producing in the time of can avoiding base excess on product purity.In addition, KOH, NaOH, LiOH without cancellation, have simplified the postprocessing working procedures of alkylated reaction after reaction finishes.
In the above-mentioned method of the present invention, the first polar organic solvent and the second polar organic solvent adopt compatible, and can dissolve to a certain extent the solvent of organic alkali and active methylene compound, preferably the first polar organic solvent and the second polar organic solvent are respectively one or more in the alcoholic solvent of polar ether kind solvent and C1～C6.While adopting polar ether kind solvent as the first polar organic solvent, inorganic strong alkali is slightly soluble in wherein, but further adds after active methylene compound, and system presents dispersed suspension preferably, and its alkylated reaction can be stablized and carry out; The alcoholic solvent that adopts C1～C6 is during as the first polar organic solvent, and inorganic strong alkali can dissolve wherein, and mixed system presents solution state, and alkylated reaction also can be stablized and carry out.
Adopt above-mentioned polar ether kind solvent that the comparatively reaction system of homogeneous can be provided for the alkylated reaction of active methylene compound.Wherein, these polar ether kind solvents include but not limited to ether, propyl ether, isopropyl ether, tetrahydrofuran (THF), propylene oxide or methyl tertiary butyl ether.Compared to other polar ether kind solvents, above-mentioned these several ether solvents have higher polarity, and the consistency of inorganic strong alkali and solvent is more excellent.On this basis, using these several solvents as the solvent of active methylene compound alkylated reaction, in its alkylation products, product content and transformation efficiency are all higher.More preferably, above-mentioned polar ether kind solvent is tetrahydrofuran (THF).Tetrahydrofuran (THF) is stronger a kind of of ether solvent Semi-polarity, usings its solvent as active methylene group alkylated reaction, is conducive to further improve inorganic strong alkali dispersiveness therein, and then is conducive to further improve product content and the transformation efficiency of alkylation products.In addition, than other polar ether kind solvents, the stability of tetrahydrofuran (THF) is higher, is conducive to improve the security of alkylated reaction, and then is conducive to the suitability for industrialized production of active methylene compound alkylation products.
In aforesaid method, can adopt the alcoholic solvent of C1～C6 arbitrarily, wherein preferably the alcoholic solvent of C1～C6 is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, Pentyl alcohol, sec.-amyl alcohol, primary isoamyl alcohol, n-hexyl alcohol or hexalin.Inorganic strong alkali all has good solvability at these alcoholic solvents, usings its solvent as alkylated reaction, can provide the more reaction system of homogeneous for active methylene compound, thereby be conducive to improve product content and the transformation efficiency of alkylation products.More preferably, the alcoholic solvent of above-mentioned C1～C6 is methyl alcohol or Virahol.Than other alcoholic solvents, methyl alcohol and Virahol have higher polarity, make inorganic strong alkali have therein higher solvability.Thereby be conducive to further improve product content and the transformation efficiency of alkylation products.Wherein, than Virahol, methyl alcohol has higher polarity, so above-mentioned alcoholic solvent methyl alcohol more preferably.In addition, preferably the first polar organic solvent is identical with the second polar organic solvent.The good solvent of consistency can provide the comparatively reaction system of homogeneous for alkylated reaction, impels reaction efficiently to carry out.
The above-mentioned method of the present invention is applicable to any active methylene compound, is wherein specially adapted to have the active methylene compound of formula I structure, and the structure of its Chinese style I is as follows:
Wherein, R
1and R
2for electron-withdrawing group.Work as R
1and R
2during for electron-withdrawing group, have in the compound of formula I structure, with R
1and R
2between the connected hydrogen atom of carbon atom there is certain acidity (α-hydrogen atom).While carrying out alkylated reaction with this compounds, its α-hydrogen atom is easily replaced by the alkyl in alkylating reagent under alkaline condition, and then forms alkylating active methylene compound.
In aforesaid method, in the active methylene compound of employing, as long as R
1and R
2for electron-withdrawing group, the hydrogen atom on the carbon atom between the two just can carry out alkylated reaction under alkaline condition.A kind of preferred embodiment in, R
1and R
2respectively independently selected from by
and the group that forms of aryl, R ' and R ' ' are respectively independently selected from the group being comprised of alkyl, alkoxyl group and thiazolinyl.Than other electron-withdrawing groups, above-mentioned nitro, itrile group, carbonyl and ester group have stronger electron-withdrawing power, and the α-hydrogen atom in its corresponding active methylene compound has higher activity.This just makes these α-hydrogen atoms more easily by alkyl, be replaced, thus the carrying out that is conducive to impel alkylated reaction.More preferably R
1and R
2respectively independently selected from by
and
the group forming, R ' and R ' ' are respectively methyl or ethyl.Than nitro, the stability of itrile group, carbonyl and the corresponding active methylene compound of ester group is higher, security is better.Than aryl, the electron-withdrawing power of itrile group, carbonyl and ester group is stronger, and the α-hydrogen atom activity in its corresponding active methylene compound is higher, can promote the carrying out of alkylated reaction.In addition,, in above-mentioned carbonyl and ester group, when R ' and R ' ' are respectively methyl or ethyl, the electron-withdrawing power of corresponding carbonyl and ester group is stronger, is also conducive to the alkylated reaction of corresponding active methylene compound.Generally speaking, above-mentioned R
1and R
2be respectively
or
and when R ' and R ' ' are respectively methyl or ethyl, when corresponding active methylene compound carries out alkylated reaction, can access the alkylate that productive rate is higher, and its alkylation process is more stable.Thereby be conducive to carrying out on a large scale of alkylated reaction.
The above-mentioned method of the present invention is applicable to various existing alkylating reagents, is wherein specially adapted to the alkyl halide class alkylating reagent of ester class alkylating reagent or C1～C2.The polarity of the alkyl halide class alkylating reagent of ester class alkylating reagent and C1～C2 is stronger, can make the α-hydrogen in active methylene compound more easily deviate from, thereby the speed of alkylated reaction is further improved.Wherein ester class alkylating reagent includes but not limited to ethyl sulfate, trimethyl phosphite 99, methyl tosylate or methyl-sulfate.Methyl-sulfate more preferably.Methyl-sulfate, for other ester class alkylating reagents, has higher polarity, and its reaction conditions is gentle, easily controls.Wherein the alkyl halide class alkylating reagent of C1～C2 includes but not limited to monobromethane, methyl chloride, methyl iodide, monochloroethane, monobromethane, iodoethane, Mono Chloro Acetic Acid or chloroethanol, more preferably monobromethane or methyl iodide.Adopt monobromethane or methyl iodide as methylating reagent, after alkylated reaction finishes, without water cancellation, can avoid alkylation products under highly basic condition, to meet water the problem of decomposing easily occurs.
According to instruction of the present invention, those skilled in the art have the ability to select concrete alkylation process, to prepare alkylation products.
A kind of preferred embodiment in, above-mentioned the first polar organic solvent and the second polar organic solvent are tetrahydrofuran (THF), inorganic strong alkali is KOH, NaOH, LiOH, the alkylation of active methylene compound comprises the following steps: at 0～40 ℃ of temperature, the KOH that is 2.5～5:1 by the mol ratio with active methylene compound, NaOH, LiOH add in tetrahydrofuran (THF), after stirring, form inorganic strong alkali-the first polar organic solvent mixed system; At 0～40 ℃ of temperature, active methylene compound is added in tetrahydrofuran (THF) to the substrate solution that formation concentration is 0.3～0.8g/mL; Substrate solution is dropped to inorganic strong alkali-the first polar organic solvent mixed system with 0.5～1g/min, the question response mixture that formation concentration is 0.1～0.3g/ml; Holding temperature is at 0～40 ℃, according to the mol ratio of alkylating reagent and active methylene compound, be 2.0～4.8:1, alkylating reagent is dropped to question response mixture with 0.2～0.3g/min, insulation reaction 2～4h, filtration obtains filtrate, after concentrated filtrate, distill, obtain alkylating described active methylene compound.
In above-mentioned embodiment, while adopting tetrahydrofuran (THF) to be solvent, the conditions such as the temperature of alkylated reaction, inorganic strong alkali and consumption, alkylating reagent and consumption are mated more, and just can obtain the alkylate that transformation efficiency is higher within a short period of time.And above-mentioned reaction conditions is gentleer, can effectively improve the security of alkylated reaction, be applicable to industrial mass production.
In another preferred embodiment, above-mentioned the first polar organic solvent and the second polar organic solvent are methyl alcohol, inorganic strong alkali is KOH, NaOH, LiOH, the alkylation of active methylene compound comprises the following steps: at 0～20 ℃ of temperature, the KOH that is 2.5～5:1 by the mol ratio with active methylene compound, NaOH, LiOH add in methyl alcohol, after stirring, form inorganic strong alkali-the first polar organic solvent mixed system; At 0～20 ℃ of temperature, active methylene compound is added in methyl alcohol to the substrate solution that formation concentration is 0.2～0.25g/mL; Substrate solution is dropped to inorganic strong alkali-the first polar organic solvent mixed system with 0.5～1g/min, the question response mixture that formation concentration is 0.05～0.1g/ml; Holding temperature is at-2～20 ℃, according to alkylating reagent and active methylene compound mol ratio, be 4～4.5, alkylating reagent is dropped to described question response mixture with 0.2～0.3g/min, after insulation reaction 2～19h, filtration obtains filtrate, after concentrated filtrate, distill, obtain alkylating active methylene compound.
In above-mentioned embodiment, while adopting methyl alcohol to be solvent, the conditions such as the temperature of alkylated reaction, inorganic strong alkali consumption are mated more, and just can obtain the alkylate that transformation efficiency is higher within a short period of time.And above-mentioned reaction conditions is gentleer, can effectively improve the security of alkylated reaction, be applicable to industrial mass production.
Below in conjunction with specific embodiment, the present invention is described in further detail, these embodiment can not be interpreted as restriction the present invention scope required for protection.
Embodiment 1
In the there-necked flask of 100ml, add KOH, under-20 ℃, the condition that stirs, add wherein 50ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under-20 ℃, the condition that stirs, 5g methyl acetoacetate is added in above-mentioned KOH/THF mixed system, form the question response mixture that methyl acetoacetate concentration is 0.1g/mL, wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Holding temperature is constant, under the condition stirring, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control temperature of reaction-20 ℃, through 15h, filter and obtain filtrate, filtrate is carried out to concentrated by rotary evaporation, obtain the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 2
In the there-necked flask of 100ml, add KOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
5g methyl acetoacetate is dissolved in 10ml THF to the substrate solution that to form concentration be 0.5g/mL under 0 ℃, the condition that stirs;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 0.5g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Holding temperature is constant, under the condition stirring, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 0 ℃ of temperature of reaction, through 4h, filter and obtain filtrate, filtrate is carried out to concentrated by rotary evaporation, obtain the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 3
In the there-necked flask of 100ml, add KOH, under 30 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
5g methyl acetoacetate is dissolved in 10ml THF to the substrate solution that to form concentration be 0.5g/mL under 30 ℃, the condition that stirs;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 0.5g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Holding temperature is constant, under the condition stirring, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 30 ℃ of temperature of reaction, through 2h, filter and obtain filtrate, filtrate is carried out to concentrated by rotary evaporation, obtain the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 4
In the there-necked flask of 100ml, add KOH, under 40 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 40 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 0.5g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Holding temperature is constant, under the condition stirring, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 40 ℃ of temperature of reaction, through 2h, filter and obtain filtrate, filtrate is carried out to concentrated by rotary evaporation, obtain the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 5
In the there-necked flask of 100ml, add KOH, under 60 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 60 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 0.5g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Holding temperature is constant, under the condition stirring, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 60 ℃ of temperature of reaction, through 2h, filter and obtain filtrate, filtrate is carried out to concentrated by rotary evaporation, obtain the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 6
In the there-necked flask of 100ml, add KOH, under 67 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 67 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 0.5g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Holding temperature is constant, under the condition stirring, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 67 ℃ of temperature of reaction, through 2h, filter and obtain filtrate, filtrate is carried out to concentrated by rotary evaporation, obtain the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 7
In the there-necked flask of 100ml, add NaOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 8
In the there-necked flask of 100ml, add KOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 9
In the there-necked flask of 100ml, add KOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 15:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 10
In the there-necked flask of 100ml, add NaOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form NaOH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned NaOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 25:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate
Embodiment 11
In the there-necked flask of 100ml, add KOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 12
In the there-necked flask of 100ml, add NaOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form NaOH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned NaOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of NaOH and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 13
In the there-necked flask of 100ml, add LiOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form LiOH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned LiOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of LiOH and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 14
In the there-necked flask of 100ml, add t-BuOK, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form t-BuOK/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned t-BuOK/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of t-BuOK and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 15
In the there-necked flask of 100ml, add NaH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form NaH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned NaH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of NaH and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.8:1, control 20 ℃ of temperature of reaction, through 4h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 16
In the there-necked flask of 100ml, add KOH, under 0 ℃, the condition that stirs, add wherein 40ml methyl alcohol, form KOH/ methanol mixed system;
Under 0 ℃, the condition that stirs, 2.5g methyl acetoacetate is dissolved in 10ml methyl alcohol, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned KOH/ methanol mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.05g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.0:1, control 20 ℃ of temperature of reaction, through 2h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 17
In the there-necked flask of 100ml, add KOH, under 0 ℃, the condition that stirs, add wherein 25ml methyl alcohol, form KOH/ methanol mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 25ml methyl alcohol, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 1g/min adds in above-mentioned KOH/ methanol mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.0:1, control temperature of reaction-2 ℃, through 19h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 18
In the there-necked flask of 100ml, add KOH, under 0 ℃, the condition that stirs, add wherein 40ml Virahol, form KOH/ Virahol mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml Virahol, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 0.5g/min adds in above-mentioned KOH/ Virahol mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and methyl acetoacetate is 4.0:1, control 20 ℃ of temperature of reaction, through 15h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 19
In the there-necked flask of 100ml, add KOH, under 0 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 0 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and the speed by above-mentioned substrate solution with 0.5g/min adds in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Under 0 ℃, the condition that stirs, speed by methyl-sulfate with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of methyl-sulfate and methyl acetoacetate is 2:1, control 20 ℃ of temperature of reaction, through 15h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Embodiment 20
In the there-necked flask of 100ml, add KOH, under 20 ℃, the condition that stirs, add wherein 40ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 20 ℃, the condition that stirs, 5g methyl acetoacetate is dissolved in 10ml THF, forms the substrate solution that methyl acetoacetate concentration is 0.5g/mL;
Holding temperature is constant, and above-mentioned substrate solution is added in above-mentioned KOH/THF mixed system, forms the question response mixture that methyl acetoacetate concentration is 0.1g/mL, and wherein the mol ratio of KOH and methyl acetoacetate is 2.5:1;
Holding temperature is constant, under the condition stirring, speed by 1-monobromethane with 0.2g/min drops in above-mentioned question response mixture, wherein the mol ratio of 1-monobromethane and methyl acetoacetate is 4:1, control 20 ℃ of temperature of reaction, through 15h, filter and obtain filtrate, filtrate is carried out to concentrated by rotary evaporation, obtain the thick product of alkylation.
Comparative example 1
Using sodium methylate as deprotonation reagent
In 100ml there-necked flask, add 7g sodium methylate/methanol mixed system, wherein the massfraction of sodium methylate is 21wt%, and adds wherein the tetrahydrofuran (THF) (THF) of 10ml, forms the mixed system of sodium methylate/methyl alcohol/THF;
Under 20 ℃, agitation condition, 1g methyl acetoacetate is added dropwise in there-necked flask, wherein the mol ratio of sodium methylate and methyl acetoacetate is 2.5:1;
Continuation is at 20 ℃, and the speed by monobromethane with 0.2g/min drops in above-mentioned question response mixture, and wherein the mol ratio of monobromethane and methyl acetoacetate is 4:1, control temperature of reaction, through 15 hours, filter and obtain filtrate, filtrate is carried out to concentrated by rotary evaporation, obtain the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl methyl acetoacetate.
Above-described embodiment and the prepared alkylation products of comparative example are carried out to characterization test.
Testing method:
1) product content: adopt the GC9900 chromatographic instrument of Beijing Jia Fen analytical instrument company to test the thick product of alkylation, calculate in the thick product of alkylation and deduct the product content after solvent with peak area normalization method; Chromatographic condition is as follows:
Instrument numbering: LAVI-YS-0059; Post type: AE-SE-54; Post specification: 30m * 0.32mm * 0.5 μ m; Carrier gas type: N
2; Before post, press (N
2): 0.06Mpa; Hydrogen: 0.12MPa; Air: 0.10MPa; Sample size: 1 μ L; Detector: FID; Hydrogen: 30mL/min; Temperature: 280 ℃; Sampler: shunting; Splitting ratio: 60:1; Temperature: 250 ℃.
Temperature programming: preliminary examination temperature 60 C, keep 1min, with the speed of 10 ℃/min, be warming up to 280 ℃, keep 5min.
2) transformation efficiency: according to the chromatogram content of alkylation products Raw, calculate the transformation efficiency of raw material.
Test result is as shown in table 1:
Table 1
| ? | Product content (%) | Transformation efficiency (%) | ? | Product content (%) | Transformation efficiency (%) |
| Embodiment 1 | 83.3 | 100 | Embodiment 11 | 99.4 | 99 |
| Embodiment 2 | 99.4 | 100 | Embodiment 12 | 99.5 | 99 |
| Embodiment 3 | 99.1 | 100 | Embodiment 13 | 99.4 | 99 |
| Embodiment 4 | 99.3 | 100 | Embodiment 14 | 86.8 | 86 |
| Embodiment 5 | 99.1 | 100 | Embodiment 15 | 96.2 | 95 |
| Embodiment 6 | 99.1 | 100 | Embodiment 16 | 100 | 100 |
| Embodiment 7 | 48.7 | 100 | Embodiment 17 | 100 | 100 |
| Embodiment 8 | 99.1 | 100 | Embodiment 18 | 95 | 100 |
| Embodiment 9 | 85.9 | 100 | Embodiment 19 | 61 | 100 |
| Embodiment 10 | 47.9 | 100 | Embodiment 20 | 74 | 100 |
| Comparative example 1 | 82.7 | 100 | ? | ? | ? |
From above data, can find out, the alkylation active methylene compound that adopts the method in the above embodiment of the present invention to prepare, its product content and transformation efficiency are all higher.Than adopt in comparative example, using that organic bases prepared as deprotonation reagent 2,2-dimethyl methyl acetoacetate, most of adopt method of the present invention prepared 2,2-dimethyl methyl acetoacetate, its product content and transformation efficiency are higher.In addition, than adopting organic bases as deprotonation reagent, in the present invention, adopt mineral alkali lower as the cost of deprotonation reagent, be more suitable for the suitability for industrialized production of alkylation active methylene compound.
To the beneficial effect of the present invention in industrial amplification production be described further combined with embodiment below:
Embodiment 21
Tetrahydrofuran (THF) (THF) to adding 406.0kg in 1000L reactor, will wherein add the LiOH of 92.1Kg, stirs, and is cooled to 5 ℃, forms LiOH/THF mixed system;
Under the condition of 20 ℃ of temperature, stirring, 58.0kg propane dinitrile is dissolved in the THF of 40.6kg, form substrate solution;
At 20 ℃ of temperature, above-mentioned substrate solution is splashed in LiOH/THF mixed system at 3h, form question response mixture, wherein the mol ratio of LiOH and propane dinitrile is 2.5:1;
In 500L reactor, add 133.4kg THF, add wherein the monobromethane of 333.7kg at 0 ℃ of temperature, 8h drips complete, forms alkylating reagent solution;
At 20 ℃ of temperature, in above-mentioned question response mixture, add alkylating reagent solution, making the wherein mol ratio of monobromethane and propane dinitrile is 4.0:1.After isothermal reaction 8h, reaction solution is proceeded to 2000L reactor, in still, drip the dilute hydrochloric acid that concentration is 260kg1.2g/L, regulate PH=5,1h dropwises, and obtains the reaction solution of acidifying, so that the inorganic impurity in reaction solution is extracted;
The reaction solution of above-mentioned acidifying is evaporated to not fluid at 25～30 ℃ of temperature, and directly, after concora crush, standing, separatory obtains organic phase and water.With after 30kg saturated common salt water washing organic phase, add 10kg anhydrous sodium sulfate drying 2h, filter and remove after siccative, at 25～30 ℃ of temperature, be evaporated to not fluid, obtain concentrated solution.The water above-mentioned separatory being obtained by 80kg ethyl acetate carries out after 2 extractions, and separatory obtains organic phase again.Merge after organic phase, with the water washing of 50kg saturated common salt once, add 20kg anhydrous sodium sulfate drying 2h, filter and remove siccative.Again at the temperature of 25～30 ℃, be evaporated to not fluid, obtain secondary concentration liquid.After twice concentrated solution merged, obtain the thick product of alkylation;
By the rectifying in 200L rectifying still of above-mentioned thick product, collecting end temperature is 100～110 ℃, and top temperature is the cut of 95～105 ℃, and obtains alkylation products 2,2-dimethyl propylene dintrile.(test mode is with embodiment 1～19) after tested, productive rate is 46.5%, and product content is 100%, and transformation efficiency is 100%.
Embodiment 22
In the there-necked flask of 1L, add KOH, under 0 ℃, the condition that stirs, add wherein 300ml tetrahydrofuran (THF) (THF), form KOH/THF mixed system;
Under 0 ℃, the condition that stirs, 30g diethyl malonate is added in above-mentioned KOH/THF mixed system, form the question response mixture that diethyl malonate concentration is 0.1g/mL, wherein the mol ratio of KOH and diethyl malonate is 5:1;
Under 0 ℃, the condition that stirs, speed by monobromethane with 0.3g/min drops in above-mentioned question response mixture, wherein the mol ratio of monobromethane and diethyl malonate is 4:1, control 20 ℃ of temperature of reaction, through 2h, filtration obtains filtrate, and filtrate is carried out to concentrated by rotary evaporation, obtains the thick product of alkylation.
By thick product underpressure distillation, obtain 2,2-dimethyl malonic ester.(test mode is with embodiment 1～19) after tested, productive rate is 45.7%, and product content is 99%, and transformation efficiency is 100%.
From embodiment 21 and 22, can find out that active methylene group alkylation provided by the present invention is applicable to large-scale industrialization and produces.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (12)
1. an alkylation for active methylene compound, is characterized in that, comprises the following steps:
Steps A: described active methylene compound is added in inorganic strong alkali-the first polar organic solvent mixed system, form question response mixture;
Step B: add alkylating reagent in described question response mixture, filter and obtain filtrate after reaction, distill after concentrated described filtrate, obtain alkylation active methylene compound.
2. method according to claim 1, is characterized in that, described steps A comprises:
Steps A 1: described active methylene compound is added to the second polar organic solvent, form substrate solution;
Steps A 2: described substrate solution is added in described inorganic strong alkali-the first polar organic solvent mixed system, form described question response mixture;
Wherein, described the first polar organic solvent and described the second polar organic solvent are identical or different.
3. method according to claim 2, is characterized in that,
In described steps A 1, at the temperature of-20～70 ℃, described active methylene compound is added to described the second polar organic solvent, form the described substrate solution that described active methylene compound concentration is 0.3～0.8g/ml;
In described steps A 2, at the temperature of-20～70 ℃, described substrate solution is added in described inorganic strong alkali-the first polar organic solvent mixed system to the described question response mixture that to form described active methylene compound concentration be 0.1～0.3g/ml.
4. according to the method in any one of claims 1 to 3, it is characterized in that, in described steps A, according to the mol ratio of inorganic strong alkali and active methylene compound, be 2.0～25:1, be preferably 2.5～5:1, described active methylene compound or described substrate solution are added in described inorganic strong alkali-the first polar organic solvent mixed system.
5. method according to claim 1, is characterized in that, in described step B, at the first temperature, the mode adopt dripping adds to described alkylating reagent in described question response mixture, drips after finishing and react 2～15h at the second temperature; The speed of preferred described dropping is 0.2～0.3g/min, and temperature of reaction is 0～70 ℃, and described the first temperature is-20～70 ℃, and described the second temperature is-20～70 ℃, and described the second temperature is higher than equaling described the first temperature.
6. method according to claim 1, is characterized in that, in described step B, according to the mol ratio of described alkylating reagent and described active methylene compound, is 2.0～4.8:1, in described question response mixture, adds alkylating reagent.
7. method according to claim 1, is characterized in that, in described inorganic strong alkali-the first polar organic solvent mixed system, described inorganic strong alkali is KOH, NaOH, LiOH.
8. method according to claim 1, is characterized in that, described the first polar organic solvent and described the second polar organic solvent are respectively one or more in the alcoholic solvent of polar ether kind solvent and C1～C6; Preferred described polar ether kind solvent is ether, propyl ether, isopropyl ether, tetrahydrofuran (THF), propylene oxide or methyl tertiary butyl ether, more preferably tetrahydrofuran (THF); The alcoholic solvent of preferred described C1～C6 is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, Pentyl alcohol, sec.-amyl alcohol, primary isoamyl alcohol, n-hexyl alcohol or hexalin, more preferably methyl alcohol or Virahol, then be preferably methyl alcohol; Preferably described the first polar organic solvent is identical with described the second polar organic solvent.
9. method according to claim 1, is characterized in that, described active methylene compound is the compound with formula I structure, and the structure of its Chinese style I is as follows:
Wherein, R
1and R
2for electron-withdrawing group; Preferred R
1and R
2respectively independently selected from by
and the group that forms of aryl, R ' and R ' ' are respectively independently selected from the group being comprised of alkyl, alkoxyl group and thiazolinyl; More preferably R
1and R
2respectively independently selected from by
and
the group forming, R ' and R ' ' are respectively methyl or ethyl.
10. method according to claim 1, is characterized in that, described alkylating reagent is the alkyl halide class alkylating reagent of ester class alkylating reagent or C1～C2; Preferred described ester class alkylating reagent is ethyl sulfate, trimethyl phosphite 99, methyl tosylate or methyl-sulfate, more preferably methyl-sulfate; The alkyl halide class alkylating reagent of preferred described C1～C2 is monobromethane, methyl chloride, methyl iodide, monochloroethane, monobromethane, iodoethane, Mono Chloro Acetic Acid or chloroethanol, more preferably monobromethane or methyl iodide.
11. methods according to claim 2, it is characterized in that, described the first polar organic solvent and the second polar organic solvent are tetrahydrofuran (THF), and described inorganic strong alkali is KOH, NaOH, LiOH, and the alkylation of described active methylene compound comprises the following steps:
At 0～40 ℃ of temperature, the KOH that is 2.5～5:1 by the mol ratio with described active methylene compound, NaOHLiOH add in tetrahydrofuran (THF), after stirring, form described inorganic strong alkali-the first polar organic solvent mixed system;
At 0～40 ℃ of temperature, described active methylene compound is added in tetrahydrofuran (THF) to the described substrate solution that formation concentration is 0.3～0.8g/mL;
Described substrate solution is dropped to described inorganic strong alkali-the first polar organic solvent mixed system with 0.5～1g/min, the described question response mixture that formation concentration is 0.1～0.3g/ml;
Holding temperature is at 0～40 ℃, according to the mol ratio of described alkylating reagent and described active methylene compound, be 2.0～4.8:1, described alkylating reagent is dropped to described question response mixture with 0.2～0.3g/min, after insulation reaction 2～4h, filtration obtains filtrate, after concentrated described filtrate, distill, obtain alkylating described active methylene compound.
12. methods according to claim 2, is characterized in that, described the first polar organic solvent and the second polar organic solvent are methyl alcohol, and described inorganic strong alkali is KOH, NaOH, LiOH, and the alkylation of described active methylene compound comprises the following steps:
At 0～20 ℃ of temperature, the KOH that is 2.5～5:1 by the mol ratio with described active methylene compound, NaOHLiOH add in methyl alcohol, after stirring, form described inorganic strong alkali-the first polar organic solvent mixed system;
At 0～20 ℃ of temperature, described active methylene compound is added in methyl alcohol to the described substrate solution that formation concentration is 0.2～0.25g/mL;
Described substrate solution is dropped to described inorganic strong alkali-the first polar organic solvent mixed system with 0.5～1g/min, the described question response mixture that formation concentration is 0.05～0.1g/ml;
Holding temperature is at-2～20 ℃, according to the mol ratio of described alkylating reagent and described active methylene compound, be 4～4.5:1, described alkylating reagent is dropped to described question response mixture with 0.2～0.3g/min, after insulation reaction 2～19h, filtration obtains filtrate, after concentrated described filtrate, distill, obtain alkylating described active methylene compound.
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| CN106824285A (en) * | 2017-03-21 | 2017-06-13 | 邯郸学院 | A kind of preparation method and applications of active methylene compound alkylation catalyst |
| CN109593047A (en) * | 2018-11-21 | 2019-04-09 | 沈阳新地药业有限公司 | A kind of alkylated continuous preparation method of active methylene group carbon- |
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| DD237436A3 (en) * | 1984-09-05 | 1986-07-16 | Dresden Arzneimittel | PROCESS FOR THE PREPARATION OF ALPHA, ALPHA DIETHYL ACETIC ACID ESTERS |
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| DD237436A3 (en) * | 1984-09-05 | 1986-07-16 | Dresden Arzneimittel | PROCESS FOR THE PREPARATION OF ALPHA, ALPHA DIETHYL ACETIC ACID ESTERS |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106824285A (en) * | 2017-03-21 | 2017-06-13 | 邯郸学院 | A kind of preparation method and applications of active methylene compound alkylation catalyst |
| CN109593047A (en) * | 2018-11-21 | 2019-04-09 | 沈阳新地药业有限公司 | A kind of alkylated continuous preparation method of active methylene group carbon- |
| CN109593047B (en) * | 2018-11-21 | 2022-12-27 | 沈阳新地药业有限公司 | Continuous process for the preparation of reactive methylene C-alkylation |
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