CN103342652A - Preparation method for N,N-dimethylamino acetate - Google Patents
Preparation method for N,N-dimethylamino acetate Download PDFInfo
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Abstract
The invention belongs to the field of chemical synthesis, and in particular relates to a novel skin penetration enhancer N,N-dimethylamino acetate. The method comprises the following steps of: reacting N,N-dimethylamino acetonitrile with sulphuric acid to obtain N,N-dimethylamino acetamide; and further reacting N,N-dimethylamino acetamide with alcohol to obtain N,N-dimethylamino acetate. Additionally, the invention further provides a method for preparing N,N-dimethylamino acetonitrile via ammoniation by taking hydroxyl acetonitrile as a raw material. By using the method disclosed by the invention for preparing N,N-dimethylamino acetate, the raw materials are simple and easily-available, and the reaction conditions are moderate; and moreover, the prepared N,N-dimethylamino acetate is free from the pollution of chloride ions, the product purity thereof is greater than 99%, and the yield of the esters thereof is greater than 86%.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly a kind of novel skin penetration enhancer N, the synthetic method of N-dimethylamino acetic ester.
Background technology
N, the ester class of N-dimethylamino acetic acid is the novel dermal osmosis accelerator of a class, hereinafter referred to as N, N-dimethylamino acetic ester, its structural formula is suc as formula shown in the III:
Wherein, R
1For having the alkyl of 1-10 carbon atom.
N, N-dimethylamino acetic ester and laurocapram (Azone, chemical name: 1-positive dodecyl aza cyclohepta ketone-2) the promoter action experiment to medicine " INDOMETHACIN " infiltration snakeskin shows as Percutaneous absorption enhancer: N, N-dimethylamino acetic ester promote INDOMETHACIN through skin absorb drug effect be laurocapram as the several times of Percutaneous absorption enhancer, and all can be by the biological degradation metabolism.N, N-dimethylamino acetic acid lauryl absorbs the promoter action result of study through skin and shows alkaline drug " clonidine ", acidic drug " INDOMETHACIN ", medicine " 5-FU ", and it is bigger 24 times than the drug absorption of not infiltrating transdermal agent to infiltrate transdermal agent in the INDOMETHACIN dissociative type; 11 times of all increases of clonidine dissociative type and non-ionic type; Hydrophilic medicament 5-FU increases more than 20 times.This compounds can be applicable to creme, paste and the liniment in medicine, the makeup, strengthens medicine to the osmotic absorption effect of skin, strengthens drug effect; Also can be applied in the plant nutrition liquid, strengthen plant to the absorption of nutritive medium, be with a wide range of applications.
The United States Patent (USP) of US4980378 discloses N, N-dimethylamino acetic ester and N, the synthetic method of compounds such as N-diethyl amino yl acetate.Its method is: Mono Chloro Acetic Acid and high fatty alcohol room temperature reaction 16 hours in the presence of triethylamine and anhydrous chloroform, make chloracetate, make N with excessive decil ethereal solution or diethylamine reaction then, N-disubstituted amido acetic ester, productive rate are 72%～94%.The shortcoming of this synthetic method is that the chloroform give solvent is used in the first step reaction, and triethylamine is as acid binding agent, and the reaction times is longer; The second step reaction is with the diethyl ether solution of the dimethylamine of 1mol/L, operates dangerously, is difficult to industrialization.
Application number is the preparation method that 93101842.0 Chinese patent discloses a kind of decyl dimethylaminoacetate, and it has improved N, the synthetic method of N-dimethylamino acetic acid certain herbaceous plants with big flowers ester.This method is: be under the solvent at solvent-free or benzene, chloroacetyl chloride and 1-certain herbaceous plants with big flowers alcohol adopt 4～10 hours synthesis of chloroacetic acid certain herbaceous plants with big flowers esters of solid-liquid phase transfer catalysis reaction, then with excessive dimethylamine gas reaction 2 hours, obtain N, N-dimethylamino acetic acid certain herbaceous plants with big flowers ester, productive rate 80.8%～86.1%.Its shortcoming is that the building-up reactions cost increases complex operation.Mainly show: the first step reaction as phase-transfer catalyst, earlier stirs into pasty state with certain herbaceous plants with big flowers alcohol, alkali and mixture of catalysts heating with TBAI or PEG-400, is cooled to just to drip chloroacetyl chloride after the room temperature and carry out acylation reaction; Catalyzer TBAI is relatively expensive, and PEG-400 is during as phase-transfer catalyst, and the reaction times is long partially; The second step reaction feeds dimethylamine gas with in the water-cooled reaction system of cryosel, need to increase dimethylamine gas and take place and e Foerderanlage, and with toluene as solvent, poisonous, easily pollute.
The CN02135085.X Chinese patent discloses a kind of N; the synthetic method of N-disubstituted glycine ester; chloroacetyl chloride and alcohol reaction are made chloracetate; then with dimethylamine or the synthetic N of diethylamine reaction; the N-disubstituted glycine ester; but in its patent, point out; the disclosed N of the United States Patent (USP) of US4980378; N-dimethylamino acetic ester and N; the synthetic method of compounds such as N-diethyl amino yl acetate, chloroform is unfavorable for chloroacetyl chloride and high fatty alcohol acylation reaction at room temperature, and toxicity is big; though triethylamine has played the effect of acid binding agent, the time of acidylating on the contrary increases.(N such as Li Weijie, synthetic and the applied research of N-dimethylamino acetic ester, Zhongshan University's journal (natural science edition), in November, 2003, the 42nd the 6th phase of volume, page number 44-46) make chloracetate by alcohol and chloroacetyl chloride room temperature reaction under condition of no solvent, again with the synthetic N of excessive dimethylamine agueous solution room temperature reaction, N-dimethylamino acetic ester, this method is not used the synthesis technique of virulent solvent and catalyzer.
But the N of above-mentioned report, the preparation of N-dimethylamino acetic ester all is to be raw material with the Mono Chloro Acetic Acid, this inevitably causes chlorion to the pollution of product.
Summary of the invention
In order to solve the above-mentioned problems in the prior art, the unforeseeable discovery of contriver when being raw material with hydroxyacetonitrile, makes N through ammonification, N-dimethylamino acetonitrile, identical reaction medium not only can prepare described N by prussiate in sulphuric acid hydrolysis step and esterif iotacation step, N-dimethylamino acetic ester, and improved N, the yield of N-dimethylamino acetic ester, avoid the pollution of chlorion, based on above-mentioned discovery, thereby finished the present invention.
The vitriol oil of the present invention refers to the sulphuric acid soln of concentration (concentration refers to the mass percent of sulfuric acid in the aqueous solution of sulfuric acid) more than or equal to 70%.If no specified otherwise, concentration is all represented weight percent among the present invention.
N among the present invention, N-dimethylamino acetonitrile Chinese alias has 2-(dimethylin) acetonitrile, 2-(dimethylamino) acetonitrile, 2-(dimethylin) acetonitrile, N, N-dimethylamino acetonitrile, N, N dimethylamine base second cyanogen.
Therefore, the object of the present invention is to provide a kind of N, the synthetic method of N-dimethylamino acetic ester has improved N, and the yield of N-dimethylamino acetic ester has been avoided the pollution of chlorion.
For achieving the above object, technical scheme of the present invention is:
A kind of preparation N, the method for N-dimethylamino acetic ester comprises the steps:
1) with weight percent more than or equal to 50% N, N-dimethylamino acetonitrile (molecular formula is shown in the I) aqueous solution and the vitriol oil obtain N through hydration reaction, N-dimethylamino ethanamide (molecular formula is shown in II) sulfate liquor, reaction formula is as follows:
2) above-mentioned N, carry out esterification with excessive alcohol in the N-dimethylamino ethanamide sulfate liquor, react the purified N of obtaining that finishes, N-dimethylamino acetic ester (molecular formula is shown in III), described alcohol are straight chain or the branched fatty alcohols with 1～10 carbon atom.This reactions steps can adopt to N, adds the form of 98% sulfuric acid in the N-dimethylamino acetonitrile aqueous solution, perhaps adopts N, and two the dropping in the reactor of the N-dimethylamino acetonitrile aqueous solution and sulfuric acid reacted, and reaction formula is as follows:
Wherein, R
1And R
2Be the alkyl with 1-10 carbon atom.
Method provided by the invention, N described in the step 1), the concentration of N-dimethylamino acetonitrile aqueous solution weight percent is 50-60%, be weight percentage 98% the vitriol oil of the described vitriol oil, described N, the mol ratio of the N-dimethylamino acetonitrile aqueous solution and the vitriol oil is 1:1-2.5, under 45 ℃～70 ℃ conditions, and hydration reaction 2～6 hours.
Method provided by the invention, N described in the step 1) produces the N of at least 95% weight percent in the N-dimethylamino ethanamide sulfate liquor, carry out described step 2 during N-dimethylamino ethanamide) reaction.
Method provided by the invention, step 2) in, described alcohol and N, the mol ratio of N-dimethylamino ethanamide is 2～6:1, esterification reaction temperature is controlled at 70 ℃～120 ℃, reacts 5～12 hours.
Method provided by the invention, step 2) alcohol described in adds when beginning that can be in the step 1) reaction, also can add when the step 1) reaction finishes.Add when the beginning in the step 1) reaction, than the N that is approximately 60%, N-dimethylamino acetonitrile, the pure and mild vitriol oil begin to carry out this synthetic method by weight percentage.N at first, N-dimethylamino acetonitrile part is by hydration, thereby obtains N, N-dimethylamino ethanamide, pure and mild a certain amount of N, the solution of N-dimethylamino acetic ester.Then with the heating of this solution so that remaining N, the acid amides esterification of N-dimethylaminoethyl and/or hydrolysis.The solution that obtains after the esterification contains N, N-dimethylamino acetic ester.Can reclaim N in this solution, N-dimethylamino acetic ester by any suitable method.
In method provided by the present invention, described N, N-dimethylamino acetonitrile can be to be obtained by commercial sources, perhaps also can be prepared by the method for any prior art record, be " the N of 19-105232 as report number, N-dimethylamino acetonitrile production technology and market conditions research report " method put down in writing in the literary composition, (
Http:// www.glosulting.com/Report-19-105232.html).
In the present invention, described N, N-dimethylamino acetonitrile also can prepare by the following method: with hydroxyacetonitrile and dimethylamine in the aqueous solution is arranged, at 40 ℃～60 ℃, pressure 0.4～1MPa, aminating reaction 0.5～1.0 hour, obtain N, the N-dimethylamino acetonitrile aqueous solution, reaction formula is as follows:
Therefore, the invention provides a kind of is that raw material prepares N by hydroxyacetonitrile, and the method for N-dimethylamino acetic ester may further comprise the steps:
(a) hydroxyacetonitrile and dimethylamine are in having the water reaction solution, 40 ℃～60 ℃ of holding temperatures, pressure 0.4～1MPa, aminating reaction 0.5～1.0 hour, after aminating reaction finishes, remove remaining dimethylamine and part water to N, the weight percent of the N-dimethylamino acetonitrile aqueous solution is more than or equal to 50%;
(b) with the N that obtains in the step (a), the N-dimethylamino acetonitrile aqueous solution and weight percent be 98% sulfuric acid under 45 ℃～70 ℃ conditions, hydration reaction 2～6 hours obtains N, N-dimethylamino ethanamide sulfate liquor;
(c) N that obtains in the step (b), N-dimethylamino ethanamide sulfate liquor and excessive alcohol carry out esterification, temperature of reaction control is at 70 ℃～120 ℃, 5～12 hours reaction times, esterification finishes and obtains N by purifying, N-dimethylamino acetic ester, described alcohol are straight chain or the branched fatty alcohols with 1～10 carbon atom.
In the method for the present invention, described hydroxyacetonitrile is the aqueous solution, and concentration is 40%～60%, preferred 50%～60%; Described dimethylamine is the aqueous solution, and concentration is 29%-33%, preferred 33%.
In the method for the present invention, the mol ratio of described hydroxyacetonitrile and dimethylamine is 1:1～1.5.
In the method for the present invention, adopt the method for underpressure distillation to remove remaining dimethylamine and part water in the step (a).
In the method for the present invention, N described in the step (b), the N of generation at least 95% weight percent carries out the reaction of described step (c) in the N-dimethylamino ethanamide sulfate liquor during N-dimethylamino ethanamide.
In the method for the present invention, described alcohol is straight chain or the branched fatty alcohol with 1～10 carbon atom, preferably has the branched fatty alcohol of 1～10 carbon atom, more preferably Virahol.
It is a kind of at the industrial N of utilization that the present invention also provides, N-dimethylamino acetic ester production equipment is produced N continuously, the method of N-dimethylamino acetic ester, described N, N-dimethylamino acetic ester production equipment comprises that the fresh feed pump 1, tubular reactor 2, vacuum distillation apparatus 3, first stirring or the piston-type reactor 4, second that set gradually stir or piston-type reactor 5; Described second stirring or piston-type reactor 5 are communicated with vacuum distillation apparatus 3 by the pipeline of band valve;
A sends into hydroxyacetonitrile and dimethylamine agueous solution in the tubular reactor 2 by fresh feed pump 1,40 ℃～60 ℃ of holding temperatures, pressure 0.4～1MPa, aminating reaction 0.5～1.0 hour, after aminating reaction finishes, enter and remove remaining dimethylamine and part water in the vacuum distillation apparatus 3, make the N that obtains, N-dimethylamino acetonitrile aqueous solution weight percent is more than or equal to 50%;
B is with the N that obtains in the steps A, the N-dimethylamino acetonitrile aqueous solution and weight percent are that 98% sulfuric acid is sent in first stirring or the piston-type reactor 4, under 45 ℃～70 ℃ conditions of temperature, and hydration reaction 2～6 hours, obtain N, N-dimethylamino ethanamide sulfate liquor;
C is with the N that obtains among the step B, N-dimethylamino ethanamide sulfate liquor is sent into second and is stirred or piston-type reactor 5, and with excessive alcohol send into second stir or piston-type reactor 5 in, carry out esterification, temperature of reaction control is at 70 ℃～120 ℃, 5～12 hours reaction times, after esterification finishes reaction solution is sent in the vacuum distillation apparatus 3, the immiscible organic solvent of adding and water extracts, underpressure distillation organic solvent then, purifying obtains N, N-dimethylamino acetic ester, described alcohol are straight chain or the branched fatty alcohols with 1～10 carbon atom.
The industrial N that utilizes of the present invention, N-dimethylamino acetic ester production equipment is produced N continuously, the method of N-dimethylamino acetic ester, N described in the step B, N-dimethylamino ethanamide sulfate liquor need not separate purification, described N, the N of generation at least 95% weight percent directly carries out the reaction of described step C in the N-dimethylamino ethanamide sulfate liquor during N-dimethylamino ethanamide.
At the industrial N that utilizes, N-dimethylamino acetic ester production equipment is produced N continuously, in the method for N-dimethylamino acetic ester, also can be directly with the N that obtains in the steps A, the N-dimethylamino acetonitrile aqueous solution and weight percent are that 98% sulfuric acid and excessive alcohol are sent in second stirring or the piston-type reactor 5, earlier under 45 ℃～70 ℃ conditions of temperature, hydration reaction 2～6 hours, then temperature of reaction is controlled at 70 ℃～120 ℃, 5～12 hours reaction times, after reaction finishes reaction solution is sent in the vacuum distillation apparatus 3, the immiscible organic solvent of adding and water extracts, underpressure distillation organic solvent then, purifying obtains N, N-dimethylamino acetic ester.In this production method process, N at first, N-dimethylamino acetonitrile be by hydration, thereby obtain N, N-dimethylamino ethanamide, pure and mild a certain amount of N, the solution of N-dimethylamino acetic ester.Then with the heating of this solution so that remaining N, the acid amides esterification of N-dimethylaminoethyl and/or hydrolysis.The solution that obtains after the esterification contains N, N-dimethylamino acetic ester.Can reclaim N in this solution, N-dimethylamino acetic ester by any suitable method.This method can be carried out equally continuously, semi-continuously and in batches.
At the industrial N that utilizes, N-dimethylamino acetic ester production equipment is produced N continuously, in the method for N-dimethylamino acetic ester, also can be directly from N, N-dimethylamino acetonitrile begins, with N, the N-dimethylamino acetonitrile aqueous solution and weight percent are that 98% sulfuric acid is sent in first stirring or the piston-type reactor 4, under 45 ℃～70 ℃ conditions of temperature, and hydration reaction 2～6 hours, obtain N, N-dimethylamino ethanamide sulfate liquor; Then with the N that obtains, N-dimethylamino ethanamide sulfate liquor is sent into second and is stirred or piston-type reactor 5, and with excessive alcohol send into second stir or piston-type reactor 5 in, carry out esterification, temperature of reaction is controlled at 70 ℃～120 ℃, 5～12 hours reaction times, after esterification finishes reaction solution is sent in the vacuum distillation apparatus 3, the immiscible organic solvent of adding and water extracts, and underpressure distillation organic solvent, purifying obtain N then, N-dimethylamino acetic ester.
In synthetic method of the present invention, N, N-dimethylamino ethanamide can suitably carry out under the pressure with the esterification of alcohol.When temperature increases, N, the esterification rate of N-dimethylamino ethanamide is accelerated.For the temperature that makes reaction surpasses the boiling point of medium, this step reaction can be carried out having under the pressure condition, for example from the normal pressure to 1Mpa.
In the method for the invention, N, N-dimethylamino ethanamide can extract purification process with the mixture that obtains after finishing with the esterification of alcohol, can reclaim N in this solution, N-dimethylamino acetic ester by any suitable method.In to reacted mixed solution, add in the ammoniacal liquor and unnecessary sulfuric acid, system PH is controlled 5～6, noted phase separation phenomena appears, immiscible organic solvent such as chloroform, toluene, butanone, mibk, ether compound such as methyl tertiary butyl ether, the Di Iso Propyl Ether etc. of adding and water extract again, the organic phase that extraction obtains is under low pressure distilled the removal light constituent, continues the product that reduction vaporization obtains purifying.Also can be chosen in after the esterif iotacation step, directly add with water-insoluble organic solvent such as chloroform, butanone, mibk, ether compound such as methyl tertiary butyl ether, Di Iso Propyl Ether etc. extract organic phase, in the presence of certain water gaging, described solvent evaporation is got purified product then.Also can select system PH is controlled 5～6, underpressure distillation or column chromatography after phase-splitting obtain highly purified N, N-dimethylamino acetic ester.
After the phase-splitting of ammonia neutralisation of sulphuric acid, the evaporation water is ammonium sulfate with the precipitation inorganic salt basically, and it can sell at this point, but it contains the organic derivative of trace.This water can carry out dilution and handle so that it does not contain N N-dimethylamino acetic ester.The solvent that is slightly soluble in water by adding can be realized this dilution, and the solvent of adding is selected from butanone, mibk, chloroform, ethyl acetate or toluene.In order to reclaim a large amount of esters, from the aqueous phase extracting N of saliferous, N-dimethylamino acetic ester carries out the dilution of organic phase mutually repeatedly.
Beneficial effect of the present invention is: the present invention has following some advantage: 1, the inventive method has realized N, and the new synthesis method of N-dimethylamino acetic ester has not only been avoided the pollution of chlorion, and has improved N, the yield of N-dimethylamino acetic ester; 2, synthetic method desired raw material of the present invention is simple and easy to, the reaction conditions gentleness, and the product purity height, the productive rate height, operation is convenient, more economical practicality.
Description of drawings
Fig. 1 is N, N-dimethylamino acetic ester production equipment structural representation.
Embodiment
Illustrated embodiment is in order better content of the present invention to be described, but is not that content of the present invention only limits to illustrated embodiment.So those of ordinary skill in the art carry out nonessential improvement and adjustment according to the foregoing invention content to embodiment, still belong to protection scope of the present invention.
Embodiment 1:N, N-dimethylamino isopropyl acetate
The N that commercial sources is bought, it is 60% the aqueous solution that N-dimethylamino acetonitrile water dissolving is mixed with weight percent, with the N of 60% concentration, N-dimethylamino acetonitrile aqueous solution 984g and the 2105 gram vitriol oils drop in the reactor simultaneously, and the temperature of control reactant is 50 ℃.After dropwising, continue insulation 3 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
To above-mentioned N, disposable adding 2526 gram Virahols in the N-dimethylamino ethanamide aqueous sulfuric acid, heat to reactor with 5 ℃/minute speed then, make its temperature reach the temperature of boiling, and making the reactor bottom temperature is 116 ℃, and head temperature is 75 ℃, keeps this situation 5 hours, evaporate the exclusive segment distillment then, the fresh Virahol that adds same quantity again replaces.
After reaction finished, with unnecessary sulfuric acid, at this moment the pH of system control noted phase separation phenomena occurred 5～6 in the ammoniacal liquor of adding 25%.Add the toluene solvant of 3000 grams, organic phase is on the upper strata, and lower floor's water is the aqueous solution that contains ammonium sulfate.Light constituent is removed in distillation under low pressure.Reduce to mmHg continuation evaporation by the temperature of increase vaporizer with pressure, obtain 994 gram N, N-dimethylamino isopropyl acetate (colourless liquid), purity is greater than 99%, and yield is 98%.
Embodiment 2:N, N-dimethylamino isopropyl acetate
N, N-dimethylamino acetic ester production equipment structural representation as shown in Figure 1, at room temperature, in tubular reactor 2, add 1000 grams, 60% hydroxyl acetonitrile aqueous solution by fresh feed pump 1, feed 1722 grams, 33% dimethylamine agueous solution then, be warming up to 60 ℃ then, pressure reaches 0.7Mpa, react after 30 minutes, stopped reaction, entering reduces pressure in the vacuum distillation apparatus 3 removes unnecessary dimethylamine and part water, obtains N, the N-dimethylamino acetonitrile aqueous solution, concentration is 60%.
With the N that obtains, the N-dimethylamino acetonitrile aqueous solution and the 2105 gram vitriol oils drop in first stirred reactor 4 simultaneously, and the temperature of control reactant is 50 ℃.After dropwising, continue insulation 3 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
With above-mentioned N, N-dimethylamino ethanamide aqueous sulfuric acid feeds in second stirred reactor 5, the disposable 2526 gram Virahols that add, 5 ℃/minute speed heats to reactor then, make its temperature reach the temperature of boiling, and to make the reactor bottom temperature be 116 ℃, head temperature is 75 ℃.Kept this situation 5 hours.The exclusive segment distillment, and replace with the fresh Virahol of same quantity.
After reaction finished, with unnecessary sulfuric acid, at this moment the pH of system control noted phase separation phenomena occurred 5～6 in the ammoniacal liquor of adding 25%.Add the toluene solvant of 3000 grams, organic phase is on the upper strata, and lower floor's water is the aqueous solution that contains ammonium sulfate.Phase-splitting solution after the extraction is entered vacuum distillation apparatus 3, and light constituent is removed in distillation under low pressure, reduces to mmHg continuation evaporation by the temperature of increase vaporizer with pressure, obtain 1406 gram N, N-dimethylamino isopropyl acetate (colourless liquid), purity are greater than 99%, and yield is 92%.
Embodiment 3:N, N-dimethylamino butylacetate
The N that commercial sources is bought, it is 50% the aqueous solution that N-dimethylamino acetonitrile water dissolving is mixed with weight percent, with the N of 50% concentration, N-dimethylamino acetonitrile aqueous solution 1179g, the 2105 gram vitriol oils and 3116g propyl carbinol join in the reactor simultaneously, and the temperature of control reactant is 50 ℃, continue insulation 3 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, the amount of N-dimethylamino acetonitrile is lower than 5%, is considered as hydration reaction and finishes substantially.5 ℃/minute speed heats to reactor then, makes its temperature reach the temperature of boiling, and to make the reactor bottom temperature be 120 ℃, and head temperature is 95 ℃.Kept this situation 5 hours.The exclusive segment distillment, and replace with the fresh butanols of same quantity.After reaction finished, with unnecessary sulfuric acid, at this moment the pH of system control noted phase separation phenomena occurred 5～6, adds the toluene solvant of 3000 grams in the ammoniacal liquor of adding 25%, and organic phase is on the upper strata, and lower floor's water is the aqueous solution that contains ammonium sulfate.Light constituent is removed in distillation under low pressure.Reduce to mmHg continuation evaporation by the temperature of increase vaporizer with pressure, obtain 1070 gram N, N-dimethylamino butylacetate (colourless liquid), purity is greater than 99%, and yield is 95%.
Embodiment 4:N, N-dimethylamino butylacetate
N, N-dimethylamino acetic ester production equipment structural representation as shown in Figure 1, at room temperature, in tubular reactor 2, add 1000 grams, 60% hydroxyl acetonitrile aqueous solution by fresh feed pump 1, feed 1722 grams, 33% dimethylamine agueous solution then, be warming up to 60 ℃ then, pressure reaches 0.7Mpa, react after 30 minutes, stopped reaction, entering reduces pressure in the vacuum distillation apparatus 3 removes unnecessary dimethylamine and part water, obtains N, the N-dimethylamino acetonitrile aqueous solution, concentration is 60%.
With the N that obtains, the N-dimethylamino acetonitrile aqueous solution and the 2105 gram vitriol oils drop in first stirred reactor 4 simultaneously, and the temperature of control reactant is 50 ℃.After dropwising, continue insulation 3 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
With above-mentioned N, N-dimethylamino ethanamide aqueous sulfuric acid feeds in second stirred reactor 5, the disposable 3115 gram propyl carbinols that add, 5 ℃/minute speed heats to reactor then, make its temperature reach the temperature of boiling, and to make the reactor bottom temperature be 120 ℃, head temperature is 95 ℃.Kept this situation 5 hours.The exclusive segment distillment, and replace with the fresh propyl carbinol of same quantity.
After reaction finished, with unnecessary sulfuric acid, the pH of system control was 5～6 in the ammoniacal liquor of adding 25%.At this moment noted phase separation phenomena appears.Add the toluene solvant of 3000 grams, organic phase is on the upper strata, and lower floor's water is the aqueous solution that contains ammonium sulfate.Phase-splitting solution after the extraction is entered vacuum distillation apparatus 3, and light constituent is removed in distillation under low pressure, reduces to mmHg continuation evaporation by the temperature of increase vaporizer with pressure, obtain 1510 gram N, N-dimethylamino butylacetate (colourless liquid), purity are greater than 99%, and yield is 90%.
Embodiment 5:N, the own ester of N-dimethylamino acetic acid
The N that commercial sources is bought, it is 60% the aqueous solution that N-dimethylamino acetonitrile water dissolving is mixed with weight percent, with the N of 60% concentration, N-dimethylamino acetonitrile aqueous solution 984g and the 2105 gram vitriol oils drop in the reactor simultaneously, and the temperature of control reactant is 60 ℃.After dropwising, continue insulation 4 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
To above-mentioned N, disposable 4284 alcohol of restraining oneself that add in the N-dimethylamino ethanamide aqueous sulfuric acid, 5 ℃/minute speed heats to reactor then, and make the pressure of reaction system reach 1Mpa, make its temperature reach the temperature of boiling, and making the reactor bottom temperature is 120 ℃, keeps this situation 10 hours.
After reaction finished, with unnecessary sulfuric acid, at this moment the pH of system control noted phase separation phenomena occurred 5～6 in the ammoniacal liquor of adding 25%.Add the toluene solvant of 2000 grams, organic phase is on the upper strata, and lower floor's water is the aqueous solution that contains ammonium sulfate.Light constituent is removed in distillation under low pressure, and it mainly is toluene, hexanol and a spot of water.Reduce to mmHg continuation evaporation by the temperature of increase vaporizer with pressure, obtain 1230 gram N, the own ester of N-dimethylamino acetic acid (colourless liquid), purity is greater than 99%, and yield is 93%.
Embodiment 6:N, the own ester of N-dimethylamino acetic acid
At room temperature, in reactor, add 1000 grams, 60% hydroxyl acetonitrile aqueous solution, feed 1722 grams, 33% dimethylamine agueous solution then, be warming up to 60 ℃ then, pressure reaches 0.7Mpa, react after 30 minutes, stopped reaction, unnecessary dimethylamine is removed in decompression then, obtains N, the N-dimethylamino acetonitrile aqueous solution, concentration is 60%.
With the N that obtains, the N-dimethylamino acetonitrile aqueous solution and the 2631 gram vitriol oils drop in the reactor simultaneously, and the temperature of control reactant is 60 ℃.After dropwising, continue insulation 4 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
To above-mentioned N, disposable 6506 alcohol of restraining oneself that add in the N-dimethylamino ethanamide aqueous sulfuric acid, 5 ℃/minute speed heats to reactor then, and make the pressure of reaction system reach 1Mpa, make its temperature reach the temperature of boiling, and making the reactor bottom temperature is 120 ℃, keeps this situation 10 hours.
After reaction finished, with unnecessary sulfuric acid, the pH of system control was 5～6 in the ammoniacal liquor of adding 25%.At this moment noted phase separation phenomena appears.Add the toluene solvant of 2000 grams, organic phase is on the upper strata, and lower floor's water is the aqueous solution that contains ammonium sulfate.Light constituent is removed in distillation under low pressure, and it mainly is toluene and hexanol, a spot of water.Reduce to mmHg continuation evaporation by the temperature of increase vaporizer with pressure, obtain 1732 gram N, the own ester of N-dimethylamino acetic acid (colourless liquid), purity is greater than 99%, and yield is 88%.
Embodiment 7:N, the misery ester of N-dimethylaminoethyl
The N that commercial sources is bought, it is 60% the aqueous solution that N-dimethylamino acetonitrile water dissolving is mixed with weight percent, with the N of 60% concentration, N-dimethylamino acetonitrile aqueous solution 984g and the 2105 gram vitriol oils drop in the reactor simultaneously, and the temperature of control reactant is 60 ℃.After dropwising, continue insulation 4 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
To above-mentioned N, the disposable 5460 gram octanols that add in the N-dimethylamino ethanamide aqueous sulfuric acid, 5 ℃/minute speed heats to reactor then, and make the pressure of reaction system reach 1Mpa, make its temperature reach the temperature of boiling, and making the reactor bottom temperature is 120 ℃, keeps this situation 10 hours.
After reaction finished, with unnecessary sulfuric acid, the pH of system control was 5～6 in the ammoniacal liquor of adding 25%.At this moment noted phase separation phenomena appears.Add the toluene solvant of 2000 grams, organic phase is on the upper strata, and lower floor's water is the aqueous solution that contains ammonium sulfate.Light constituent is removed in distillation under low pressure, and it mainly is toluene and octanol, a spot of water.Reduce to mmHg continuation evaporation by the temperature of increase vaporizer with pressure, obtain 1431 gram N, the misery ester of N-dimethylaminoethyl (colourless liquid), purity is greater than 99%, and yield is 94%.
Embodiment 8:N, the misery ester of N-dimethylaminoethyl
At room temperature, in reactor, add 1000 grams, 60% hydroxyl acetonitrile aqueous solution, feed 1722 grams, 33% dimethylamine agueous solution then, be warming up to 55 ℃ then, pressure reaches 0.4Mpa, react after 45 minutes, stopped reaction, unnecessary dimethylamine is removed in decompression then, obtains N, the N-dimethylamino acetonitrile aqueous solution, concentration is 57%.
With the N that obtains, the N-dimethylamino acetonitrile aqueous solution and the 2631 gram vitriol oils drop in the reactor simultaneously, and the temperature of control reactant is 55 ℃.After dropwising, continue insulation 3 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
To above-mentioned N, the disposable 5473 gram octanols that add in the N-dimethylamino ethanamide aqueous sulfuric acid, 5 ℃/minute speed heats to reactor then, and make the pressure of reaction system reach 1Mpa, make its temperature reach the temperature of boiling, and making the reactor bottom temperature is 130 ℃, keeps this situation 12 hours.
After reaction finished, with unnecessary sulfuric acid, the pH of system control was 5～6 in the ammoniacal liquor of adding 25%.At this moment noted phase separation phenomena appears.Add the toluene solvant of 2500 grams, organic phase is on the upper strata, and lower floor's water is the aqueous solution that contains ammonium sulfate.Light constituent is removed in distillation under low pressure, and it mainly is toluene and octanol, a spot of water.Reduce to mmHg continuation evaporation by the temperature of increase vaporizer with pressure, obtain 2062 gram N, the misery ester of N-dimethylaminoethyl (colourless liquid), purity is greater than 99%, and yield is 91%.
Embodiment 9:N, N-dimethylamino acetic acid certain herbaceous plants with big flowers ester
At room temperature, in reactor, add 1000 grams, 60% hydroxyl acetonitrile aqueous solution, feed 1700 grams, 33% dimethylamine agueous solution then, be warming up to 60 ℃ then, pressure reaches 0.7Mpa, react after 30 minutes, stopped reaction, unnecessary dimethylamine is removed in decompression then, obtains N, the N-dimethylamino acetonitrile aqueous solution, concentration is 60%.
With the N that obtains, the N-dimethylamino acetonitrile aqueous solution and the 1579 gram vitriol oils drop in the reactor simultaneously, and the temperature of control reactant is 65 ℃.After dropwising, continue insulation 4 hours, with high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
To above-mentioned N, the disposable positive certain herbaceous plants with big flowers alcohol of 3332 grams that adds in the N-dimethylamino ethanamide aqueous sulfuric acid, 5 ℃/minute speed heats to reactor then, and make the pressure of reaction system reach 1Mpa, make its temperature reach the temperature of boiling, and making the reactor bottom temperature is 130 ℃, keeps this situation 12 hours.
After reaction finished, with unnecessary sulfuric acid, the pH of system control was 5～6 in the ammoniacal liquor of adding 25%.At this moment noted phase separation phenomena appears.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, with saturated salt solution washing, anhydrous adding 30 dried over sodium sulfate remove solvent under reduced pressure, and residue is through rapid column chromatography (silica gel is the 100-300 order), ethyl acetate is as eluent, steam except eluent, obtain 2200 gram N, N-dimethylamino acetic acid certain herbaceous plants with big flowers ester (colourless liquid), purity is greater than 99%, and yield is 86%.
Embodiment 10:N, N-dimethylamino acetic acid certain herbaceous plants with big flowers ester
The N that commercial sources is bought, it is 60% the aqueous solution that N-dimethylamino acetonitrile water dissolving is mixed with weight percent, with the N of 60% concentration, N-dimethylamino acetonitrile aqueous solution 981g and the 2105 gram vitriol oils drop in the reactor simultaneously, and the temperature of control reactant is 65 ℃.After dropwising, continue insulation 4 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
To above-mentioned N, the disposable positive certain herbaceous plants with big flowers alcohol of 6645 grams that adds in the N-dimethylamino ethanamide aqueous sulfuric acid, 5 ℃/minute speed heats to reactor then, and make the pressure of reaction system reach 1Mpa, make its temperature reach the temperature of boiling, and making the reactor bottom temperature is 130 ℃, keeps this situation 12 hours.
After reaction finished, with unnecessary sulfuric acid, the pH of system control was 5～6 in the ammoniacal liquor of adding 25%.At this moment noted phase separation phenomena appears.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, with saturated salt solution washing, anhydrous adding 30 dried over sodium sulfate, the underpressure distillation desolventizing, residue is through rapid column chromatography (silica gel is the 100-300 order), ethyl acetate is as eluent, steam except eluent, obtain 1618 gram N, N-dimethylamino acetic acid certain herbaceous plants with big flowers ester (colourless liquid), purity is greater than 99%, and yield is 94%.
Embodiment 11:N, N-dimethylamino acetic acid lauryl
N, N-dimethylamino acetic ester production equipment structural representation as shown in Figure 1, at room temperature, in tubular reactor 2, add 1000 grams, 60% hydroxyl acetonitrile aqueous solution by fresh feed pump 1, feed 1722 grams, 33% dimethylamine agueous solution then, be warming up to 60 ℃ then, pressure reaches 0.7Mpa, react after 30 minutes, stopped reaction, entering reduces pressure in the vacuum distillation apparatus 3 removes unnecessary dimethylamine and water, obtains N, the N-dimethylamino acetonitrile aqueous solution, concentration is 60%.
With the N that obtains, the N-dimethylamino acetonitrile aqueous solution and the 2631 gram vitriol oils drop in first stirred reactor 4 simultaneously, and the temperature of control reactant is 60 ℃.After dropwising, continue insulation 4 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
With above-mentioned N, N-dimethylamino ethanamide aqueous sulfuric acid feeds in second stirred reactor 5, the disposable 6441 gram lauryl alcohols that add, 5 ℃/minute speed heats to reactor then, and make the pressure of reaction system reach 1Mpa, make its temperature reach the temperature of boiling, and to make the reactor bottom temperature be 130 ℃, kept this situation 10 hours.
After reaction finished, with unnecessary sulfuric acid, the pH of system control was 5～6 in the ammoniacal liquor of adding 25%.At this moment noted phase separation phenomena appears.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, with saturated salt solution washing, anhydrous adding 30 dried over sodium sulfate remove solvent under reduced pressure, and residue is through rapid column chromatography (silica gel is the 100-300 order), ethyl acetate is as eluent, steam except eluent, obtain 2426 gram N, N-dimethylamino acetic acid lauryl (colourless liquid), purity is greater than 99%, and yield is 86%.
Embodiment 12:N, N-dimethylamino acetic acid lauryl
The N that commercial sources is bought, it is 60% the aqueous solution that N-dimethylamino acetonitrile water dissolving is mixed with weight percent, with the N of 60% concentration, N-dimethylamino acetonitrile aqueous solution 981g and the 2105 gram vitriol oils drop in the reactor simultaneously, and the temperature of control reactant is 60 ℃.After dropwising, continue insulation 4 hours, high performance liquid chromatography middle control analysis N, the residual volume of N-dimethylamino acetonitrile is worked as N, and the amount of N-dimethylamino acetonitrile is lower than 5%, can be considered as hydration reaction and finish substantially, obtain N, N-dimethylamino ethanamide aqueous sulfuric acid.
To above-mentioned N, the disposable 5217 gram lauryl alcohols that add in the N-dimethylamino ethanamide aqueous sulfuric acid, 5 ℃/minute speed heats to reactor then, and make the pressure of reaction system reach 1Mpa, make its temperature reach the temperature of boiling, and making the reactor bottom temperature is 130 ℃, keeps this situation 10 hours.
After reaction finished, with unnecessary sulfuric acid, the pH of system control was 5～6 in the ammoniacal liquor of adding 25%.At this moment noted phase separation phenomena appears.Tell organic layer, water layer is used ethyl acetate extraction again, merges organic layer, with saturated salt solution washing, anhydrous adding 30 dried over sodium sulfate remove solvent under reduced pressure, and residue is through rapid column chromatography (silica gel is the 100-300 order), ethyl acetate is as eluent, steam except eluent, obtain 1689 gram N, N-dimethylamino acetic acid lauryl (colourless liquid), purity is greater than 99%, and yield is 88%.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although with reference to preferred embodiment the present invention is had been described in detail, those of ordinary skill in the art is to be understood that, can make amendment or be equal to replacement technical scheme of the present invention, and not breaking away from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of the claim scope of the present invention.
Claims (11)
1. one kind prepares N, and the method for N-dimethylamino acetic ester is characterized in that, may further comprise the steps:
1) with weight percent more than or equal to 50% N, the N-dimethylamino acetonitrile aqueous solution and the vitriol oil obtain N through hydration reaction, N-dimethylamino ethanamide sulfate liquor;
2) alcohol is joined above-mentioned N, in the N-dimethylamino ethanamide sulfate liquor, carry out esterification, reaction finishes and obtains N, and N-dimethylamino acetic ester, described alcohol are straight chain or the branched fatty alcohols with 1～10 carbon atom; Described N, the molecular formula of N-dimethylamino acetic ester is shown in III:
2. method according to claim 1, it is characterized in that, N described in the step 1), the concentration of N-dimethylamino acetonitrile aqueous solution weight percent is 50-60%, be weight percentage 98% the vitriol oil of the described vitriol oil, described N, the mol ratio of the N-dimethylamino acetonitrile aqueous solution and the described vitriol oil is 1:1-2.5, under 45 ℃～70 ℃ conditions, hydration reaction 2～6 hours.
3. method according to claim 1 is characterized in that, N described in the step 1) produces the N of at least 95% weight percent in the N-dimethylamino ethanamide sulfate liquor, carry out described step 2 during N-dimethylamino ethanamide) reaction.
4. method according to claim 1 is characterized in that step 2) in, described alcohol and N, the mol ratio of N-dimethylamino ethanamide is 2～6:1, esterification reaction temperature is controlled at 70 ℃～120 ℃, reacts 5～12 hours.
5. method according to claim 1 is characterized in that step 2) described in alcohol add in the beginning of step 1) reaction or when finishing.
6. method according to claim 1, it is characterized in that, described N, N-dimethylamino acetonitrile is obtained by following prepared in reaction by hydroxyacetonitrile and dimethylamine: hydroxyacetonitrile and dimethylamine are in having the water reaction solution, 40 ℃～60 ℃ of holding temperatures, pressure 0.4～1MPa, aminating reaction 0.5～1.0 hour.
7. method according to claim 6 is characterized in that, comprises following step of carrying out:
(a) hydroxyacetonitrile and dimethylamine are in having the water reaction solution, 40 ℃～60 ℃ of holding temperatures, pressure 0.4～1MPa, aminating reaction 0.5～1.0 hour, after aminating reaction finishes, remove remaining dimethylamine and part water to N, the weight percent of the N-dimethylamino acetonitrile aqueous solution is more than or equal to 50%;
(b) with the N that obtains in the step (a), the N-dimethylamino acetonitrile aqueous solution and weight percent be 98% sulfuric acid under 45 ℃～70 ℃ conditions, hydration reaction 2～6 hours obtains N, N-dimethylamino ethanamide sulfate liquor;
(c) N that obtains in the step (b), N-dimethylamino ethanamide sulfate liquor and excessive alcohol carry out esterification, temperature of reaction control is at 70 ℃～120 ℃, 5～12 hours reaction times, esterification finishes and obtains N by purifying, N-dimethylamino acetic ester, described alcohol are straight chain or the branched fatty alcohols with 1～10 carbon atom.
8. method according to claim 7 is characterized in that, hydroxyacetonitrile described in the step a) is the aqueous solution, and concentration is 40%～60%; Described dimethylamine is the aqueous solution, and concentration is 29%-33%; The mol ratio of described hydroxyacetonitrile and described dimethylamine is 1:1-1.5.
9. method according to claim 7 is characterized in that, adopts the method for underpressure distillation to remove remaining dimethylamine and part water in the step a).
10. utilize N, N-dimethylamino acetic ester production equipment is produced N continuously, the method of N-dimethylamino acetic ester, it is characterized in that: described N, N-dimethylamino acetic ester production equipment comprises that the fresh feed pump (1), tubular reactor (2), vacuum distillation apparatus (3), first stirring or the piston-type reactor (4), second that set gradually stir or piston-type reactor (5); Described second stirring or piston-type reactor (5) are communicated with vacuum distillation apparatus (3) by the pipeline of band valve;
A sends into hydroxyacetonitrile and dimethylamine agueous solution in the tubular reactor (2) by fresh feed pump (1), 40 ℃～60 ℃ of holding temperatures, pressure 0.4～1MPa, aminating reaction 0.5～1.0 hour, after aminating reaction finishes, enter and remove remaining dimethylamine and part water in the vacuum distillation apparatus (3), make the N that obtains, N-dimethylamino acetonitrile aqueous solution weight percent is more than or equal to 50%;
B is with the N that obtains in the steps A, the N-dimethylamino acetonitrile aqueous solution and weight percent are that 98% sulfuric acid is sent in first stirring or the piston-type reactor (4), under 45 ℃～70 ℃ conditions of temperature, and hydration reaction 2～6 hours, obtain N, N-dimethylamino ethanamide sulfate liquor;
C is with the N that obtains among the step B, N-dimethylamino ethanamide sulfate liquor is sent into second and is stirred or piston-type reactor (5), and with excessive alcohol send into second stir or piston-type reactor (5) in, carry out esterification, temperature of reaction control is at 70 ℃～120 ℃, 5～12 hours reaction times, after esterification finishes reaction solution is sent in the vacuum distillation apparatus (3), the immiscible organic solvent of adding and water extracts, underpressure distillation organic solvent then, purifying obtains N, N-dimethylamino acetic ester, described alcohol are straight chain or the branched fatty alcohols with 1～10 carbon atom.
11. method according to claim 10, it is characterized in that, N described in the step B, N-dimethylamino ethanamide sulfate liquor need not separate purification, described N, produce the N of at least 95% weight percent in the N-dimethylamino ethanamide sulfate liquor, carry out the reaction of described step C during N-dimethylamino ethanamide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1314880A (en) * | 1999-06-09 | 2001-09-26 | 安万特作物科学公司 | Novel method for preparing optically active alpha-aminonitriles |
| JP2003176261A (en) * | 2001-10-05 | 2003-06-24 | Showa Denko Kk | Method for producing aminoacetonitrile and glycine derivative |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1314880A (en) * | 1999-06-09 | 2001-09-26 | 安万特作物科学公司 | Novel method for preparing optically active alpha-aminonitriles |
| JP2003176261A (en) * | 2001-10-05 | 2003-06-24 | Showa Denko Kk | Method for producing aminoacetonitrile and glycine derivative |
Non-Patent Citations (1)
| Title |
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| 李伟杰等: "N,N-二甲基甘氨酸酯的催化合成", 《化学试剂》 * |
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