Synthesis method of 3-methoxy-N, N-dimethyl propionamide

Abstract

The invention relates to a synthesis method of 3-methoxy-N, N-dimethyl propionamide, and belongs to the technical field of organic synthesis. Methyl 3-methoxy propionate, N, N-dimethyl formamide and water are used as raw materials, Lewis acid is used as a catalyst, mixing heating, heat preservation stirring reaction and rectification are performed, and the 3-methoxy-N, N-dimethyl propionamide is obtained. According to the method, the methyl 3-methoxypropionate is used as a raw material, the N, N-dimethylformamide is used as a function substitute reagent of dimethylamine gas, the lewis acid is used as a catalyst, the raw material is wide in source and easy to transport and store, and high yield can be obtained through simple combination of several types of lewis acid catalysts. The method is simple and efficient in technological process, low in cost, high in reaction yield and few in by-product, and has a high industrial application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 3-methoxy-N,N-dimethylpropionamide. Background Art

[0002] 3-Methoxy-N,N-dimethylpropionamide (MMPA) is a polar aprotic solvent with an amide functional group. It has the advantages of high boiling point, strong polarity, low viscosity, strong dissolving power, high permeability, low toxicity, and good stability. As an amide solvent, it has extremely strong solubility, can be mixed with a variety of solvents, and can dissolve polymers such as polyimide and polyvinylidene fluoride to a high degree. MMPA has similar boiling point and dissolving power to the traditional solvent N-methylpyrrolidone (NMP), so it can well replace NMP with similar performance and potential genotoxicity. It can be widely used in chemical, plastic, coating, pesticide, medicine, pigment, electronics and other industries, and has broad application prospects. The current methods for preparing MMPA mainly include the following.

[0003] Patents WO2008 / 102615 and WO2013 / 153754 use methyl 3-methoxypropionate (MMP) as a raw material, and react with dimethylamine (DMA) under the action of a catalyst to generate MMPA (Formula I). ​​The reaction uses a strong base (such as sodium methoxide, potassium tert-butoxide, etc.) as a catalyst. After the reaction, it needs to be neutralized with an acid and then filtered. The process operation is complicated and produces a large amount of solid waste. In addition, in order to improve the selectivity of the reaction, polyols (such as glycerol and ethylene glycol, etc.) are used as solvents. However, such solvents have a high boiling point and a high recycling cost. Even if they are reused as residues after product distillation, the operation is complicated due to the high viscosity. Patent CN106966923A uses 3-methoxypropionic acid as a raw material, and reacts with dimethylamine in a closed container at high temperature for condensation and dehydration to generate MMPA (Formula II). This reaction is an equilibrium reaction with a low equilibrium constant. The by-product water must be removed from the reaction system to change the equilibrium, thereby achieving a higher conversion rate. However, in a closed system, it is difficult to remove water by distillation alone, and the dimethylamine raw material will be removed at the same time as the water; removing water by adsorbent is only suitable for small-scale reactions and is not suitable for industrial-scale production. In addition, both of the above-mentioned condensation reactions use dimethylamine gas as raw material, which has high transportation and storage costs; at the same time, the reaction needs to be carried out in a pressure vessel, which has high equipment investment costs.

[0004] Formula I: ; Formula II: ; Patent WO2010 / 126086 uses N,N-dimethylacrylamide (DMAA) as a raw material, and reacts with methanol in an oxo-Michael addition reaction under a catalyst to generate MMPA (Formula III). Although the reaction conditions are relatively mild, the preparation steps of the raw material DMAA are many and the cost is high, which leads to high cost of MMPA, which is not conducive to its industrial application. Patent CN115894275A uses 3-methoxypropionamide as a raw material, and reacts with dimethyl carbonate in an N-alkylation reaction under an alkaline catalyst to generate MMPA (Formula IV). However, in this method, the molar feed ratio of primary amide to dimethyl carbonate is 1:50, dimethyl carbonate is greatly excessive, and the utilization efficiency of the reaction device is extremely low, which is not suitable for industrial-scale production.

[0005] Equation III: ; Formula IV: ; In summary, the current synthesis technology of 3-methoxy-N,N-dimethylpropionamide has great limitations and lacks a route suitable for industrial production, so the existing technology needs to be further developed. Summary of the invention

[0006] In view of the deficiencies in the above-mentioned prior art, the purpose of the present invention is to provide a method for synthesizing 3-methoxy-N,N-dimethylpropionamide, which has the advantages of simple and efficient preparation method, low cost, high reaction yield, high product purity and broad application prospects.

[0007] The technical solution of the present invention is achieved in this way: The invention provides a method for synthesizing 3-methoxy-N,N-dimethylpropionamide. The method comprises taking methyl 3-methoxypropionate (MMP), N,N-dimethylformamide (DMF) and water as raw materials, taking Lewis acid as a catalyst, mixing and heating, and performing heat preservation and stirring reaction to obtain a reaction liquid containing 3-methoxy-N,N-dimethylpropionamide.

[0008] Preferably, the method further comprises: distilling the reaction liquid to obtain 3-methoxy-N,N-dimethylpropionamide (MMPA).

[0009] Preferably, the distillation is vacuum distillation.

[0010] The specific reaction equation is as follows: ; Preferably, the molar ratio of methyl 3-methoxypropionate, N,N-dimethylformamide and water is 1:(1.5-3):(0.1-1).

[0011] Preferably, the heating is to a temperature greater than the boiling point of the by-product methyl formate.

[0012] Preferably, the heating temperature is 50-100°C.

[0013] Preferably, the reaction time is 2-24 hours.

[0014] Preferably, the Lewis acid is any one or more of a halide, acetate, sulfate, trifluoroacetate or trifluoromethanesulfonate of Al, Fe, Zn, Ca, Mg, Ni, Cu, Sc or La.

[0015] In the present invention, the reaction process can actually be divided into three processes: DMF hydrolysis to generate dimethylamine and formic acid, MMP and dimethylamine undergo amine ester exchange reaction, and formic acid and methanol generate methyl formate. On this basis, a suitable catalyst combination can be selected according to the different reaction processes. For example, the catalyst for DMF hydrolysis to generate dimethylamine and formic acid is preferably Ni, Cu and Zn salts; the catalyst for MMP and dimethylamine to undergo amine ester exchange reaction is preferably Mg, Ca, Ni, Sc, La salts; the catalyst for formic acid and methanol to generate methyl formate is preferably Al, Fe, Zn salts; the total amount of the catalyst added is 1%-10% of the molar mass of the raw material MMP.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The synthesis method of 3-methoxy-N, N-dimethylpropionamide provided by the present invention is compared with the synthesis method using dimethylamine gas as an aminolysis reagent. DMF is used as a substitute reagent for dimethylamine gas, and the raw material source is wide and easy to transport and store; the reaction device can select a normal pressure reactor, and the equipment investment cost is low and the operation safety is high; 3-methoxypropionic acid methyl ester, as a commercialized product, has a shorter synthesis step and lower cost than N, N-dimethylacrylamide and 3-methoxypropionamide; the invention uses Lewis acid and cheaper hydrated Lewis acid salt, which can effectively reduce the cost of the catalyst, and as a residue of distillation purification, the catalyst can be recycled; in the whole reaction process, the by-product is mainly methyl formate, which can be volatilized and removed at the reaction temperature. The process of the present invention is simple and efficient, low in cost, high in reaction yield, few by-products, and has a high industrial application prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The following is the reaction mechanism of the synthesis method of the present invention. DETAILED DESCRIPTION

[0018] The present invention will be described in detail below in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0019] Example 1 Methyl 3-methoxypropionate (590.7 g, 5.0 mol), N,N-dimethylformamide (731.0 g, 10.0 mol), water (18.0 g, 1.0 mol) and Zn(OAc)2 (45.9 g, 0.25 mol) were added to a normal pressure reactor equipped with a heater and a stirring device, stirred and heated to 70 ° C, and kept warm for 12 hours. During the reaction, the by-product methyl formate evaporated and discharged from the reaction system. Sampling and detection of methyl 3-methoxypropionate content no longer changed, and the insulation was stopped and cooled to room temperature. The reaction liquid was heated in a distillation kettle and vacuum distilled to obtain 480.8 g of the product 3-methoxy-N,N-dimethylpropionamide, with a gas chromatographic purity of 99.2% and a molar yield of 73.3%.

[0020] Example 2 3-methoxypropionic acid methyl ester (590.7g, 5.0mol), N,N-dimethylformamide (731.0g, 10.0mol), water (36.0g, 2.0mol) and Cu(OAc)2 (45.4g, 0.25mol) were added to a normal pressure reactor equipped with a heater and a stirring device, stirred and heated to 70°C, and kept warm for 12 hours. During the reaction, the by-product methyl formate evaporated and discharged from the reaction system. Sampling and detection of 3-methoxypropionic acid methyl ester content no longer changed, and the insulation was stopped and cooled to room temperature. The reaction liquid was heated in a distillation kettle and vacuum distilled to obtain 497.2g of the product 3-methoxy-N,N-dimethylpropionamide, with a gas chromatographic purity of 99.6% and a molar yield of 75.8%.

[0021] Example 3 3-methoxypropionic acid methyl ester (590.7g, 5.0mol), N,N-dimethylformamide (731.0g, 10.0mol), water (36.0g, 2.0mol), Cu(OAc)2 (18.2g, 0.1mol) and FeCl3 (24.3g, 0.15mol) were added to a normal pressure reactor equipped with a heater and a stirring device, stirred and heated to 70°C, and kept warm for 13h. During the reaction, the by-product methyl formate evaporated and discharged from the reaction system. Sampling and detection of 3-methoxypropionic acid methyl ester content no longer changed, and the insulation was stopped and cooled to room temperature. The reaction liquid was heated in a distillation kettle and vacuum distilled to obtain 506.3g of the product 3-methoxy-N,N-dimethylpropionamide, with a gas chromatographic purity of 99.2% and a molar yield of 77.2%.

[0022] Example 4 3-methoxypropionic acid methyl ester (590.7g, 5.0mol), N,N-dimethylformamide (731.0g, 10.0mol), water (36.0g, 2.0mol), Cu(OAc)2 (18.2g, 0.1mol), FeCl3 (16.2g, 0.1mol) and Sc(OTf)3 (9.8g, 0.02mol) were added to a normal pressure reactor equipped with a heater and a stirring device, stirred and heated to 70°C, and kept warm for 8h. During the reaction, the by-product methyl formate evaporated and discharged from the reaction system. Sampling and detection of 3-methoxypropionic acid methyl ester content no longer changed, stop keeping warm, and cool to room temperature. The reaction liquid was heated in a distillation kettle and vacuum distilled to obtain 559.5g of the product 3-methoxy-N,N-dimethylpropionamide, with a gas chromatographic purity of 99.4% and a molar yield of 85.3%.

[0023] Example 5 Methyl 3-methoxypropionate (590.7 g, 5.0 mol), N,N-dimethylformamide (731.0 g, 10.0 mol), water (36.0 g, 2.0 mol), Cu(OAc)2·H2O (20.0 g, 0.1 mol), FeCl3 (16.2 g, 0.1 mol) and Sc(OTf)3 (9.8 g, 0.02 mol) were added to a normal pressure reactor equipped with a heater and a stirring device, stirred and heated to 70°C, and kept warm for 8 hours. During the reaction, the byproduct methyl formate evaporated and discharged from the reaction system. Samples were taken to detect that the content of methyl 3-methoxypropionate no longer changed, and the heat preservation was stopped and cooled to room temperature. The reaction liquid was heated in a rectification kettle for vacuum distillation, and the residue containing the Lewis acid catalyst in the rectification kettle was put into the reactor again to catalyze the aminolysis reaction of MMP. The molar yields of the Lewis acid catalyst for the first, second, third and fourth use were 86.2%, 85.4%, 80.4% and 71.5%, respectively.

[0024] Example 6 3-methoxypropionic acid methyl ester (590.7g, 5.0mol), N,N-dimethylformamide (731.0g, 10.0mol), water (36.0g, 2.0mol), NiSO4·6H2O (26.3g, 0.1mol), Ca(OAc)2 (15.8g, 0.1mol) and AlCl3 (13.3g, 0.1mol) were added to a normal pressure reactor equipped with a heater and a stirring device, stirred and heated to 70°C, and kept warm for 24 hours. During the reaction, the by-product methyl formate evaporated and discharged from the reaction system. Samples were taken to detect that the content of 3-methoxypropionic acid methyl ester no longer changed, and the insulation was stopped and cooled to room temperature. The reaction liquid was heated in a distillation kettle and vacuum distilled to obtain 541.8g of the product 3-methoxy-N,N-dimethylpropionamide, with a gas chromatographic purity of 99.2% and a molar yield of 82.6%.

[0025] Example 7 3-methoxypropionic acid methyl ester (590.7g, 5.0mol), N,N-dimethylformamide (731.0g, 10.0mol), water (36.0g, 2.0mol), Zn(OAc)2·2H2O (43.9g, 0.2mol), MgCl2 (9.5g, 0.1mol) and La(OTf)3 (58.6g, 0.1mol) (13.3g, 0.1mol) were added to a normal pressure reactor equipped with a heater and a stirring device, stirred and heated to 100°C, and kept warm for 2h. During the reaction, the by-product methyl formate evaporated and discharged from the reaction system. Samples were taken to detect that the content of 3-methoxypropionic acid methyl ester no longer changed, and the heat preservation was stopped and cooled to room temperature. The reaction liquid was heated in a distillation kettle and vacuum distilled to obtain 608.0g of the product 3-methoxy-N,N-dimethylpropionamide, with a gas chromatographic purity of 99.6% and a molar yield of 92.7%.

[0026] Example 8 3-methoxypropionic acid methyl ester (590.7g, 5.0mol), N,N-dimethylformamide (731.0g, 10.0mol), water (36.0g, 2.0mol), Zn(OAc)2·2H2O (65.9g, 0.3mol), Sc(OTf)3 (49.2g, 0.1mol) and La(OTf)3 (58.6g, 0.1mol) (13.3g, 0.1mol) were added to a normal pressure reactor equipped with a heater and a stirring device, stirred and heated to 50℃, and kept warm for 10h. During the reaction, the byproduct methyl formate evaporated and discharged from the reaction system. The content of 3-methoxypropionic acid methyl ester was no longer changed after sampling and detection, and the temperature was stopped and cooled to room temperature. The reaction liquid was heated in a distillation kettle and subjected to vacuum distillation to obtain 621.9 g of the product 3-methoxy-N,N-dimethylpropionamide with a gas chromatographic purity of 99.3% and a molar yield of 94.4%.

[0027] Comparative Example 1 Compared with Example 5, the difference is that no water is added. 347.0 g of the product 3-methoxy-N,N-dimethylpropionamide is obtained with a gas chromatography purity of 99.0% and a molar yield of 52.9%.

[0028] Comparative Example 2 Compared with Example 5, the difference is that the heating temperature is increased from 70° C. to 110° C. 186.3 g of the product 3-methoxy-N,N-dimethylpropionamide is obtained, with a gas chromatography purity of 86.9% and a molar yield of 28.4%.

[0029] Comparative Example 3 Compared with Example 5, the difference is that the raw material is replaced by 3-methoxypropionic acid from methyl 3-methoxypropionate. The target product 3-methoxy-N,N-dimethylpropionamide is not observed.

[0030] Comparative Example 4 Compared with Example 5, the difference is that the raw material is replaced by ethyl 3-methoxypropionate instead of methyl 3-methoxypropionate, and 384.3 g of the product 3-methoxy-N,N-dimethylpropionamide is obtained, with a gas chromatographic purity of 95.3% and a molar yield of 58.6%.

[0031] Comparative Example 5 Compared with Example 5, the difference is that the raw material is replaced by 3-methoxypropionic acid propyl ester instead of 3-methoxypropionic acid methyl ester, and 163.3 g of the product 3-methoxy-N,N-dimethylpropionamide is obtained, with a gas chromatography purity of 88.1% and a molar yield of 24.9%.

[0032] The present invention provides a novel method for synthesizing 3-methoxy-N,N-dimethylpropionamide. Figure 1As shown, DMF is used as a substitute for dimethylamine. It is hydrolyzed in situ under Lewis acid catalysis to generate dimethylamine and formic acid. Dimethylamine and Lewis acid-activated MMP undergo amine ester exchange reaction to generate product MMPA and by-product methanol. Formic acid and methanol undergo esterification reaction to generate methyl formate, and by-product water is used as a reagent for hydrolysis of DMF. During the entire reaction process, methyl formate is the main by-product. When a Zn salt that is easy to catalyze the hydrolysis of DMF to generate dimethylamine is selected as the only catalyst, the reaction yield can reach 73.3% (Example 1); when a Cu salt that is easy to catalyze the hydrolysis of DMF and the amine ester exchange reaction is selected as the only catalyst, the reaction yield is slightly improved (Example 2); when an Fe salt that is easy to catalyze the esterification reaction is added to the reaction system, the reaction yield is further improved to 77.2% (Example 3); when a Sc salt catalyst that is easier to catalyze the amine ester exchange reaction is introduced into the reaction system, the reaction yield is significantly improved to 85.3% (Example 4). This shows that through a simple combination of Lewis acid catalysts, the effects of various Lewis acids can be fully utilized, and the yield can be significantly improved; and the combined use of this Lewis acid catalyst can reduce the use of more expensive catalysts, which is beneficial to reducing the use cost of the catalyst. Lewis acid catalysts are easy to absorb moisture to form hydrated metal salts. When hydrated metal salts are used as catalysts, the reaction yield remains basically unchanged (Example 5). Since the production cost of hydrated metal salts is lower, the use of hydrated metal salts as catalysts is more conducive to reducing the cost of catalysts. In addition, as a residue of distillation purification, the Lewis acid catalyst can be recycled 3 times (Example 5). When other Lewis acid catalyst combinations are used, higher yields can also be obtained by adjusting the reaction temperature and time (Examples 6-8).

[0033] Comparison between Comparative Example 1 and Example 5 shows that if there is no water in the initial reaction system, the reaction proceeds very slowly and the yield is significantly reduced, which indicates that the presence of water is very necessary in the initial stage of the reaction, which can promote the hydrolysis of DMF to generate dimethylamine, which then undergoes an amine ester exchange reaction with methyl 3-methoxypropionate to generate the product MMPA. After the reaction proceeds to a certain stage, the water generated by the acid-alcohol esterification reaction can be used as a reagent for the hydrolysis of DMF. Comparison between Comparative Example 2 and Example 5 shows that when the heating temperature is increased from 70°C to 110°C, the reaction yield is significantly reduced. This is because the methanol generated in the reaction system leaves the reaction system through atmospheric distillation due to its low boiling point, and the reaction cycle is interrupted, resulting in a significant reduction in the water content in the reaction system for the hydrolysis of DMF.

[0034] Comparison between Comparative Example 3 and Example 5 shows that when the raw material methyl 3-methoxypropionate is replaced by 3-methoxypropionic acid, no target product is observed, which indicates that it is difficult for 3-methoxypropionic acid to react with dimethylamine under normal pressure. Comparison between Comparative Example 4 and Example 5 shows that when the raw material methyl 3-methoxypropionate is replaced by ethyl 3-methoxypropionate, the yield is significantly reduced. Comparison between Comparative Example 5 and Example 5 shows that when the raw material methyl 3-methoxypropionate is replaced by ethyl 3-methoxypropionate, the yield is greatly reduced even if the reaction time is extended. This indicates that the greater the steric hindrance of the ester group, the lower the activity of the aminolysis reaction, and the slower the reaction proceeds; at the same time, the greater the hydrocarbon structure of the reaction byproduct alcohol, the greater the steric hindrance, and the slower the reaction rate with the DMF hydrolysis product formic acid, thereby affecting the reaction rate of the entire catalytic system. In addition, compared with methyl 3-methoxypropionate, ethyl 3-methoxypropionate and propyl 3-methoxypropionate have larger molecular weights, poor atom economy, and higher costs.

[0035] It should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for a person skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 3-methoxy-N,N-dimethylpropionamide, characterized in that: include: Using methyl 3-methoxypropionate, N,N-dimethylformamide and water as raw materials, Lewis acid as catalyst, mixing, heating, heat preservation and stirring to react, and obtaining a reaction liquid containing 3-methoxy-N,N-dimethylpropionamide.

2. The synthesis method according to claim 1, characterized in that Also includes: The reaction solution is distilled to obtain 3-methoxy-N,N-dimethylpropionamide.

3. The synthesis method according to claim 2, characterized in that The distillation is vacuum distillation.

4. The synthesis method according to claim 1 or 2, characterized in that The molar ratio of the methyl 3-methoxypropionate, N,N-dimethylformamide and water is 1:1.5-3:0.1-1.

5. The synthesis method according to claim 1 or 2, characterized in that: The heating is performed to a temperature greater than the boiling point of the by-product methyl formate.

6. The synthesis method according to claim 5, characterized in that The heating temperature is 50-100°C.

7. The synthesis method according to claim 1 or 2, characterized in that: The reaction time is 2-24h.

8. The synthesis method according to claim 1 or 2, characterized in that: The catalyst is any one or more of halides, acetates, sulfates, trifluoroacetates or trifluoromethanesulfonates of Al, Fe, Zn, Ca, Mg, Ni, Cu, Sc or La.

9. The synthesis method according to claim 1 or 2, characterized in that: The amount of the catalyst used is 1-10% of the molar mass of the methyl 3-methoxypropionate.

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