CN105693535B - The preparation method of 3-N, N- dimethylamino ethyl acrylate - Google Patents

Abstract

The present invention provides a kind of preparation method of 3-N, N-dimethylamino ethyl acrylate, the method provided by the invention mixes 3-N, N-dimethylamino ethyl acrylate crude product with polymerization inhibitor and distills under reduced pressure, Obtain 3-N, N-dimethylamino ethyl acrylate; And make described inhibitor be 2,6-dinitro-p-cresol, o-sec-butyl-4,6-dinitrophenol, 2,4 -Dimethyl-6-tert-butylphenol, 2,6-di-tert-butyl-p-cresol, 2,2,6,6-tetramethylpiperidine nitroxide, 2,2,6,6-tetra Two or more of methylpiperidone, N-methyl-2-pyrrolidone, dimethylthiophenylenediamine and organic sulfonic acid compound; the present invention selects specific polymerization inhibitor and 3-N, The N-dimethylaminoethyl acrylate crude product is mixed and distilled under reduced pressure, so that the 3-N, N-dimethylaminoethyl acrylate obtained by distillation has a high purity and a high yield.

Description

The preparation method of 3-N,N-ethyl dimethylaminoacrylate

technical field

The invention relates to the field of organic synthesis, in particular to a preparation method of ethyl 3-N,N-dimethylaminoacrylate.

Background technique

3-N,N-Dimethylaminoethyl acrylate is an important fine chemical intermediate, specifically a key intermediate for the synthesis of quinolone antibacterial drugs. Quinolones are widely used because of their broad antibacterial spectrum, strong antibacterial activity, few adverse reactions, and can be used in combination with other antibiotics. They are currently the most widely used antibacterial drugs in clinical practice.

There are many reports on the synthesis method of 3-N, N-dimethylaminoethyl acrylate, such as foreign patents US544619, W02000000460, EP388744, US5030747, Chinese patents CN 101293850A and CN 103833565 A, all for 3-N, N-dimethyl The synthesis process of ethyl aminoacrylate has been improved, but the yield of high-purity ethyl 3-N,N-dimethylaminoacrylate obtained by the currently disclosed preparation method is still relatively low.

Contents of the invention

In view of this, the technical problem to be solved by this invention is to provide a kind of preparation method of 3-N,N-dimethylaminoacrylate ethyl ester, the 3-N,N-dimethylaminoacrylate ethyl ester prepared by the preparation method provided by the invention The ester has high purity and high yield.

The invention provides a method for preparing 3-N,N-dimethylaminoethyl acrylate, comprising:

Mix the crude 3-N,N-dimethylaminoethyl acrylate with a polymerization inhibitor and distill under reduced pressure to obtain 3-N,N-dimethylaminoethyl acrylate;

The polymerization inhibitor is 2,6-dinitro-p-cresol, o-sec-butyl-4,6-dinitrophenol, 2,4-dimethyl-6-tert-butylphenol, 2,6- Di-tert-butyl-p-cresol, 2,2,6,6-tetramethylpiperidine nitrogen oxide, 2,2,6,6-tetramethylpiperidone, N-methyl-2-pyrrolidone, di Two of methylthiophenylenediamine, methanesulfonic acid, toluenesulfonic acid, xylenesulfonic acid, cumenesulfonic acid, dodecylbenzenesulfonic acid, pentadecylbenzenesulfonic acid and dinonylnaphthalenesulfonic acid species or two or more.

Preferably, the molar ratio of the crude 3-N,N-dimethylaminoethyl acrylate to the polymerization inhibitor is 1:(0.01-0.20).

Preferably, the molar ratio of the crude 3-N,N-dimethylaminoethyl acrylate to the polymerization inhibitor is 1:(0.02-0.05).

Preferably, the temperature of the vacuum distillation is 80-90°C.

Preferably, the crude product of ethyl 3-N,N-dimethylaminoacrylate is prepared according to the following method:

1) Ethyl acetate, alkali and carbon monoxide are mixed and reacted to obtain ethyl formoacetate;

2) Reaction of ethyl formoacetate with dimethylamine hydrochloride to obtain crude product of ethyl 3-N,N-dimethylaminoacrylate.

Preferably, the base is sodium ethylate, potassium ethylate or lithium ethylate.

Preferably, the molar ratio of the ethyl acetate to the base is (1.0-2.0):1.

Preferably, it is characterized in that the reaction solvent in step 1) is one or more of toluene, xylene, tetrahydrofuran and 1,4-dioxane.

Preferably, the pressure of the carbon monoxide is 24-26 bar.

Preferably, the reaction temperature of step 2) is 15-40°C.

Compared with the prior art, the present invention provides a method for preparing 3-N, N-dimethylaminoethyl acrylate, the method provided by the invention combines 3-N, N-dimethylaminoethyl acrylate crude The polymerization agent is mixed and distilled under reduced pressure to obtain 3-N,N-dimethylaminoethyl acrylate; and the polymerization inhibitor is 2,6-dinitro-p-cresol, o-sec-butyl-4,6-di Nitrophenol, 2,6-dimethyl-4-tert-butylphenol, 2,6-di-tert-butyl-p-cresol, 2,2,6,6-tetramethylpiperidine nitrogen oxide, 2, Two or more of 2,6,6-tetramethylpiperidone, N-methyl-2-pyrrolidone, dimethylthiophenylenediamine and organic sulfonic acid compounds; Polymerizing agent and 3-N,N-dimethylaminoethyl acrylate crude product are mixed and distilled under reduced pressure, so that the purity of 3-N,N-dimethylaminoacrylate ethyl ester obtained by distillation is high, and the yield is also high. The experimental results show that The purity of ethyl 3-N,N-dimethylaminoacrylate prepared by the preparation method provided by the invention is as high as 99.9%, and the yield is more than 97.8%.

Detailed ways

The invention provides a method for preparing 3-N,N-dimethylaminoethyl acrylate, comprising:

Mix the crude 3-N,N-dimethylaminoethyl acrylate with a polymerization inhibitor and distill under reduced pressure to obtain 3-N,N-dimethylaminoethyl acrylate;

The polymerization inhibitor is 2,6-dinitro-p-cresol, o-sec-butyl-4,6-dinitrophenol, 2,4-dimethyl-6-tert-butylphenol, 2,6- Di-tert-butyl-p-cresol, 2,2,6,6-tetramethylpiperidine nitrogen oxide, 2,2,6,6-tetramethylpiperidone, N-methyl-2-pyrrolidone, di Two of methylthiophenylenediamine, methanesulfonic acid, toluenesulfonic acid, xylenesulfonic acid, cumenesulfonic acid, dodecylbenzenesulfonic acid, pentadecylbenzenesulfonic acid and dinonylnaphthalenesulfonic acid species or two or more.

According to the present invention, the present invention mixes the crude product of 3-N,N-dimethylaminoethyl acrylate with a polymerization inhibitor and distills it under reduced pressure to obtain 3-N,N-dimethylaminoethyl acrylate; wherein, the polymerization inhibitor Preferred are 2,6-dinitro-p-cresol, o-sec-butyl-4,6-dinitrophenol, 2,4-dimethyl-6-tert-butylphenol, 2,6-di-tert-butyl p-cresol, 2,2,6,6-tetramethylpiperidine nitroxide, 2,2,6,6-tetramethylpiperidone, N-methyl-2-pyrrolidone and dimethylthiobenzene Two or more of diamines, more preferably 2,6-dinitro-p-cresol, o-sec-butyl-4,6-dinitrophenol, 2,4-dimethyl-6-tert Two or more of butylphenol 2,6-di-tert-butyl-p-cresol and 2,2,6,6-tetramethylpiperidine nitrogen oxide; the 3-N,N-dimethyl The molar ratio of ethyl aminoacrylate crude product to the polymerization inhibitor is preferably 1:(0.01～0.20), more preferably 1:(0.02～0.05), most preferably 1:(0.03～0.04); the decompression The temperature of the distillation is preferably 80-90° C., more preferably 82-86° C.; the vacuum degree of the vacuum distillation is preferably 5-10 mmHg.

In the present invention, the present invention has no special requirements on the source of the crude product of 3-N,N-dimethylaminoethyl acrylate, and the crude product prepared by known preparation methods in the art can be used. The present invention is preferably prepared according to the following method:

1) Ethyl acetate, alkali and carbon monoxide are mixed and reacted to obtain ethyl formoacetate;

2) Reaction of ethyl formoacetate with dimethylamine hydrochloride to obtain crude product of ethyl 3-N,N-dimethylaminoacrylate.

According to the present invention, ethyl acetate, alkali and carbon monoxide are mixed and reacted in the present invention to obtain ethyl formoacetate; wherein, the temperature of the reaction is preferably 60-75°C, more preferably 65-70°C; the ethyl acetate The molar ratio of the ester to the base is preferably (1.0-2.0): 1, more preferably (1.5-1.8): 1; in the reaction system, the pressure of the carbon monoxide is preferably 24-26 bar, more preferably 25 bar ~26bar; the solvent of the reaction is preferably one or more of toluene, xylene, tetrahydrofuran and 1,4-dioxane, more preferably toluene or xylene; the base is preferably sodium ethylate, ethanol Potassium or lithium ethylate; The present invention has no special requirement to the source of the alkali described in the present invention, can buy or can be made by oneself, preferably prepare according to the following method during self-made: metal and ethanol are mixed reaction in organic solvent, obtain alkali; Said reaction The temperature is preferably 90 to 150°C, more preferably 100 to 110°C; the solvent for the reaction is preferably tetrahydrofuran, dioxane, cyclohexane, benzene, toluene, ethanol, isopropanol, dimethylformamide , dimethyl sulfoxide and N-methylpyrrolidone or one or more.

According to the present invention, the present invention also reacts ethyl formyl acetate with dimethylamine hydrochloride to obtain the crude product of ethyl 3-N,N-dimethylaminoacrylate, wherein the reaction temperature is preferably 15-40°C , more preferably 20-25°C. More specifically, the preparation process of crude 3-N,N-dimethylaminoethyl acrylate is as follows:

The preparation method of 3-N,N-ethyl dimethylaminoacrylate provided by the present invention comprises mixing the crude 3-N,N-ethyl dimethylaminoacrylate with a polymerization inhibitor and distilling under reduced pressure to obtain 3-N,N- Ethyl dimethylaminoacrylate; and make the inhibitor be 2,6-dinitro-p-cresol, o-sec-butyl-4,6-dinitrophenol, 2,4-dimethyl-6- tert-butylphenol, 2,6-di-tert-butyl-p-cresol, 2,2,6,6-tetramethylpiperidine nitrogen oxide, 2,2,6,6-tetramethylpiperidone, N -Two or more of methyl-2-pyrrolidone, dimethylthiophenylenediamine and organic sulfonic acid compound; the present invention combines specific polymerization inhibitor with 3-N,N-dimethylaminoacrylic acid The crude product of the ester is mixed and distilled under reduced pressure, so that the purity of the 3-N,N-dimethylaminoacrylate ethyl ester obtained by distillation is high, and 3-N,N-dimethylaminoacrylate ethyl ester has less loss in the purification process, thereby improving the The yield of pure product of ethyl 3-N,N-dimethylaminoacrylate.

A clear and complete description will be made below in conjunction with the technical solutions of the embodiments of the present invention. Apparently, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Example 1

Measure 110g of absolute ethanol and 250g of toluene and mix them evenly in a constant pressure dropping funnel, add 360g of toluene in a 2000mL round bottom flask, replace the reaction flask with nitrogen and add 50g of sodium metal into the reaction flask under nitrogen protection, and heat up When the metal sodium is completely melted at 100°C, slowly add the mixture of toluene and ethanol dropwise, and the dropwise addition is completed in about 0.5 hours, and the temperature in the reaction bottle is maintained at 100-105°C, and the temperature is kept at 100°C for 30 minutes. The reaction is completed when no bubbles pop out. After the reaction was completed, excess ethanol and toluene were distilled off to obtain a sodium ethoxide toluene solution.

The sodium ethoxide toluene solution prepared above was pressed into an autoclave, and 285 g of ethyl acetate and 100 g of toluene were added. Start the stirring, fill the reactor with carbon monoxide gas, control the temperature of the reactor at 65°C-70°C, the pressure of the reactor rises to 24-26bar, and the reaction is completed in about 4 hours. After cooling down to room temperature, the pressure is released to obtain ethyl formoacetate .

Add 610g of 35% dimethylamine hydrochloride aqueous solution into a 2000mL round bottom flask, start stirring, and control the temperature at 15-20°C, slowly drop the ethyl formyl acetate material in the autoclave into the flask In the process, the temperature is controlled at 20-25° C., and the reaction is completed in 3 hours. The liquid was separated at room temperature, and the organic phase was concentrated to obtain 348.1 g of crude ethyl 3-N,N-dimethylaminoacrylate, which was detected by HPLC with a purity of 89.5%.

Add 348.1 g of the crude product of 3-N,N-dimethylaminoethyl acrylate to a 1000 mL round bottom flask, and simultaneously add 2,4-dimethyl-6-tert-butylphenol (3.88 g), 2,2, 6,6-Tetramethylpiperidine nitrogen oxide (3.40g), heated and distilled under reduced pressure, collected fractions at 82～86℃/5mmHg, received 304.7g of ethyl 3-N,N-dimethylaminoacrylate, collected Yield 97.8%, HPLC detection, purity 99.9%.

Example 2

Measure 110g of absolute ethanol and 250g of toluene and mix them evenly in a constant pressure dropping funnel, add 360g of toluene into a 2000mL round bottom flask, replace the reaction flask with nitrogen and add 48g of sodium metal into the reaction flask under nitrogen protection, and heat up When the metal sodium is completely melted at 100°C, slowly add the mixture of toluene and ethanol dropwise, and the dropwise addition is completed in about 0.5 hours, and the temperature in the reaction bottle is maintained at 100-105°C, and the temperature is kept at 100°C for 30 minutes. The reaction is completed when no bubbles pop out. After the reaction finishes, excess ethanol and toluene are removed by distillation to obtain sodium ethylate toluene solution;

The sodium ethoxide toluene solution prepared above was pressed into an autoclave, and 280 g of ethyl acetate and 100 g of toluene were added. Start the stirring, fill the reactor with carbon monoxide gas, control the temperature of the reactor at 65°C-70°C, the pressure of the reactor rises to 24-26bar, and the reaction is completed in about 4 hours. After cooling down to room temperature, the pressure is released to obtain ethyl formoacetate ;

Add 610g of 35% dimethylamine hydrochloride aqueous solution into a 2000mL round bottom flask, start stirring, and control the temperature at 15-20°C, slowly drop the ethyl formyl acetate material in the autoclave into the flask In the process, the temperature is controlled at 20-25° C., and the reaction is completed in 3 hours. The liquid was separated at room temperature, and the organic phase was concentrated to obtain 317 g of crude ethyl 3-N,N-dimethylaminoacrylate, which was detected by HPLC with a purity of 94.3%.

Add 317g of the 3-N,N-dimethylaminoethyl acrylate crude product obtained in the previous step into a 1000mL round-bottomed flask, and simultaneously add 2,6-di-tert-butyl-4-methylphenol (4.80g), 2, 2,6,6-Tetramethylpiperidine nitrogen oxide (3.40g) was heated and distilled, and the fraction at 82～86℃/5mmHg was collected to obtain 293.1g of ethyl 3-N,N-dimethylaminoacrylate. The yield was 98.1%, the HPLC detection purity is 99.9%.

Comparative example 1

Measure 110g of absolute ethanol and 250g of toluene and mix them evenly in a constant pressure dropping funnel, add 360g of toluene into a 2000mL round bottom flask, replace the reaction flask with nitrogen and add 48g of sodium metal into the reaction flask under nitrogen protection, and heat up When the metal sodium is completely melted at 100°C, slowly add the mixture of toluene and ethanol dropwise, and the dropwise addition is completed in about 0.5 hours, and the temperature in the reaction bottle is maintained at 100-105°C, and the temperature is kept at 100°C for 30 minutes. The reaction is completed when no bubbles pop out. After the reaction finishes, excess ethanol and toluene are removed by distillation to obtain sodium ethylate toluene solution;

The sodium ethoxide toluene mixture prepared above was hydraulically injected into the autoclave, and 285 g of ethyl acetate and 100 g of toluene were added. Start stirring, fill the reactor with carbon monoxide gas, control the temperature of the reactor at 65°C-70°C, the pressure of the reactor rises to 24-26bar, and the reaction is completed in about 4 hours, and the pressure is released after it drops to room temperature.

Add 610g of 35% dimethylamine hydrochloride aqueous solution into a 2000mL round-bottomed flask, start stirring, and control the temperature at 15-20°C, slowly drop the materials in the autoclave into the flask, and control the temperature at 20°C -25°C, 3 hours and the reaction is over. The liquid was separated at room temperature, and the organic phase was concentrated to obtain 328.6 g of crude product of ethyl 3-N,N-dimethylaminoacrylate with a purity of 90.9%.

Add the obtained crude 3-N,N-dimethylaminoacrylate ethyl ester into a 1000mL round bottom flask, add 2,4-dimethyl-6-tert-butylphenol (3.88g), heat and distill, and collect 82~ The 86°C/5mmHg fraction was 278.5g, the yield was 93.2%, and the HPLC content was 99.8%.

Comparative example 2

Measure 110g of absolute ethanol and 250g of toluene and mix them evenly in a constant pressure dropping funnel, add 360g of toluene into a 2000mL round bottom flask, replace the reaction flask with nitrogen and add 48g of sodium metal into the reaction flask under nitrogen protection, and heat up When the metal sodium is completely melted at 100°C, slowly add the mixture of toluene and ethanol dropwise, and the dropwise addition is completed in about 0.5 hours, and the temperature in the reaction bottle is maintained at 100-105°C, and the temperature is kept at 100°C for 30 minutes. The reaction is completed when no bubbles pop out. After the reaction finishes, excess ethanol and toluene are removed by distillation to obtain sodium ethylate toluene solution;

The sodium ethoxide toluene mixture prepared above was hydraulically injected into the autoclave, and 280 g of ethyl acetate and 100 g of toluene were added. Start stirring, fill the reactor with carbon monoxide gas, control the temperature of the reactor at 65°C-70°C, the pressure of the reactor rises to 24-26bar, and the reaction is completed in about 4 hours, and the pressure is released after it drops to room temperature.

Add 610g of 35% dimethylamine hydrochloride aqueous solution into a 2000mL round-bottomed flask, start stirring, and control the temperature at 15-20°C, slowly drop the materials in the autoclave into the flask, and control the temperature at 20°C -25°C, 3 hours and the reaction is over. The liquid was separated at room temperature, and the organic phase was concentrated to obtain 335.2 g of crude product of ethyl 3-N,N-dimethylaminoacrylate with a purity of 89.1%.

Add the crude product of ethyl 3-N,N-dimethylaminoacrylate prepared above into a 1000mL round bottom flask, add 2,2,6,6-tetramethylpiperidine nitrogen oxide (3.40g), heat and distill, 276.7 g of fractions at 82-86° C./5 mmHg were collected, the yield was 92.7%, and the HPLC content was 99.8%.

The descriptions of the above embodiments are only used to help understand the method and core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (10)

1. a kind of preparation method of 3-Dimethylamino-acrylic acid ethyl ester, including：

3-Dimethylamino-acrylic acid ethyl ester crude product is mixed into vacuum distillation with polymerization inhibitor, obtains 3-N, N- dimethylamino propylene Acetoacetic ester；

The polymerization inhibitor is one kind and 2,2,6,6- in 2,4 dimethyl 6 tert butyl phenol and DBPC 2,6 ditertiary butyl p cresol Tetramethyl piperidine nitrogen hopcalite.

2. preparation method according to claim 1, it is characterised in that the 3-Dimethylamino-acrylic acid ethyl ester crude product Molar ratio with the polymerization inhibitor is 1：(0.01~0.20).

3. preparation method according to claim 1, it is characterised in that the 3-Dimethylamino-acrylic acid ethyl ester crude product Molar ratio with the polymerization inhibitor is 1：(0.02~0.05).

4. preparation method according to claim 1, it is characterised in that the temperature of the vacuum distillation is 80~90 DEG C.

5. preparation method according to claim 1, it is characterised in that the 3-Dimethylamino-acrylic acid ethyl ester crude product Prepare in accordance with the following methods：

1) by ethyl acetate, alkali and carbon monoxide hybrid reaction, formyl acetic acid ethyl ester is obtained；

2) formyl acetic acid ethyl ester and dimethylamine hydrochloride are reacted, obtains 3-Dimethylamino-acrylic acid ethyl ester crude product.

6. preparation method according to claim 5, it is characterised in that the alkali is sodium ethoxide, potassium ethoxide or lithium ethoxide.

7. preparation method according to claim 5, it is characterised in that the molar ratio of the ethyl acetate and the alkali is (1.0~2.0)：1.

8. preparation method according to claim 5, it is characterised in that the solvent of the step 1) reaction is toluene, diformazan One or more in benzene, tetrahydrofuran and Isosorbide-5-Nitrae-dioxane.

9. preparation method according to claim 5, it is characterised in that the pressure of the carbon monoxide is 24~26bar.

10. preparation method according to claim 5, it is characterised in that the temperature of the step 2) reaction is 15~40 DEG C.