A method for synthesizing 3-methylaminopropanoic acid

Abstract

The application discloses a synthesis method of 3-methylamino propionic acid and belongs to the technical field of organic synthesis. 3-amino propionic acid ester is dissolved in hexafluoroisopropanol to form a uniform solution, in the solution, trimethyl phosphate is added dropwise to perform N-alkylation reaction, after the N-alkylation reaction is completed, lye is added to perform saponification, and the saponification product is subjected to acidification, so that 3-methylamino propionic acid is obtained. The method can obtain 3-methylamino propionic acid at a high yield, is simple in operation, mild in condition, easy in product separation, and favorable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to a synthesis method of 3-methylamino propionic acid, in particular to a method for synthesizing 3-methylamino propionic acid from 3-aminopropionic acid ester through N-methylation reaction and saponification reaction, and belongs to the technical field of organic synthesis. BACKGROUND

[0002] 3-methylamino propionic acid is an important organic synthesis intermediate as an amino acid derivative, which is widely used in the fields of medicine, pesticide and functional material due to its biological activity and chemical stability, and can be used for synthesizing various drugs and pesticides.

[0003] In recent years, with the improvement of synthesis technology, the production efficiency has been significantly improved. Related synthesis of 3-methylamino propionic acid can be prepared by hydrolysis of 3-aminopropionitrile alkaline solution (see synthesis route ① below), or by deprotection of N-protected methylpropionic acid (see synthesis route ② below), another method is to obtain 3-methylamino propionic acid directly by amination reaction of propenoic acid and methylamine (see synthesis route ③ below), and 3-methylamino propionic acid can also be synthesized by alkylating 2-bromopropionic acid with methylamine (see synthesis route ④ below).

[0004]

[0005] However, the current method has many defects, including harsh reaction conditions, high cost of raw materials and insufficient product purity. Therefore, it is particularly critical and urgent to research and develop an efficient and environmentally friendly synthesis process of 3-methylamino propionic acid. Enterprises and research institutions at home and abroad are actively developing and promoting the expansion of its production process and application field. The demand for 3-methylamino propionic acid in the market continues to grow, so it is of great practical significance and broad application prospect to promote its research and development. SUMMARY

[0006] In view of the defects of the prior art, the purpose of the present application is to provide a synthesis method of 3-methylamino propionic acid, which uses phosphoric acid trimethyl ester as an N-methylation reagent, and realizes high selectivity conversion of 3-aminopropionic acid ester to 3-methylamino propionic acid ester under the catalysis of hexafluoroisopropanol, so as to obtain 3-methylamino propionic acid with high yield. The method is simple in operation, mild in conditions, easy to separate the product, and can realize high yield synthesis of 3-methylamino propionic acid.

[0007] In order to achieve the above technical purpose, the present application provides a synthesis method of 3-methylamino propionic acid, which is to dissolve 3-aminopropionic acid ester in hexafluoroisopropanol to form a uniform solution, and then add phosphoric acid trimethyl ester dropwise for N-alkylation reaction in the solution. After the N-alkylation reaction is completed, an alkali solution is added for saponification, and the saponification product is acidified to obtain the product.

[0008] The present application aims to improve the synthesis efficiency and selectivity of 3-methylamino propionate. On one hand, since both hydrogens contained in the nitrogen atom of 3-amino propionate have certain reactivity, especially prone to by-product 3-(dimethylamino) propionate methyl ester of double N-alkylation, the present application pre-dissolves 3-amino propionate in hexafluoroisopropanol, then controls the slow drop of high-activity trimethyl phosphate methylating agent in the solution system, so as to effectively avoid the double N-alkylation reaction caused by the excessive local concentration of trimethyl phosphate, and convert into 3-methylamino propionate with high selectivity. On the other hand, the present application uses hexafluoroisopropanol as the reaction medium, which not only acts as a solvent to fully dissolve and disperse 3-amino propionate and reduce the occurrence of side reactions, but also provides a strong hydrogen bond network to enhance the N-alkylation reactivity of 3-methylamino propionate, thereby improving the synthesis efficiency of 3-methylamino propionate.

[0009] As a preferred scheme, the 3-amino propionate has the following molecular structure:

[0010] wherein R is C1-C5 alkyl. The shorter the molecular chain of the R group as a leaving group, the higher the reactivity, therefore R is further preferably methyl or ethyl.

[0011] As a preferred scheme, the concentration of 3-amino propionate in the solution is ≤0.5 mol / L. With the decrease of the concentration of 3-amino propionate in the solution, the yield of the N-alkylation reaction product of 3-amino propionate shows a trend of first increasing and then leveling off, and when the concentration of 3-amino propionate is reduced to 1 mol / 3 mL, there is almost no effect on the increase of the yield of the N-alkylation reaction product of 3-amino propionate. Therefore, the concentration of 3-amino propionate in the solution is further preferably 0.3-0.5 mol / L.

[0012] As a preferred scheme, the molar ratio of the 3-amino propionate methyl ester to the trimethyl phosphate is 1:1.0-1.1. The amount of trimethyl phosphate needs to be strictly controlled, and excessive trimethyl phosphate will increase the conversion rate of the double N-alkylation product, thereby reducing the yield of the single N-alkylation product. A small amount of trimethyl phosphate will cause a small amount of 3-amino propionate methyl ester not to be completely converted. The molar ratio of the 3-amino propionate methyl ester to the trimethyl phosphate is further preferably 1:1.05-1.1.

[0013] As a preferred scheme, the adding rate of trimethyl phosphate is controlled to be 5-10 seconds per drop. The adding rate of trimethyl phosphate needs to be strictly controlled. If the adding rate is too fast, the local concentration of trimethyl phosphate and generated 3-methylaminopropanamide methyl ester is too high, and the reaction will continue to occur N-alkylation conversion into double N-alkylation product. Of course, the slower the adding rate of trimethyl phosphate is, the more conducive to obtaining 3-methylaminopropanamide methyl ester with high selectivity, but the reaction efficiency will also be reduced.

[0014] As a preferred scheme, the conditions of the N-alkylation reaction are that the temperature is 0-60℃, and the time is 1-4 hours. The temperature of the N-alkylation reaction is too high or too low is not conducive to the substitution reaction. The lower the temperature is, the lower the efficiency of the alkylation reaction is. The higher the temperature of the alkylation reaction is, the conversion rate of double alkylation is increased. Therefore, the further preferred temperature is 10-30℃. The further preferred time is 2-3 hours.

[0015] As a preferred scheme, the conditions of the saponification reaction are that the temperature is 80-110℃, and the time is 2-3 hours. The alkali solution used in the saponification reaction can be sodium hydroxide solution. The saponification reaction is mainly the hydrolysis process of 3-methylaminopropanamide methyl ester. In theory, most of the inorganic strong alkali solutions can be achieved. Under the preferred saponification reaction conditions, 3-methylaminopropanamide can be converted into 3-methylaminopropanoic acid with a conversion rate of more than 99%, and almost 100% conversion can be achieved.

[0016] The molecular structure of 3-methylaminopropanoic acid of the present application is as follows:

[0017]

[0018] Compared with the prior art, the technical scheme of the present application has the beneficial technical effects:

[0019] The present application uses 3-methylaminopropanamide methyl ester as a raw material, and obtains 3-methylaminopropanoic acid through N-methylation and hydrolysis saponification. The present application has the characteristics of good reaction selectivity, high yield of target product, low cost of raw material, simple operation, mild conditions, and easy separation of product. DETAILED DESCRIPTION

[0020] The following specific examples are intended to further illustrate the present application, but not to limit the protection scope of the claims.

[0021] The terms used in the present application have the meanings generally understood by those of ordinary skill in the art, unless otherwise specified.

[0022] The experimental methods used in the following examples are conventional methods, unless otherwise specified.

[0023] The reagents, materials, instruments, etc. used in the following examples, unless otherwise specified, can be obtained commercially.

[0024] The main chemical reaction equation involved in the present application is as follows:

[0025]

[0026] wherein R is -CH3, -CH2CH3.

[0027] The following optimization experiments take 3-aminopropionic acid ester and trimethyl phosphate as an example to explore the best reaction conditions.

[0028] The following optimization experiments are all carried out according to the following process: in a reaction vessel, 1 mmol of 3-aminopropionic acid methyl ester and an appropriate amount of solvent are added to mix the substrate uniformly, and a methylation reagent (1.1 mmol) is slowly added dropwise to the reaction kettle, the dropwise adding speed (6 drops / s) and the reaction temperature are controlled to ensure smooth reaction, after the dropwise adding is completed, the reaction is carried out for 2 hours, and the plate detection is carried out, after the reaction is completed, the solvent is rotary evaporated, and column chromatography is carried out to obtain the product. Then, a base solution (1.1 mol of NaOH is used to prepare a 35% aqueous solution) is added, and saponification is carried out at a temperature of 100℃ for 3 hours, after the saponification is completed, the heating is stopped, and the reaction is cooled to room temperature. The reaction is subjected to post-treatment, the pH is adjusted to 1.5, and then filtration, drying, etc. are carried out to remove impurities and by-products, and high-purity 3-methylamino propionic acid is obtained.

[0029] The conditions of the optimization experiment groups and the yield of 3-methylamino propionic acid under the corresponding conditions are as follows:

[0030]

[0031] a: trimethyl phosphate, 1.2 equivalents.

[0032] b: trimethyl phosphate, 1.3 equivalents.

[0033] It can be seen from experiment groups 1-3 and 8 that among ethanol, hexafluoroisopropanol, dichloromethane, and N,N-dimethylformamide, only hexafluoroisopropanol solvent can promote the smooth progress of the N methylation reaction between P(OMe)3 and 3-aminopropionic acid ester, and other solvents cannot effectively catalyze the alkylation reaction, mainly because hexafluoroisopropanol can provide a strong hydrogen bond network, which plays a good catalytic role, so that the N-alkylation reaction occurs smoothly.

[0034] It can be seen from experiment groups 4-6 and 8 that by replacing different methylation reagents such as methyl iodide, tetramethylammonium fluoride, and dimethyl sulfate, it is found that the conversion rates of appropriate methyl iodide and dimethyl sulfate are not high, and the product is basically not detected by using tetramethylammonium fluoride, therefore, trimethyl phosphate is used as a methyl source reagent.

[0035] From the experimental groups 7~9, it can be seen that: appropriately increasing the amount of solvent with 1, 2, 3 mL, it is found that appropriately increasing the amount of solvent can improve the conversion rate of the reaction, but the yield of 3 mL no longer changes, therefore, 2 mL of solvent is used.

[0036] From the experimental groups 10~15 and 8, it can be seen that: with the increase of the reaction temperature, the product yield shows a trend of first rising, reaching the peak, and then decreasing, mainly because with the increase of the temperature, the activity of the substrate increases, which can improve the product yield, but if the temperature is too high, the side reaction increases, which can promote the reaction to convert to the double N-alkylated product, therefore, the preferred temperature is 10~30℃.

[0037] From the experimental groups 16~17 and 8, it can be seen that: increasing the amount of trimethyl phosphate with 1.2, 1.3 equivalents, with the increase of the amount, the product does not increase obviously, and there is a trend of a small amount of decrease, therefore, 1.1 equivalent is selected.

[0038] According to the above optimization test results, the best experimental conditions are selected:

[0039] 1) HFIP is used as the solvent; 2) trimethyl phosphate is used as the methyl source reagent; 3) the amount of HFIP relative to 3-aminopropanamide is 1 mmol / 2 mL; 4) the amount of trimethyl phosphate relative to 3-aminopropanamide is 1.1 equivalent; 5) the reaction temperature is 25℃. Under the preferred reaction conditions, the best 3-methylamino propanamide yield can be obtained.

[0040] Example 1

[0041] In a three-necked flask, 2 mmol of 3-aminopropanamide 20.62 mg and 4 mL of hexafluoroisopropanol were added and stirred uniformly, 2.2 mmol of trimethyl phosphate 36.10 mg was slowly added dropwise, the dropping speed was controlled (6 drops / s), after the addition was completed, the reaction was stirred at room temperature (25℃) for 2 hours, then the plate was detected, after the reaction was completed, the hexafluoroisopropanol was removed by rotary evaporation, column chromatography was performed, and the product 3-methylamino propanamide was obtained. Then an alkaline solution (using 1.1 mol NaOH to prepare a 35% aqueous solution) was added, and the saponification was carried out at 100℃ for 3 hours, after the saponification was completed, the heating was stopped, and the reaction was cooled to room temperature. The reaction was post-treated, the pH was adjusted to 1.5, then it was filtered, dried, etc. to remove impurities and by-products, and high-purity 3-methylamino propanamide was obtained, and the total yield was 77%. The characterization of 3-methylamino propanamide: 1 H NMR (400 MHz, D2O) δ 3.17 (t, J = 6.6 Hz, 2H), 2.70 (s, 3H), 2.54 (t, J =6.6 Hz, 2H). 13C NMR (101 MHz, D20) δ 177.97, 45.92, 32.56, 32.38.

[0042] Example 2

[0043] In a three-necked flask, 2 mmol of 3-aminopropanoic acid methyl ester 20.62 mg and 5 mL of hexafluoroisopropanol were added and stirred uniformly, 2.2 mmol of trimethyl phosphate 36.10 mg was added dropwise, the dropping speed was controlled (8 drops / s), after the dropwise addition was completed, the reaction was stirred at room temperature (25 °C) for 2 hours, then the plate was detected, after the reaction was completed, the hexafluoroisopropanol was removed by rotary evaporation, and column chromatography was performed to obtain the product 3-methylaminopropanoic acid methyl ester. Then, a base solution (1.1 mol of NaOH was used to prepare a 35% aqueous solution) was added, and the saponification was performed at 85 °C for 4 hours, after the saponification was completed, the heating was stopped, and the reaction was cooled to room temperature. The reaction was post-treated, the pH was adjusted to 1.5, and then filtration, drying, etc. were performed to remove impurities and by-products, and high-purity 3-methylaminopropanoic acid was obtained, and the total yield was 75%.

[0044] Comparative Example 1

[0045] In a three-necked flask, 2 mmol of 3-aminopropanoic acid methyl ester 20.62 mg and 5 mL of hexafluoroisopropanol were added and stirred uniformly, 2.2 mmol of trimethyl phosphate 36.10 mg was added dropwise, the dropping speed was controlled (8 drops / s), after the dropwise addition was completed, the reaction was stirred at room temperature (25 °C) for 2 hours, then the plate was detected, after the reaction was completed, the hexafluoroisopropanol was removed by rotary evaporation, and column chromatography was performed to obtain the product 3-methylaminopropanoic acid methyl ester. Then, a base solution (1.1 mol of NaOH was used to prepare a 35% aqueous solution) was added, and the saponification was performed at 85 °C for 4 hours, after the saponification was completed, the heating was stopped, and the reaction was cooled to room temperature. The reaction was post-treated, the pH was adjusted to 1.5, and then filtration, drying, etc. were performed to remove impurities and by-products, and high-purity 3-methylaminopropanoic acid was obtained, and the total yield was 75%.

Claims

1. A process for the synthesis of 3-methylamino propionic acid, characterized by: The 3-aminopropionic acid ester is dissolved in hexafluoroisopropanol to form a uniform solution, and in the solution, trimethyl phosphate is added dropwise to perform an N-alkylation reaction, and after the N-alkylation reaction is completed, lye is added to perform saponification, and the saponification product is acidified to obtain the product; the 3-aminopropionic acid ester has the following molecular structure: wherein R is a C1-C5 alkyl group.

2. The method of claim 1, wherein: The concentration of 3-aminopropanoate in the solution is ≤0.5 mol / L.

3. The method of claim 1, wherein: The molar ratio of the methyl 3-aminopropanoate to the trimethyl phosphate is 1:1.0~1.

1.

4. The method of claim 1, wherein: The adding rate of the trimethyl phosphate is controlled to be 5~10 seconds per drop.

5. The method of claim 1 to 4, wherein the method is characterized by: The N-alkylation reaction is carried out at a temperature of 0~60℃ for 1~4 hours.

6. The method according to any one of claims 1~4, wherein: The saponification reaction is carried out at a temperature of 80~110℃ for 2~3 hours.

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