CN108147977B

CN108147977B - Preparation method of N-p-aminobenzoyl-L-glutamic acid

Info

Publication number: CN108147977B
Application number: CN201711446991.6A
Authority: CN
Inventors: 胡国宜; 胡锦平; 李喜龙; 郑奎; 奚小金
Original assignee: Jiangsu Sunlight Pharmaceutical Chemical Material Co ltd
Current assignee: Changzhou Sunlight Pharmaceutical Co ltd
Priority date: 2017-12-27
Filing date: 2017-12-27
Publication date: 2020-09-25
Anticipated expiration: 2037-12-27
Also published as: CN108147977A

Abstract

The invention discloses a preparation method of N-p-aminobenzoyl-L-glutamic acid, which comprises the following steps: taking p-nitrobenzoic acid as a starting material, oxalyl chloride as an acyl chlorination reagent, tetrahydrofuran and DMF as a mixed solvent, and carrying out acyl chlorination reaction to prepare p-nitrobenzoyl chloride; secondly, the p-nitrobenzoyl chloride prepared in the step one and sodium glutamate are subjected to condensation reaction to prepare N-p-nitrobenzoyl-L-glutamic acid; using hydrazine hydrate as a reducing agent and ferric chloride hexahydrate as a catalyst, and carrying out reduction reaction on the N-p-nitrobenzoyl-L-glutamic acid prepared in the step II to prepare the N-p-aminobenzoyl-L-glutamic acid. According to the invention, oxalyl chloride is selected as an acyl chlorination reagent in a mixed solvent of tetrahydrofuran and DMF, hydrazine hydrate is selected as a reducing agent in a reduction reaction, ferric chloride hexahydrate is selected as a catalyst, and finally N-p-aminobenzoyl-L-glutamic acid with the purity of more than or equal to 99.9% can be obtained.

Description

Preparation method of N-p-aminobenzoyl-L-glutamic acid

Technical Field

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a preparation method of N-p-aminobenzoyl-L-glutamic acid.

Background

The N-p-aminobenzoyl-L-glutamic acid is an intermediate for synthesizing the antianemia folic acid, and has the following structure:

。

chinese patent document CN105439895A discloses a method for preparing N-p-aminobenzoyl-L-glutamic acid, which comprises using p-nitrobenzoic acid as starting material, first making p-nitrobenzoyl chloride through acyl chlorination, then making N-p-nitrobenzoyl-L-glutamic acid through condensation reaction with sodium glutamate, and finally making N-p-aminobenzoyl-L-glutamic acid through reduction reaction. The method has the following disadvantages: the purity of the N-p-aminobenzoyl-L-glutamic acid is less than 99.9 percent.

Disclosure of Invention

The invention aims to solve the problems and provides a preparation method of N-p-aminobenzoyl-L-glutamic acid with the purity of more than or equal to 99.9 percent.

The technical scheme for realizing the purpose of the invention is as follows: a preparation method of N-p-aminobenzoyl-L-glutamic acid comprises the following steps: taking p-nitrobenzoic acid as a starting material, and preparing p-nitrobenzoyl chloride through an acyl chlorination reaction; secondly, the p-nitrobenzoyl chloride prepared in the step one and sodium glutamate are subjected to condensation reaction to prepare N-p-nitrobenzoyl-L-glutamic acid; thirdly, the N-p-nitrobenzoyl-L-glutamic acid prepared in the step two is subjected to reduction reaction to prepare the N-p-aminobenzoyl-L-glutamic acid.

In order to obtain N-p-aminobenzoyl-L-glutamic acid with the purity of more than or equal to 99.9 percent, oxalyl chloride is taken as an acyl chlorination reagent in the acyl chlorination reaction of the step I, and tetrahydrofuran and N, N-dimethylformamide (hereinafter, both are abbreviated as DMF) are taken as a mixed solvent; meanwhile, the reduction reaction in the third step takes hydrazine hydrate as a reducing agent and ferric trichloride hexahydrate as a catalyst.

The molar dosage of the oxalyl chloride is 1-5 times, preferably 1.5-2.5 times and more preferably 2 times of that of the p-nitrobenzoic acid.

The volume ratio of tetrahydrofuran to DMF in the mixed solvent is 15: 1-5: 1, preferably 12: 1-10: 1, and more preferably 11: 1.

The molar consumption of the hydrazine hydrate is 1-5 times, preferably 2-4 times and more preferably 3 times of that of the p-nitrobenzoic acid.

The molar amount of ferric chloride hexahydrate is 1-5%, preferably 2-4%, and more preferably 3% of that of p-nitrobenzoic acid.

The reaction temperature of the acyl chlorination in the step I is the reflux temperature.

The condensation reaction temperature of the second step is 0-10 ℃, and the pH value of the reaction system is 7-10.

The reduction reaction of the third step is carried out in an alcohol solvent, preferably methanol.

The invention has the following positive effects: (1) according to the invention, oxalyl chloride is selected as an acyl chlorination reagent in a mixed solvent of tetrahydrofuran and DMF, and meanwhile, hydrazine hydrate is selected as a reducing agent and ferric trichloride hexahydrate is selected as a catalyst in the reduction reaction, so that the N-p-aminobenzoyl-L-glutamic acid with the purity of more than or equal to 99.9% can be finally obtained. (2) The method has the advantages of simple operation, high process safety, low production cost, high reaction yield and small environmental pollution, and is suitable for industrial production.

Detailed Description

(example 1)

The method for preparing N-p-aminobenzoyl-L-glutamic acid of this example had the following steps:

adding 16.7g of p-nitrobenzoic acid (0.1 mol), 55mL of tetrahydrofuran and 5mL of DMF into a reaction device, stirring and heating to 55 +/-1 ℃, slowly dropwise adding 25.4g of oxalyl chloride (0.2 mol), heating to reflux after dropwise adding, and reacting completely.

After the reaction is finished, the temperature is reduced to room temperature (20 +/-5 ℃, the same is carried out below), and a solution containing the paranitrobenzoyl chloride is obtained for later use.

Adding 75g of water and 16.9g of sodium glutamate (0.1 mol) into a reaction device, adjusting the pH value to 8 by using 1mol/L of sodium hydroxide aqueous solution under stirring, then cooling to 5 +/-1 ℃, slowly dripping the solution containing the paranitrobenzoyl chloride obtained in the step I, keeping the pH =8 in the dripping process, and keeping the temperature for 5 +/-1 ℃ after dripping till the reaction is completed.

After the reaction, the pH value is adjusted to 1 by dilute hydrochloric acid, the mixture is crystallized, filtered, and after a filter cake is washed by water, the mixture is dried under reduced pressure to obtain 29.3g of N-p-nitrobenzoyl-L-glutamic acid with the purity of 99.4 percent (HPLC) and the yield of two steps by the p-nitrobenzoic acid of 99.0 percent.

③ adding 29.3g of N-p-nitrobenzoyl-L-glutamic acid obtained in the step II, 118g of methanol and 0.81g of ferric chloride hexahydrate (0.003 mol) into a reaction device, slowly dripping 15.0g of hydrazine hydrate (0.3 mol) under stirring, and stirring at room temperature until the reaction is completed.

After the reaction is finished, hydrochloric acid is used for adjusting the pH value to 3.5, crystallization and filtration are carried out, a filter cake is washed by methanol, and then the N-p-aminobenzoyl-L-glutamic acid 25.7g is obtained by decompression and drying, wherein the purity is 99.95 percent (HPLC), and the yield in three steps is 96.6 percent based on p-nitrobenzoic acid.

(examples 2 to 5)

The preparation method of each example is basically the same as that of example 1 except for the differences shown in Table 1.

TABLE 1

	Example 1	Example 2	Example 3	Example 4	Example 5
						Oxalyl chloride	25.4g	25.4g	25.4g	19.05g	31.75g
Tetrahydrofuran (THF)	55mL	50mL	60mL	55mL	55mL
						DMF	5mL	5mL	5mL	5mL	5mL
Hydrazine hydrate	15.0g	15.0g	15.0g	20.0g	10.0g
						Ferric chloride hexahydrate	0.81g	1.08g	0.54g	0.81g	0.81g
N-p-aminobenzoyl-L-glutamic acid	25.7g	25.8g	25.1g	25.6g	25.0g
						Three-step total yield	96.6%	97.0%	94.4%	96.2%	94.0%
Purity of	99.95%	99.96%	99.91%	99.96%	99.92%

(comparative examples 1 to 6)

The comparative examples were prepared substantially the same as in example 1, except that the differences are shown in Table 2.

TABLE 2

Example 1

Comparative example 1

Comparative example 2

Comparative example 3

Comparative example 4

Comparative example 5

Comparative example 6

Mixed solvent

55mL tetrahydrofuran + 5mL of DMF

55mL of dichloroethane + 5mL of DMF

55mL tetrahydrofuran + 5mL of DMF

55mL of dichloroethane + 5mL of DMF

55mL tetrahydrofuran + 5mL of DMF

Acyl chlorination reagent （0.2mol）

Oxalyl chloride

Thionyl chloride

Oxalyl chloride

Thionyl chloride

Oxalyl chloride

Reducing agent (0.3 mol)

Hydrazine hydrate

Ammonium formate

Catalyst (0.003 mol)

Ferric chloride hexahydrate

Chlorination of hexahydrateIron

Ferric chloride hexahydrate

Palladium carbon catalyst

N-p-aminobenzoyl- L-glutamic acid

25.7g

25.1g

25.2g

24.2g

23.8g

24.6g

25.0g

Three-step total yield

96.6%

94.4%

94.7%

91.0%

89.5%

92.5%

94.0%

Purity of

99.95%

99.81%

99.77%

99.58%

99.43%

99.62%

99.72%

Claims

1. A preparation method of N-p-aminobenzoyl-L-glutamic acid comprises the following steps: taking p-nitrobenzoic acid as a starting material, and preparing p-nitrobenzoyl chloride through an acyl chlorination reaction; secondly, the p-nitrobenzoyl chloride prepared in the step one and sodium glutamate are subjected to condensation reaction to prepare N-p-nitrobenzoyl-L-glutamic acid; thirdly, the N-p-nitrobenzoyl-L-glutamic acid prepared in the step two is subjected to reduction reaction to prepare N-p-aminobenzoyl-L-glutamic acid;

the method is characterized in that:

in the acyl chlorination reaction of the step I, oxalyl chloride is used as an acyl chlorination reagent, and tetrahydrofuran and N, N-dimethylformamide are used as a mixed solvent; the reduction reaction of the third step takes hydrazine hydrate as a reducing agent and ferric trichloride hexahydrate as a catalyst;

the molar dosage of the oxalyl chloride is 2-5 times of that of the p-nitrobenzoic acid;

the volume ratio of tetrahydrofuran to N, N-dimethylformamide in the mixed solvent is 11: 1-5: 1;

the molar consumption of the hydrazine hydrate is 3-5 times of that of the p-nitrobenzoic acid;

the molar amount of ferric chloride hexahydrate is 3-5% of that of p-nitrobenzoic acid.