CN112500304B

CN112500304B - Preparation method of 6-aminocaproic acid

Info

Publication number: CN112500304B
Application number: CN202011635755.0A
Authority: CN
Inventors: 马斌; 吴燕枫; 尹文娟; 徐芳芳
Original assignee: Changzhou Lanling Pharmaceutical Co ltd
Current assignee: Changzhou Lanling Pharmaceutical Co ltd
Priority date: 2020-12-31
Filing date: 2020-12-31
Publication date: 2023-05-30
Anticipated expiration: 2040-12-31
Also published as: CN112500304A

Abstract

The invention discloses a preparation method of 6-aminocaproic acid, which takes caprolactam as a raw material and is obtained through alkaline hydrolysis, neutralization treatment, desalination treatment and refining treatment; the alkaline hydrolysis is carried out by caprolactam, sodium hydroxide and water under a certain temperature and a certain pressure; the certain temperature is 115-125 ℃, the certain pressure is 0.15-0.3 MPa, and the reaction time of alkaline hydrolysis is not more than 1.5h. The alkaline hydrolysis method shortens the hydrolysis time by pressurization, and can effectively inhibit the generation of byproducts under the condition of ensuring the complete hydrolysis, thereby not only having higher reaction yield, but also having higher product purity.

Description

Preparation method of 6-aminocaproic acid

Technical Field

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of 6-aminocaproic acid.

Background

6-aminocaproic acid, formula: c (C) ₆ H ₁₃ NO ₂ Is an important functional chemical, is widely used in the medical field as a hemostatic at home and abroad, can block fibrinolytic enzyme after being dissolved in water, thereby inhibiting the dissolution of fibrin and effectively preventing and treating various bleeding caused by the increase of fibrinolytic activity.

At present, the preparation method of 6-aminocaproic acid mainly comprises a chemical synthesis method, a biological synthesis method and a caprolactam hydrolysis method. The chemical synthesis method has the following defects: longer synthetic route, higher raw material cost, difficult control of byproducts and lower yield. The disadvantage of the biosynthesis method is that: expensive catalytic enzymes are needed, the reaction period is long, and the reaction conditions are severe.

The hydrolysis of caprolactam is classified into an acidic hydrolysis method (see U.S. Pat. No. 3,979A, chinese patent No. CN101125821A, CN109369430A, CN110256268A, CN111100025A, etc.) and an alkaline hydrolysis method.

The acid hydrolysis method has the advantages that: the hydrolysis effect is better, and the purity of the product is higher.

Disadvantages of the acid hydrolysis method include: some of the reaction conditions are harsh, some of the reaction conditions have higher production cost, some of the reaction conditions have larger environmental pollution, and some of the reaction conditions have lower yield.

For alkaline hydrolysis, chinese patent document CN106632474a example 1 discloses: 1. hydrolysis reaction: 220g of caprolactam and 140g of sodium hydroxide are put into a 500ml bottle, the temperature is raised, the reflux reaction is carried out for 5 hours, and 230 water is added for dilution to obtain hydrolysate after the reaction is finished. 353 hydrolysate is added into a 1000ml bottle, 230g of 30% industrial hydrochloric acid is added dropwise to adjust the pH to 4, and the mixture is poured out for standby. 2. Diazotization reaction: … ….

The 6-aminocaproic acid referred to in this document is only in an intermediate transition state and is not isolated and purified, and therefore, neither the purity of the product nor the reaction yield is characterized.

Chinese patent document CN108546234A discloses a preparation method of 6-aminocaproic acid, which is obtained by taking caprolactam as a raw material, and performing alkaline hydrolysis, neutralization treatment, desalination treatment and refining treatment; the alkaline hydrolysis is to react caprolactam with sodium hydroxide and water for 1 to 5 hours at the temperature of 100 to 110 ℃, and the mol ratio of the caprolactam to the sodium hydroxide is 1:1 to 1:1.3; the neutralization treatment is to cool the material after alkaline hydrolysis to room temperature and neutralize the material with dilute sulfuric acid to ph=7.5; the desalination treatment is to carry out electrodialysis desalination on the neutralized material, and the desalination treatment is ended with the sulfate radical content in effluent liquid being less than 100 ppm.

This document only emphasizes that the reaction yields are high, substantially above 95%, but does not have any characterization of the product purity as such. In addition, this document uses electrodialysis for desalination, which is demanding for the neutralization treatment (ph=7.5).

Disclosure of Invention

The invention aims to solve the defect of low purity of the existing caprolactam alkaline hydrolysis method, and provides a preparation method of 6-aminocaproic acid with high reaction yield and high product purity.

The technical scheme for realizing the aim of the invention is as follows: a process for preparing 6-aminocaproic acid from caprolactam includes such steps as alkaline hydrolysis, neutralizing, desalting and refining.

The applicant found through a number of experiments that: although alkaline hydrolysis has a high hydrolysis rate, it is based on the fact that if the hydrolysis time is long, by-products which are difficult to remove by recrystallization are produced, resulting in a low purity of the product although it has a high hydrolysis yield.

Applicants have also found through extensive experimentation that: the pressurizing can lead the alkaline hydrolysis to be carried out forward, thereby ensuring that the alkaline hydrolysis can be completed in a shorter time and effectively inhibiting the generation of byproducts.

The alkaline hydrolysis is carried out by mixing caprolactam with sodium hydroxide and water at a certain temperature and a certain pressure.

The certain temperature is 115-125 ℃, preferably 120 ℃.

The certain pressure is 0.15-0.3 MPa, preferably 0.2MPa.

The reaction time of the alkaline hydrolysis is not more than 1.5 hours, preferably 1 hour.

The mole ratio of the caprolactam to the sodium hydroxide is 1:1.1-1:1.3.

The neutralization treatment is to cool the material after alkaline hydrolysis to room temperature (15-25 ℃, the same applies below), and neutralize the material with hydrochloric acid to ph=7-8.

The concentration of the hydrochloric acid is 15 to 25wt%, preferably 20wt%.

The desalination treatment is to carry out reverse osmosis desalination on the neutralized material.

The desalination treatment is finished by taking the content of chloride ions in effluent liquid as the endpoint, wherein the content of chloride ions in effluent liquid is less than or equal to 10 mg/L.

The refining treatment is substantially the same as in the prior art.

The invention has the positive effects that:

(1) The alkaline hydrolysis method shortens the hydrolysis time by pressurization, and can effectively inhibit the generation of byproducts under the condition of ensuring the complete hydrolysis, thereby not only having higher reaction yield, but also having higher product purity.

(2) The method adopts reverse osmosis to remove the salt, so that the cost of the salt removal is low, the salt removal rate is high, and the operation is simple.

Detailed Description

Example 1

The preparation method of 6-aminocaproic acid of this example has the following steps:

(1) 5.0g of caprolactam, 2.1g of sodium hydroxide and 25g of softened water are added into a 100mL reaction flask, the pressure is increased to 0.2MPa, the temperature is increased to 120 ℃, and alkaline hydrolysis reaction is carried out for 1h.

(2) The alkaline hydrolyzed material of step (1) was cooled to room temperature and neutralized to ph=7.7±0.1 with hydrochloric acid having a concentration of 20wt%.

(3) And (3) pressurizing the material subjected to the neutralization treatment in the step (2) and carrying out desalination treatment by a reverse osmosis device, wherein the content of chloride ions in effluent liquid is less than or equal to 10 mg/L.

(4) Decolorizing the desalted material in the step (3) with active carbon, filtering, concentrating the filtrate at 50-65 deg.c under reduced pressure to near dryness, adding ethanol while hot, stirring to crystallize, cooling and throwing to obtain coarse 6-aminocaproic acid product.

Recrystallizing the crude product with mixed solvent of ethanol and water (7:1), cooling, filtering, and drying to obtain 5.71g 6-aminocaproic acid product with yield of 98.5% and purity (HPLC) of 99.3%.

Example 2 to example 9

The preparation method of each example is basically the same as that of example 1, except that: the temperature, pressure and time of the alkaline hydrolysis reaction are shown in Table 1.

Comparative examples 1 to 8

The preparation method of each comparative example was basically the same as in example 1, except that: the temperature, pressure and time of the alkaline hydrolysis reaction are shown in Table 1.

TABLE 1

Temperature (temperature)

Pressure of

Time

Weight of (E)

Yield is good

Purity of

Example 1

120℃

0.2MPa

1.0h

5.71g

98.5%

99.3%

Example 2

120℃

0.2MPa

1.2h

5.73g

98.9%

98.7%

Example 3

120℃

0.2MPa

0.8h

5.62g

97.0%

99.5%

Example 4

120℃

0.15MPa

1.2h

5.70g

98.3%

98.4%

Example 5

120℃

0.3MPa

0.8h

5.67g

97.8%

99.4%

Example 6

115℃

0.2MPa

1.2h

5.71g

98.5%

Example 7

125℃

0.2MPa

0.8h

5.63g

97.1%

99.4%

Example 8

115℃

0.3MPa

1.0h

5.70g

98.3%

99.3%

Example 9

125℃

0.15MPa

1.0h

5.69g

98.2%

99.2%

Comparative example 1

105℃

0.1MPa

1.0h

5.38g

92.8%

99.4%

Comparative example 2

105℃

0.1MPa

2.0h

5.69g

98.2%

97.4%

Comparative example 3

105℃

0.1MPa

3.0h

5.74g

99.0%

95.8%

Comparative example 4

120℃

0.1MPa

1.0h

5.46g

94.2%

99.4%

Comparative example 5

120℃

0.1MPa

2.0h

5.71g

98.5%

97.2%

Comparative example 6

120℃

0.1MPa

3.0h

5.75g

99.2%

95.3%

Comparative example 7

120℃

0.2MPa

1.5h

5.74g

99.0%

98.0%

Comparative example 8

120℃

0.2MPa

2.0h

5.76g

99.4%

96.9%

(examples 10 to 11)

The preparation method of each example is basically the same as that of example 1, except that: the feeding amount is shown in Table 2.

TABLE 2

	Example 1	Example 10	Example 11
				Reaction device	100mL reaction bottle	1L reaction bottle	100L reaction kettle
Caprolactam	5g	100g	10kg
				Sodium hydroxide	2.1g	42g	4.2kg
Softened water	25g	500g	50kg
				Weight of (E)	5.71g	114.4g	11.35kg
Yield is good	98.5%	98.7%	97.9%
				Purity of	99.3%	99.1%	99.5%

Claims

1. A preparation method of 6-aminocaproic acid, it takes caprolactam as raw material, through alkaline hydrolysis, neutralization treatment, desalination treatment, refining treatment get final product; the method is characterized in that:

the alkaline hydrolysis is carried out by caprolactam, sodium hydroxide and water under a certain temperature and a certain pressure;

the certain temperature is 115-125 ℃, the certain pressure is 0.15-0.3 MPa, and the reaction time of alkaline hydrolysis is 1h.

2. The method for producing 6-aminocaproic acid according to claim 1, wherein: the certain temperature is 120 ℃, and the certain pressure is 0.2MPa.

3. The process for the preparation of 6-aminocaproic acid according to claim 1 or 2, characterized in that: the mole ratio of the caprolactam to the sodium hydroxide is 1:1.1-1:1.3.

4. The process for the preparation of 6-aminocaproic acid according to claim 1 or 2, characterized in that: the neutralization treatment is to cool the material after alkaline hydrolysis to room temperature and neutralize the material with hydrochloric acid until the pH value is 7-8.

5. The method for producing 6-aminocaproic acid according to claim 4, wherein: the concentration of the hydrochloric acid is 15-25 wt%.

6. The method for producing 6-aminocaproic acid according to claim 5, wherein: the concentration of the hydrochloric acid is 20wt%.

7. The process for the preparation of 6-aminocaproic acid according to claim 1 or 2, characterized in that: the desalination treatment is to carry out reverse osmosis desalination on the neutralized material.

8. The method for producing 6-aminocaproic acid according to claim 7, wherein: the desalination treatment is finished by taking the content of chloride ions in effluent liquid as the endpoint, wherein the content of chloride ions in effluent liquid is less than or equal to 10 mg/L.