CN113354558B

CN113354558B - Preparation method of 2-amino-5-fluorobenzonitrile

Info

Publication number: CN113354558B
Application number: CN202110785253.4A
Authority: CN
Inventors: 张国强; 王昌军; 秦英
Original assignee: Wuxi Shuangqi Technology Co ltd
Current assignee: Wuxi Shuangqi Technology Co ltd
Priority date: 2021-07-12
Filing date: 2021-07-12
Publication date: 2022-03-11
Anticipated expiration: 2041-07-12
Also published as: CN113354558A

Abstract

The invention discloses a preparation method of 2-amino-5-fluorobenzonitrile, which comprises the following specific steps: (1) taking 2, 5-difluorobenzaldehyde as an initial raw material, and carrying out condensation reaction with hydroxylamine hydrochloride under the condition of triethylamine to generate a compound III; (2) dehydrating the compound III and phosphorus oxychloride to generate a compound IV; (3) aminolysis of compound IV with ammonia to form compound I; i.e. the 2-amino-5-fluorobenzonitrile. The preparation method has higher yield.

Description

Preparation method of 2-amino-5-fluorobenzonitrile

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of 2-amino-5-fluorobenzonitrile.

Background

2-amino-5-fluorobenzonitrile is a key intermediate, and WO2006/129120 discloses the following route for the synthesis of 2-amino-5-fluorobenzonitrile compound I:

in the synthesis method, the four-step reaction is performed in the process of synthesizing the 2-amino-5-fluorobenzonitrile compound I, the route is long, and the palladium-carbon hydrogenation is used for the final step of reduction, so that the cost is high, and the industrial amplification generation is not facilitated.

Disclosure of Invention

In view of the above problems in the prior art, the present applicant provides a process for preparing 2-amino-5-fluorobenzonitrile. The preparation method has higher yield.

The technical scheme of the invention is as follows:

a process for the preparation of 2-amino-5-fluorobenzonitrile according to the following synthetic route:

the method comprises the following specific steps:

(1) taking 2, 5-difluorobenzaldehyde as an initial raw material, and carrying out condensation reaction with hydroxylamine hydrochloride under the condition of triethylamine to generate a compound III;

(2) dehydrating the compound III and phosphorus oxychloride to generate a compound IV;

(3) aminolysis of compound IV with ammonia to form compound I; i.e. the 2-amino-5-fluorobenzonitrile.

In the step (1), the reaction solvent is one or more of dichloromethane, ethyl acetate and trichloromethane.

In the step (1), the molar ratio of the 2, 5-difluorobenzaldehyde to the hydroxylamine hydrochloride and the triethylamine is 1: 1.2-1.4: 2.0.

In the step (1), the reaction conditions are as follows: the temperature is 20-40 ℃, and the reaction time is 2-4 h.

In the step (2), the reaction solvent is N, N-dimethylformamide.

In the step (2), the molar ratio of the compound III to the phosphorus oxychloride is 1: 2.0-3.0.

In the step (2), the reaction conditions are as follows: the temperature is 40-80 ℃, and the reaction time is 2-6 h.

In the step (3), the reaction solvent is one or more of N, N-dimethylformamide and dimethyl sulfoxide.

In the step (3), the molar ratio of the compound IV to ammonia gas is 1: 5.0-10.0.

In the step (3), the reaction conditions are as follows: the temperature is 20-40 ℃, and the reaction time is 2-6 h.

The beneficial technical effects of the invention are as follows:

the invention takes 2, 5-difluorobenzaldehyde as the starting material, and has the advantages of short route, low price of the raw material, 92 percent of the lowest yield in each step and about 83 percent of the total yield.

Drawings

FIG. 1 is a scheme showing the preparation of 2-amino-5-fluorobenzonitrile obtained in example 1¹An H-NMR spectrum;

FIG. 2 is a GC spectrum of 2-amino-5-fluorobenzonitrile obtained in example 1.

Detailed Description

The present invention will be described in detail with reference to the accompanying drawings and examples.

Example 1

A process for the preparation of 2-amino-5-fluorobenzonitrile which comprises the steps of:

(1) adding 142g (1mol) of 2, 5-difluorobenzaldehyde, 500ml of dichloromethane, 83.4g (1.2mol) of hydroxylamine hydrochloride and 202g (2mol) of triethylamine into a reaction bottle, stirring at 20 ℃ for reacting for 4 hours, and carrying out HPLC tracking reaction until the 2, 5-difluorobenzaldehyde is completely reacted; the organic layer was washed with 1000ml of water and concentrated to yield 149.2g of compound III in molar yield: 95 percent.

(2) Adding 78.5g (0.5mol) of compound III, 200ml of N, N-dimethylformamide and 153g (1mol) of phosphorus oxychloride into a reaction bottle, stirring for 6 hours at 80 ℃, and carrying out HPLC tracking reaction until the compound III is completely reacted; quenched into 1000ml of ice water, filtered and dried to obtain 59g of compound IV, molar yield: 85 percent.

(3) Adding 41.7g (0.3mol) of compound IV, 100ml of N, N-dimethylformamide, introducing 25.5g (1.5mol) of ammonia gas at 20 ℃, keeping the temperature and stirring for 6 hours after the addition is finished, and carrying out HPLC tracking reaction until the compound IV is completely reacted; quenched into 500ml of ice water, filtered, and the solid dried to give 38.8g of compound I, molar yield: 95 percent.

FIG. 1 is a hydrogen spectrum of 2-amino-5-fluorobenzonitrile,¹H-NMR(400MHz,CDCl₃)δ:7.27～7.07(m,2H，Ph-H),6.72～6.69(m,1H，Ph-H)，4.26(s,2H，NH₂)。

FIG. 2 is a gas chromatogram of 2-amino-5-fluorobenzonitrile, and it can be seen that the purity of 2-amino-5-fluorobenzonitrile is 100%.

Example 2

(1) adding 142g (1mol) of 2, 5-difluorobenzaldehyde, 500ml of trichloromethane, 90.35g (1.3mol) of hydroxylamine hydrochloride and 202g (2mol) of triethylamine into a reaction bottle, stirring and reacting at 30 ℃ for 2 hours after the addition is finished, and carrying out HPLC tracking reaction until the 2, 5-difluorobenzaldehyde is completely reacted; the organic layer was washed with 1000ml of water and concentrated to give 146g of compound III in molar yield: 93 percent.

(2) Adding 78.5g (0.5mol) of compound III, 200ml of N, N-dimethylformamide and 191.3g (1.25mol) of phosphorus oxychloride into a reaction bottle, stirring for 2 hours at 60 ℃, and carrying out HPLC tracking reaction until the compound III is completely reacted; quenched into 1000ml of ice water, filtered and dried to obtain 61.2g of compound IV, molar yield: 88 percent.

(3) Adding 41.7g (0.3mol) of compound IV, 100ml of N, N-dimethylformamide, introducing 35.7g (2.1mol) of ammonia gas at 40 ℃, keeping the temperature and stirring for 4 hours after the addition is finished, and carrying out HPLC tracking reaction until the compound IV is completely reacted; quenched into 500ml of ice water, filtered, and the solid dried to give 37.9g of compound I, molar yield: 93 percent.

Example 3

(1) adding 142g (1mol) of 2, 5-difluorobenzaldehyde, 500ml of ethyl acetate, 97.3g (1.3mol) of hydroxylamine hydrochloride and 202g (2mol) of triethylamine into a reaction bottle, stirring for 3 hours at the completion of the addition at 40 ℃, and carrying out HPLC tracking reaction until the 2, 5-difluorobenzaldehyde is completely reacted; the organic layer was washed with 1000ml of water and concentrated to give 144.4g of compound III in molar yield: 92 percent.

(2) Adding 78.5g (0.5mol) of compound III, 200ml of N, N-dimethylformamide and 229.5g (1.5mol) of phosphorus oxychloride into a reaction bottle, stirring for 4 hours at 40 ℃, and carrying out HPLC tracking reaction until the compound III is completely reacted; quenched into 1000ml of ice water, filtered and dried to obtain 64g of compound IV, molar yield: 92 percent.

(3) Adding 41.7g (0.3mol) of compound IV and 100ml of dimethyl sulfoxide into a reaction bottle, introducing 51g (3mol) of ammonia gas at 30 ℃, keeping the temperature and stirring for 2 hours after the addition is finished, and carrying out HPLC tracking reaction until the compound IV is completely reacted; quenched into 500ml of ice water, filtered, and the solid dried to give 36.7g of compound I, molar yield: 90 percent.

Claims

1. A preparation method of 2-amino-5-fluorobenzonitrile is characterized by comprising the following synthetic routes:

the method comprises the following specific steps:

2. The preparation method according to claim 1, wherein in the step (1), the reaction solvent is one or more of dichloromethane, ethyl acetate and chloroform.

3. The preparation method according to claim 1, wherein in the step (1), the molar ratio of the 2, 5-difluorobenzaldehyde to the hydroxylamine hydrochloride and the triethylamine is 1: 1.2-1.4: 2.0.

4. The method according to claim 1, wherein in the step (1), the reaction conditions are: the temperature is 20-40 ℃, and the reaction time is 2-4 h.

5. The method according to claim 1, wherein in the step (2), the reaction solvent is N, N-dimethylformamide.

6. The preparation method according to claim 1, wherein in the step (2), the molar ratio of the compound III to the phosphorus oxychloride is 1: 2.0-3.0.

7. The method according to claim 1, wherein in the step (2), the reaction conditions are: the temperature is 40-80 ℃, and the reaction time is 2-6 h.

8. The method according to claim 1, wherein in the step (3), the reaction solvent is one or more of N, N-dimethylformamide and dimethylsulfoxide.

9. The method according to claim 1, wherein in the step (3), the molar ratio of the compound IV to the ammonia gas is 1:5.0 to 10.0.

10. The production method according to claim 1, wherein in the step (3), the reaction conditions are: the temperature is 20-40 ℃, and the reaction time is 2-6 h.