阅读说明：本技术 一种联产n-甲基-2-氟苯胺和结晶磺胺的制备方法 (Preparation method for co-production of N-methyl-2-fluoroaniline and crystalline sulfanilamide ) 是由 刘涛 张中涛 徐海 于 2020-03-31 设计创作，主要内容包括：本发明公开了一种联产N-甲基-2-氟苯胺和结晶磺胺的制备方法,包括如下步骤：S1、取邻氟苯胺、对乙酰胺基苯磺酰氯、缚酸剂进行缩合反应得到得物质A；S2、取物质A与甲基化试剂、碱性物质进行甲基化反应,接着进行氨基脱保护得到物质B；最后取物质B与胺化剂进行氨解反应得到N-甲基-2-氟苯胺和结晶磺胺。本发明以邻氟苯胺和对乙酰胺基苯磺酰氯为原料,同步制得N-甲基-2-氟苯胺和结晶磺胺两种物质,且收率较高。(The invention discloses a preparation method for co-producing N-methyl-2-fluoroaniline and crystalline sulfanilamide, which comprises the following steps: s1, carrying out condensation reaction on o-fluoroaniline, p-acetamido benzene sulfonyl chloride and an acid-binding agent to obtain a substance A; s2, performing methylation reaction on the extract substance A, a methylation reagent and an alkaline substance, and performing amino deprotection to obtain a substance B; and finally, carrying out ammonolysis reaction on the substance B and an aminating agent to obtain the N-methyl-2-fluoroaniline and the crystalline sulfanilamide. The invention takes o-fluoroaniline and p-acetamido benzene sulfonyl chloride as raw materials to synchronously prepare two substances, namely N-methyl-2-fluoroaniline and crystal sulfanilamide, and has higher yield.)

1. A preparation method for co-producing N-methyl-2-fluoroaniline and crystalline sulfanilamide is characterized by comprising the following steps:

s1, carrying out condensation reaction on o-fluoroaniline, p-acetamido benzene sulfonyl chloride and an acid-binding agent to obtain a substance A;

s2, performing methylation reaction on the extract substance A, a methylation reagent and an alkaline substance, and performing amino deprotection to obtain a substance B; finally, carrying out ammonolysis reaction on the substance B and an aminating agent to obtain N-methyl-2-fluoroaniline and crystalline sulfanilamide;

wherein the structural formulas of the substance A and the substance B are shown as follows:

2. the process for the preparation of a co-product of N-methyl-2-fluoroaniline and a crystalline sulfonamide as claimed in claim 1, wherein in S1 the acid-binding agent comprises triethylamine, pyridine or N, N-diisopropylethylamine; preferably, in S1, the acid scavenger is triethylamine.

3. The production process for co-producing N-methyl-2-fluoroaniline and crystalline sulfonamide as claimed in claim 1 or 2, characterized in that in S2, the methylating agent comprises methyl iodide, methyl bromide or dimethyl sulfate; preferably, in S2, the methylating agent is methyl iodide; preferably, in S2, the basic substance includes sodium hydride, methyl lithium or butyl lithium; preferably, in S2, the basic substance is sodium hydride.

4. The process for the co-production of N-methyl-2-fluoroaniline and crystalline sulfonamide according to any one of claims 1-3, characterized in that in S2 the aminating agent is aqueous ammonia.

5. The process for the preparation of co-production of N-methyl-2-fluoroaniline and crystalline sulfonamide as claimed in any one of claims 1 to 4, wherein in S1, the condensation reaction is carried out at room temperature for a reaction time of 2 to 3 hours; preferably, in S2, the temperature of the methylation reaction is-5 to 0 ℃, and the reaction time is 2-4 h; preferably, in S2, the temperature of the amino deprotection reaction is 25-60 ℃, and the reaction time is 5-30 min; preferably, in S2, the ammonolysis reaction time is 4-5 h.

6. The process for the preparation of a co-product of N-methyl-2-fluoroaniline and a crystalline sulfonamide as claimed in any one of claims 1 to 5, wherein in S1, the molar ratio of o-fluoroaniline, p-acetamidobenzenesulfonyl group and acid-binding agent is 1:1.01 to 1.1:1.1 to 1.5; preferably, in S2, the molar ratio of the substance A, the methylating agent and the basic substance is 1:1.05-1.5: 1.05-2.0; preferably, in S2, the molar ratio of substance B to aminating agent is 1: 1.5-5.0.

7. The process for the co-production of N-methyl-2-fluoroaniline and crystalline sulfonamide according to any one of claims 1 to 6, characterized in that, in S1, the reaction solvent for the condensation reaction comprises dichloromethane, tetrahydrofuran or N, N-dimethylaniline; preferably, in S2, the reaction solvent for methylation is tetrahydrofuran or n.n-dimethylaniline.

8. The process for the preparation of co-production of N-methyl-2-fluoroaniline and crystalline sulfonamide according to any one of claims 1 to 7, characterized in that in S1 the specific preparation step of substance a comprises: dissolving o-fluoroaniline and p-acetamido benzene sulfonyl chloride in a reaction solvent, adding an acid-binding agent, and carrying out condensation reaction to obtain a substance A; preferably, after the condensation reaction, the product is purified to obtain a substance A; preferably, the specific steps of purification are: after condensation reaction, dichloromethane and water are added for extraction, and a dichloromethane layer is taken, washed, dried and concentrated to obtain a substance A.

9. The process for the preparation of co-production of N-methyl-2-fluoroaniline and crystalline sulfonamide according to any one of claims 1-8, characterized in that in S2 the specific preparation step of substance B comprises: and (3) uniformly mixing the substance A, the methylation reagent and the reaction solvent, adding an alkaline substance, uniformly mixing, carrying out methylation reaction, adding water for quenching reaction, removing the reaction solvent, and carrying out amino deprotection reaction to obtain a substance B.

10. The process for the preparation of co-production of N-methyl-2-fluoroaniline and crystalline sulfonamide according to any one of claims 1 to 9, wherein in S2, the specific steps of the ammonolysis reaction comprise: uniformly mixing the substance B with an aminating agent, refluxing for ammonolysis reaction, then crystallizing, filtering to obtain a filter cake to obtain crystalline sulfanilamide, extracting the filtrate with an organic solvent, and concentrating an organic layer to obtain N-methyl-2-fluoroaniline; preferably, the organic solvent comprises dichloromethane, ethyl acetate, toluene; preferably, the crystallization temperature is 0-5 ℃.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a preparation method for co-producing N-methyl-2-fluoroaniline and crystalline sulfanilamide.

Background

The N-methyl-2-fluoroaniline and the crystal sulfanilamide are important chemical intermediates and raw materials. The dosage of the N-methyl-2-fluoroaniline is increased rapidly every year, and the market demand is large. The crystal sulfanilamide is a main raw material for synthesizing sulfanilamide medicines, is also an intermediate of herbicide asulam, and can be directly used as a veterinary medicine.

Currently, the synthesis method of N-methyl-2-fluoroaniline is many and can be roughly divided into the following routes:

1. in the literature (catalysis science & Technology,6(22), 7956-. The yield of the synthetic route is too low, the total yield of the N-methyl-2-fluoroaniline is about 5 percent, and the synthetic route is not easy to be industrially produced and is shown as the following route 1:

2. in the literature (Organic L etters,14(15), 3948-:

3. in patent CN107973721, o-fluoroaniline is used as a raw material, and reacts with paraformaldehyde under the action of an acid-binding agent to obtain an intermediate 1, and the intermediate 1 is reduced by hydrogen to obtain a target product. The synthetic route needs hydrogen and an acid-binding agent, the generation cost is high, the total yield of N-methyl-2-fluoroaniline with certain potential safety hazard is about 83%, and the synthetic route is shown as a route 3:

the industrial production method of the crystalline sulfanilamide is single, and the specific synthetic route is as follows: acetanilide is used as a raw material and reacts with chlorosulfonic acid to obtain an intermediate 1, the intermediate 1 reacts with ammonia water to obtain an intermediate 2, and the intermediate 2 is hydrolyzed to obtain the crystalline sulfanilamide. The synthesis route is long and the production cost is high. The total yield of crystalline sulfonamides is about 90%, and the synthetic route is shown in scheme 4:

in summary, the existing production processes of N-methyl-2-fluoroaniline and crystal sulfanilamide often have the problems of difficulty in controlling the generation of a byproduct, namely polysubstituted methyl, higher production cost, difficulty in operation, more three wastes and the like. It is therefore desirable to provide new methods of preparation.

Disclosure of Invention

Based on the technical problems in the background art, the invention provides a preparation method for co-producing N-methyl-2-fluoroaniline and crystal sulfanilamide.

The invention provides a preparation method for co-producing N-methyl-2-fluoroaniline and crystalline sulfanilamide, which comprises the following steps:

s1, carrying out condensation reaction on o-fluoroaniline, p-acetamido benzene sulfonyl chloride and an acid-binding agent to obtain a substance A;

s2, performing methylation reaction on the extract substance A, a methylation reagent and an alkaline substance, and performing amino deprotection to obtain a substance B; finally, carrying out ammonolysis reaction on the substance B and an aminating agent to obtain N-methyl-2-fluoroaniline and crystalline sulfanilamide;

wherein the structural formulas of the substance A and the substance B are shown as follows:

the "ammonolysis reaction" refers to a process in which an organic compound having various functional groups is reacted with an aminating agent to form an amine compound.

Preferably, in S1, the acid scavenger comprises triethylamine, pyridine, or N, N-diisopropylethylamine, etc.

Preferably, in S1, the acid scavenger is triethylamine.

Preferably, in S2, the methylating agent includes methyl iodide, methyl bromide or dimethyl sulfate, etc.

Preferably, in S2, the methylating agent is methyl iodide.

Preferably, in S2, the basic substance includes sodium hydride, methyl lithium, butyl lithium or the like.

Preferably, in S2, the basic substance is sodium hydride.

The sodium hydride is commercially available, and is usually a solution of sodium hydride in an oil such as kerosene, liquid paraffin, or the like.

Preferably, in S2, the aminating agent is aqueous ammonia.

Preferably, in S1, the condensation reaction temperature is room temperature and the reaction time is 2-3 h.

Preferably, in S2, the temperature of the methylation reaction is-5 to 0 ℃ and the reaction time is 2 to 4 hours.

Preferably, in S2, the temperature of the amino deprotection reaction is 25-60 ℃ and the reaction time is 5-30 min.

Preferably, in S2, the ammonolysis reaction time is 4-5 h.

Preferably, in S1, the molar ratio of the o-fluoroaniline, the p-acetamidobenzenesulfonyl group and the acid-binding agent is 1:1.01-1.1: 1.1-1.5.

Preferably, in S2, the molar ratio of the substance A, the methylating agent and the basic substance is 1:1.05-1.5: 1.05-2.0.

Preferably, in S2, the molar ratio of substance B to aminating agent is 1: 1.5-5.0.

Preferably, in S1, the reaction solvent for the condensation reaction includes dichloromethane, tetrahydrofuran, N-dimethylaniline, or the like.

Preferably, in S2, the reaction solvent for methylation is tetrahydrofuran or n.n-dimethylaniline.

Preferably, in S1, the specific preparation step of substance a includes: dissolving o-fluoroaniline and p-acetamido benzene sulfonyl chloride in a reaction solvent, adding an acid-binding agent, and carrying out condensation reaction to obtain a substance A.

Preferably, the condensation reaction is followed by purification to give substance A.

Preferably, the specific steps of purification are: after condensation reaction, dichloromethane and water are added for extraction, and a dichloromethane layer is taken, washed, dried and concentrated to obtain a substance A.

Preferably, in S2, the specific preparation step of substance B includes: and (3) uniformly mixing the substance A, the methylation reagent and the reaction solvent, adding an alkaline substance, uniformly mixing, carrying out methylation reaction, adding water for quenching reaction, removing the reaction solvent, and carrying out amino deprotection reaction to obtain a substance B.

In the preparation of substance B, the next ammonolysis reaction was carried out without purification.

Preferably, in S2, the specific steps of the ammonolysis reaction include: and (3) uniformly mixing the substance B with an aminating agent, refluxing for ammonolysis reaction, then crystallizing, filtering to obtain a filter cake to obtain crystalline sulfanilamide, extracting the filtrate with an organic solvent, and concentrating an organic layer to obtain the N-methyl-2-fluoroaniline.

Preferably, the organic solvent includes dichloromethane, ethyl acetate, toluene, and the like.

Preferably, the crystallization temperature is 0-5 ℃.

Has the advantages that:

1. the invention creatively uses o-fluoroaniline and p-acetamido benzene sulfonyl chloride as raw materials to obtain a substance A through condensation reaction, the substance A performs methylation and amino deprotection reaction to obtain a substance B, the substance B performs ammonolysis reaction to synchronously prepare two substances of N-methyl-2-fluoroaniline and crystalline sulfonamide, the production cost and the production period are reduced, the atom economy is facilitated, the yield of the N-methyl-2-fluoroaniline and the yield of the crystalline sulfonamide are both high, the yield of the N-methyl-2-fluoroaniline reaches 83%, and the yield of the crystalline sulfonamide reaches 85%;

2. the raw materials of the invention are cheap and easy to obtain; the route is short, the operation is simple, and the post-treatment is simple and convenient; and the operation process is simplified, the pollution to the environment is reduced, and the method is suitable for industrial mass production.

Drawings

FIG. 1 is a synthetic route diagram of the present invention.

Detailed Description

The technical solution of the present invention will be described in detail below with reference to specific examples.