阅读说明：本技术 一种合成洛度沙胺或其二乙酯的方法 (Method for synthesizing lodoxylamine or diethyl ester thereof ) 是由 饶亮明 孙占奎 于 2021-10-18 设计创作，主要内容包括：本发明提供了一种合成洛度沙胺或其二乙酯的方法。合成中,选用巯基乙酸或巯基乙酸乙酯作为反应物与3,5-二氨基-4氯苯腈反应,再向反应体系中加入盐与碱性化合物,在氧气与室温条件下反应,反应完毕后,向反应体系中加入水,除去液体,即得目标化合物。该方法具有操作简单、收率高、环保、以及对操作者友好等优点。(The invention provides a method for synthesizing lodoxylamine or diethyl ester thereof. During synthesis, mercaptoacetic acid or ethyl thioglycolate is selected as a reactant to react with 3, 5-diamino-4-chlorobenzonitrile, salt and an alkaline compound are added into a reaction system, the reaction is carried out under the conditions of oxygen and room temperature, after the reaction is finished, water is added into the reaction system, and liquid is removed, so that the target compound is obtained. The method has the advantages of simple operation, high yield, environmental protection, operator friendliness and the like.)

1. A process for synthesizing lodoxylamine or its diethyl ester includes dissolving 3, 5-diamino-4-chlorobenzonitrile and mercaptoacetic acid or ethyl mercaptoacetate in organic solvent, adding salt and alkaline compound, reacting at room temp in oxygen to obtain lodoxylamine and lodoxylamine diethyl ester,

the reaction path is as follows:

2. the method for synthesizing lodoxylamine or diethyl ester thereof according to claim 1, wherein the molar ratio of 3, 5-diamino-4 chlorobenzonitrile to mercaptoacetic acid and 3, 5-diamino-4 chlorobenzonitrile to ethyl thioglycolate is 1:2 to 1:4, preferably 1: 3.

3. The process for the synthesis of lodoxylamine or its diethyl esters as claimed in claim 1, characterized in that the basic compound is triethylamine, diisopropylethylamine, triphenylphosphine, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium bicarbonate, preferably potassium carbonate.

4. The process for the synthesis of lodoxylamine or diethyl ester thereof as claimed in claim 1, characterized in that the molar ratio of the added base to 3, 5-diamino-4-chlorobenzonitrile is 0.1 to 2.0:1, preferably 0.2 to 0.8: 1.

5. The process for the synthesis of lodoxylamine or its diethyl ester as claimed in claim 1, characterized in that the organic solvent is acetonitrile, dichloromethane, 1, 2-dichloroethane, preferably acetonitrile.

6. The process for the synthesis of lodoxylamine or its diethyl ester as claimed in claim 1, characterized in that the salt used in the reaction is cuprous iodide, cupric oxide, cupric acetate, cuprous bromide, cupric chloride, cobalt chloride, preferably cupric acetate.

7. The process for the synthesis of lodoxylamine or diethyl ester thereof as claimed in claim 1, wherein the molar ratio of copper acetate to 3, 5-diamino-4-chlorobenzonitrile is 0.05-0.3: 1, preferably 0.1-0.2: 1.

8. The process for the synthesis of lodoxylamine or diethyl ester thereof as claimed in claim 1, characterized in that the reaction time is 10 to 30 hours, preferably 20 hours.

9. The method of any one of claims 1 to 8, further comprising: and respectively adding water into final reaction liquid for synthesizing the lodoxylamine and the lodoxylamine diethyl ester to separate out solids, and removing the liquid to respectively obtain the lodoxylamine and lodoxylamine diethyl ester solids.

Technical Field

The invention relates to the field of medicine synthesis, in particular to a method for synthesizing lodoxylamine or diethyl ester thereof.

Background

The lovastatin, the diethyl ester thereof and the tromethamine derivative have the functions of resisting asthma and allergy and are a new generation of antiallergic drugs. It is a mast cell stabilizer, and its stabilizing action on mast cells is far superior to that of chromoglycine and sodium chromoglycinate. The traditional Chinese medicine composition is mainly clinically suitable for local treatment of ophthalmic diseases, such as various allergic eye diseases, such as vernal keratoconjunctivitis, conjunctivitis, catarrhal conjunctivitis, giant papillary blepharoconjunctivitis, allergic or idiosyncratic keratoconjunctivitis, and allergic reactions which are unknown in etiology and are generally caused by airborne antigens and contact lenses. The product has good safety in the affected area, and generally has no adverse reaction. The structural formula of the lodoxylamine and the derivative thereof is as follows:

at present, there are two main methods for synthesizing the lodoxylamine, one of which is the method reported in Journal of Medicinal Chemistry (1978,21, 930) -935 and U.S. Pat. No. 3,93679, which uses 3, 5-diamino-4-chlorobenzonitrile as raw material to perform acylation reaction with oxalyl chloride monoethyl ester to obtain the diethyl ester of the lodoxylamine, then hydrolyzes under alkaline condition, and finally acidifies to obtain the lodoxylamine. The synthesis steps are as follows:

another method is CN108863846,2018, A reports that 3, 5-diamino-4-chlorobenzonitrile is used as a raw material to react with oxalyl chloride, and then the reaction product is quenched by water to obtain the target product of the lodoxylamine. The synthesis steps are as follows:

both of the above methods require the use of highly active oxalyl chloride and oxalyl chloride monoethyl ester as starting materials. The oxalyl chloride compound is active in property and extremely easy to hydrolyze, and can generate violent reaction when meeting moisture to release toxic gas: carbon monoxide, carbon dioxide and hydrogen chloride, which have certain dangers. Meanwhile, the substances have high toxicity and corrosiveness, can seriously stimulate eyes, skin and respiratory tract, and are easy to induce anaphylactic reaction.

In conclusion, the existing method for synthesizing the lodoxylamine has the problems of environmental unfriendliness, high risk, small synthesis batch and the like.

Disclosure of Invention

Aiming at the defects of the process, the invention provides a method for synthesizing the lodoxylamine or the diethyl ester thereof, and the method has the advantages of simple operation, high yield, environmental protection, operator friendliness and the like.

The synthetic route for synthesizing the lodoxylamine or the lodoxylamine diethyl ester is as follows:

dissolving 3, 5-diamino-4-chlorobenzonitrile, mercaptoacetic acid and ethyl mercaptoacetate in an organic solvent respectively, adding copper acetate and an alkaline compound, and reacting under the conditions of oxygen and room temperature to obtain the lodoxylamine and the lodoxylamine diethyl ester respectively.

When the salt is copper acetate, the reaction principle is that mercaptoacetic acid and ethyl mercaptoacetate respectively generate alpha-carbonyl thioacid with copper acetate and oxygen in situ. Because the activity of the alpha-carbonyl thioacid is very high, the alpha-carbonyl thioacid can react with 3, 5-diamino-4-chlorobenzonitrile under the alkaline condition, and the target product is obtained with high yield. The reaction principle of synthesizing the diethyl lothalamide is expressed by the following chemical formula:

the reactants of thioglycolic acid and ethyl thioglycolate used in the technical scheme of the invention have low toxicity, mild reaction conditions, simple experimental operation and environmental friendliness.

Furthermore, the molar ratio of the 3, 5-diamino-4-chlorobenzonitrile to mercaptoacetic acid and the molar ratio of the 3, 5-diamino-4-chlorobenzonitrile to ethyl thioglycolate are 1: 2-1: 4, and 1:3 is preferred.

Further, the base is triethylamine, diisopropylethylamine, triphenylphosphine, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium bicarbonate, preferably potassium carbonate.

Further, the molar ratio of the base to the 3, 5-diamino-4-chlorobenzonitrile is 0.1-2.0: 1, preferably 0.2-0.8: 1.

Further, the organic solvent is acetonitrile, dichloromethane, dichloroethane, preferably acetonitrile.

Further, the salt used in the reaction is cuprous iodide, cupric oxide, cupric acetate, cuprous bromide, cupric chloride, cobalt chloride, preferably cupric acetate.

Further, the molar ratio of the copper acetate to the 3, 5-diamino-4-chlorobenzonitrile is 0.05-0.3: 1, preferably 0.1-0.2: 1.

Further, the reaction time is 10 to 30 hours, preferably 20 hours.

Further, the synthesis method further comprises: and adding water into the final reaction solution, separating out the solid of the lodoxylamine and the diethyl ester of the lodoxylamine, and removing the liquid to respectively obtain the solid of the lodoxylamine and the diethyl ester of the lodoxylamine.

The above-mentioned methods for removing the liquid include, but are not limited to, centrifugation, filtration and the like, which are conventional means for removing the liquid, and these methods may be used alone or in combination.

In the embodiment of the invention, the yield of the synthesized lodoxylamine by the method can reach 90%.

The invention has the beneficial effects that:

the invention provides a new method for synthesizing the lodoxa and the diethyl ester thereof, which avoids the danger caused by using oxalyl compounds, and the reactants of thioglycolic acid and ethyl thioglycolate have low toxicity, mild reaction conditions, simple experimental operation, environmental protection to experimenters and environment, and the reaction yield can reach 90%.

Detailed Description

The technical solution of the present invention is further defined below with reference to the specific embodiments, but the scope of the claims is not limited to the description.

Example 1

3, 5-diamino-4-chlorobenzonitrile (16.7 g, 0.1mol) and thioglycolic acid (27.6 g, 0.3mol) were dissolved in acetonitrile (200ml), and copper acetate (3.6 g, 0.02mol) and potassium carbonate (27.6 g, 0.2mol) were added to stir the reaction under oxygen for 20 hours. Water (50ml) was added to precipitate a solid, which was then filtered with suction to give 28.9 g of solid lodoxylamine in 93% yield.¹HNMR(400MHz,d₆-DMSO)δ10.58(s)，8.04(s)；¹³C NMR(101MHz,CDCl₃)δ161.75,157.58,136.40,128.66,126.74,117.75,110.59。

Example 2

3, 5-diamino-4-chlorobenzonitrile (16.7 g, 0.1mol) and ethyl thioglycolate (36.0 g, 0.3mol) were dissolved in acetonitrile (200ml), and copper acetate (3.6 g, 0.02mol) and potassium carbonate (27.6 g, 0.2mol) were added to stir the reaction under oxygen for 20 hours. Water (50ml) is added, solid is precipitated and is filtered, 28.6 g of the diethyl lothalamide can be obtained, and the yield is 92%. Melting point: 177 to 178 ℃.¹HNMR(400MHz,d₆-DMSO)δ10.58(s)，8.04(s)，4.12(q)，1.22(t)。

Example 3

3, 5-diamino-4-chlorobenzonitrile (16.7 g, 0.1mol) and thioglycolic acid (27.6 g, 0.3mol) were dissolved in dichloromethane (200ml), copper acetate (3.6 g, 0.02mol) and potassium carbonate (27.6 g, 0.2mol) were added, and the reaction was stirred under oxygen for 20 hours. Water (50ml) was added to precipitate a solid, which was then filtered under suction to give 25.5 g of lodoxylamine as a solid in 82% yield.¹HNMR(400MHz,d₆-DMSO)δ10.58(s)，8.04(s)；¹³C NMR(101MHz,CDCl₃)δ161.75,157.58,136.40,128.66,126.74,117.75,110.59。

Example 4

3, 5-diamino-4-chlorobenzonitrile (16.7 g, 0.1mol) and thioglycolic acid (27.6 g, 0.3mol) were dissolved in 1, 2-dichloroethane (200ml), and copper acetate (3.6 g, 0.02mol) and potassium carbonate (27.6 g, 0.2mol) were added and the reaction was stirred under oxygen for 20 hours. Water (50ml) was added to precipitate a solid, which was then filtered under suction to give 23.3 g of lodoxylamine solid in 75% yield.¹HNMR(400MHz,d₆-DMSO)δ10.58(s)，8.04(s)；¹³C NMR(101MHz,CDCl₃)δ161.75,157.58,136.40,128.66,126.74,117.75,110.59。

Example 5

3, 5-diamino-4-chlorobenzonitrile (16.7 g, 0.1mol) and thioglycolic acid (27.6 g, 0.3mol) were dissolved in acetonitrile (200ml), and copper acetate (3.6 g, 0.02mol) and sodium carbonate (21.2 g, 0.2mol) were added and the reaction was stirred under oxygen for 20 hours. Water (50ml) was added to precipitate a solid, which was then filtered under suction to give 23.9 g of lodoxylamine solid in 77% yield.¹HNMR(400MHz,d₆-DMSO)δ10.58(s)，8.04(s)；¹³C NMR(101MHz,CDCl₃)δ161.75,157.58,136.40,128.66,126.74,117.75,110.59。

Example 6

3, 5-diamino-4-chlorobenzonitrile (16.7 g, 0.1mol) and thioglycolic acid (27.6 g, 0.3mol) were dissolved in acetonitrile (200ml), and copper acetate (3.6 g, 0.02mol) and triethylamine (20.2 g, 0.2mol) were added to stir the reaction under oxygen for 20 hours. Water (50ml) was added to precipitate a solid, which was then filtered with suction to obtain 27.1 g of lodoxylamine solid with a yield of 87%.¹HNMR(400MHz,d₆-DMSO)δ10.58(s)，8.04(s)；¹³C NMR(101MHz,CDCl₃)δ161.75,157.58,136.40,128.66,126.74,117.75,110.59。

Example 7

3, 5-diamino-4-chlorobenzonitrile (16.7 g, 0.1mol) and thioglycolic acid (27.6 g, 0.3mol) were dissolved in acetonitrile (200ml), and copper oxide (1.6 g, 0.02mol) and potassium carbonate (27.6 g, 0.2mol) were added to stir the reaction under oxygen for 20 hours. Water (50ml) was added to precipitate a solid, which was then filtered with suction to obtain 27.7 g of solid lodoxylamine with a yield of 90%.¹HNMR(400MHz,d₆-DMSO)δ10.58(s)，8.04(s)；¹³C NMR(101MHz,CDCl₃)δ161.75,157.58,136.40,128.66,126.74,117.75,110.59。

Example 8

3, 5-diamino-4-chlorobenzonitrile (16.7 g, 0.1mol) and thioglycolic acid (27.6 g, 0.3mol) were dissolved in acetonitrile (200ml), and copper chloride (2.7 g, 0.02mol) and potassium carbonate (27.6 g, 0.2mol) were added to stir the reaction under oxygen for 20 hours. Water (50ml) was added to precipitate a solid, which was then filtered under suction to give 25.5 g of lodoxylamine as a solid in 82% yield.¹HNMR(400MHz,d₆-DMSO)δ10.58(s)，8.04(s)；¹³C NMR(101MHz,CDCl₃)δ161.75,157.58,136.40,128.66,126.74,117.75,110.59。

The above description is further intended to describe the present invention in detail with reference to specific embodiments, and it should not be construed that the specific embodiments of the present invention are limited to these descriptions. It will be apparent to those skilled in the art that various changes, substitutions and alterations can be made without departing from the spirit and scope of the invention.