A kind of preparation method of lodoxamide tromethamine intermediate

Abstract

The invention belongs to the technical field of medicine chemical engineering, and particularly discloses a preparation method of a lodoxamide tromethamine intermediate of lodoxamide. The method comprises the following steps of (1) dissolving 3,5-diamino-4-chlorobenzonitrile into an organic solvent to form a solution A; (2) dissolving oxalyl chloride into the organic solvent to form a solution B;(3) slowly dripping the solution A into the solution B; in the dripping process, controlling the temperature of the reaction liquid at -20 to 0 DEG C; after the reaction is completed, slowly drippinga certain amount of ice water into the reaction liquid; after the dripping is completed, continuously performing stirring for 0.5 to 1h; then, performing suction filtering; drying obtained filter caketo obtain lodoxamide. The reaction steps of the method are few; the operation is facilitated; the yield is greatly improved and can reach 90 percent or higher; meanwhile, the related impurities of the product lodoxamide are few; the product purity is high; the HPLC purity can reach 99.5 percent or higher; great significance is realized on the synthesis of the lodoxamide tromethamine medicine.

Description

technical field

[0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of lodoxamide tromethamine intermediate. Background technique

[0002] Lodoxamide tromethamine is a new generation of anti-allergy drugs. It can prevent the chemotaxis of eosinophils while stabilizing mast cell membranes, so it has double anti-allergic effects. Its stabilizing effect on mast cell membranes is 2500 times that of cromolyn sodium, so it is effective for spring catarrhal conjunctivitis, seasonal Conjunctivitis, atopic conjunctivitis, and other ocular allergies (such as allergic reactions to chemicals, dust, and contact lenses) have a fairly good effect. A large number of clinical studies at home and abroad have shown that the curative effect of lodoxamide tromethamine on allergic conjunctivitis is better than 20% cromolyn sodium eye drops, and it has good safety and generally has no adverse reactions. Lodoxamid...

Examples

Embodiment 1

[0034] A preparation method of lodoxamide tromethamine intermediate lodoxamide, the steps are as follows:

[0035] Add 1.5mol oxalyl chloride and 500ml dichloromethane into a dry 5L three-necked flask, cool down to -10°C to 0°C in an ice-salt bath, and take another 0.60mol 3,5-diamino-4-chlorobenzonitrile (Wuhan Development Co., Ltd. Nuo Pharmaceutical Technology Co., Ltd.) was dissolved in 800ml of dichloromethane and added to a dry 1L constant pressure dropping funnel, and the dichloromethane solution of 3,5-diamino-4-chlorobenzonitrile was slowly dropped into the grass under stirring. In the acid chloride dichloromethane solution, the dropping speed is controlled during the dropping process to ensure that the temperature of the reaction solution is between -10°C and 0°C. After the dropwise addition is completed, TLC traces it. After the reaction of the raw materials is completed, slowly add 2L of ice water to the reaction solution. After the dropwise addition was completed,...

Embodiment 2

[0037] A preparation method of lodoxamide tromethamine intermediate lodoxamide, the steps are as follows:

[0038] Add 1.2mol oxalyl chloride and 500ml ethyl acetate into a dry 5L three-necked flask, cool down to -20°C to -10°C in a low-temperature cooling liquid circulation pump, and take another 0.60mol 3,5-diamino-4-chloro Dissolve benzonitrile in 800ml ethyl acetate and add it to a dry 1L constant pressure dropping funnel, slowly drop the ethyl acetate solution of 3,5-diamino-4-chlorobenzonitrile into ethyl oxalyl chloride acetate while stirring In the solution, control the rate of addition during the dropping process to ensure that the temperature of the reaction solution is at -20°C to -10°C. After the dropwise addition is completed, TLC will track it. After the reaction of the raw materials is completed, slowly add 2L of ice water to the reaction solution. After the addition was completed, continue to stir for 0.5 h and then filter with suction, collect the filter cake ...

Embodiment 3

[0040] A preparation method of lodoxamide tromethamine intermediate lodoxamide, the steps are as follows:

[0041] Add 1.8mol oxalyl chloride and 500ml DMF into a dry 5L three-necked flask, cool down to -10°C to 0°C in an ice-salt bath, and dissolve another 0.60mol 3,5-diamino-4-chlorobenzonitrile in 800ml DMF Add it into a dry 1L constant pressure dropping funnel, slowly drop the DMF solution of 3,5-diamino-4-chlorobenzonitrile into the DMF solution of oxalyl chloride under stirring, and control the dropping speed during the dropping process to ensure the reaction The temperature of the solution is -10°C ~ 0°C. After the dropwise addition is completed, TLC traces. After the reaction of the raw materials is completed, slowly add 2L of ice water to the reaction solution. After the dropwise addition, continue to stir for 0.5h and then filter with suction to collect the filter cake. After drying in a blast oven at 60°C, 173.8 g of off-white solid lodoxamide was obtained, with a y...

technical field

[0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of lodoxamide tromethamine intermediate. Background technique

[0002] Lodoxamide tromethamine is a new generation of anti-allergy drugs. It can prevent the chemotaxis of eosinophils while stabilizing mast cell membranes, so it has double anti-allergic effects. Its stabilizing effect on mast cell membranes is 2500 times that of cromolyn sodium, so it is effective for spring catarrhal conjunctivitis, seasonal Conjunctivitis, atopic conjunctivitis, and other ocular allergies (such as allergic reactions to chemicals, dust, and contact lenses) have a fairly good effect. A large number of clinical studies at home and abroad have shown that the curative effect of lodoxamide tromethamine on allergic conjunctivitis is better than 20% cromolyn sodium eye drops, and it has good safety and generally has no adverse reactions. Lodoxamid...

Examples

Embodiment 1

[0034] A preparation method of lodoxamide tromethamine intermediate lodoxamide, the steps are as follows:

[0035] Add 1.5mol oxalyl chloride and 500ml dichloromethane into a dry 5L three-necked flask, cool down to -10°C to 0°C in an ice-salt bath, and take another 0.60mol 3,5-diamino-4-chlorobenzonitrile (Wuhan Development Co., Ltd. Nuo Pharmaceutical Technology Co., Ltd.) was dissolved in 800ml of dichloromethane and added to a dry 1L constant pressure dropping funnel, and the dichloromethane solution of 3,5-diamino-4-chlorobenzonitrile was slowly dropped into the grass under stirring. In the acid chloride dichloromethane solution, the dropping speed is controlled during the dropping process to ensure that the temperature of the reaction solution is between -10°C and 0°C. After the dropwise addition is completed, TLC traces it. After the reaction of the raw materials is completed, slowly add 2L of ice water to the reaction solution. After the dropwise addition was completed,...

Embodiment 2

[0037] A preparation method of lodoxamide tromethamine intermediate lodoxamide, the steps are as follows:

[0038] Add 1.2mol oxalyl chloride and 500ml ethyl acetate into a dry 5L three-necked flask, cool down to -20°C to -10°C in a low-temperature cooling liquid circulation pump, and take another 0.60mol 3,5-diamino-4-chloro Dissolve benzonitrile in 800ml ethyl acetate and add it to a dry 1L constant pressure dropping funnel, slowly drop the ethyl acetate solution of 3,5-diamino-4-chlorobenzonitrile into ethyl oxalyl chloride acetate while stirring In the solution, control the rate of addition during the dropping process to ensure that the temperature of the reaction solution is at -20°C to -10°C. After the dropwise addition is completed, TLC will track it. After the reaction of the raw materials is completed, slowly add 2L of ice water to the reaction solution. After the addition was completed, continue to stir for 0.5 h and then filter with suction, collect the filter cake ...

Embodiment 3

[0040] A preparation method of lodoxamide tromethamine intermediate lodoxamide, the steps are as follows:

[0041] Add 1.8mol oxalyl chloride and 500ml DMF into a dry 5L three-necked flask, cool down to -10°C to 0°C in an ice-salt bath, and dissolve another 0.60mol 3,5-diamino-4-chlorobenzonitrile in 800ml DMF Add it into a dry 1L constant pressure dropping funnel, slowly drop the DMF solution of 3,5-diamino-4-chlorobenzonitrile into the DMF solution of oxalyl chloride under stirring, and control the dropping speed during the dropping process to ensure the reaction The temperature of the solution is -10°C ~ 0°C. After the dropwise addition is completed, TLC traces. After the reaction of the raw materials is completed, slowly add 2L of ice water to the reaction solution. After the dropwise addition, continue to stir for 0.5h and then filter with suction to collect the filter cake. After drying in a blast oven at 60°C, 173.8 g of off-white solid lodoxamide was obtained, with a y...

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