Preparation method of robenidine hydrochloride

Abstract

The invention discloses a preparation method of robenidine hydrochloride. 1, 3-diaminoguanidine hydrochloride as a raw material, methanol as a solvent and p-chlorobenzaldehyde undergoes a condensation reaction to produce the robenidine hydrochloride. The preparation method comprises adding 1, 3-diaminoguanidine hydrochloride and methanol into a reactor, heating the raw materials to a temperature of 45-55 DEG C until the reactants are completely dissolved, adjusting pH of the solution to 1.5-2 by hydrochloric acid methanol, dropwisely adding a p-chlorobenzaldehyde-methanol solution into the reaction solution at a temperature of 45-55 DEG C at a stirring speed of 80r / min, after dropwise addition, carrying out a reflux reaction process for 1-2h, carrying out distillation to recover methanol, adding water into the reaction product, carrying out beating, and carrying out filtration, water washing and drying to obtain robenidine hydrochloride. The condensation reaction under waterless conditions is conducive to smooth reaction and greatly improves a reaction yield. The solvent can be recovered and recycled, product content is high, further purification is avoided and high economical efficiency and environmental friendliness are obtained.

Description

technical field

[0001] The invention belongs to the technical field of veterinary drug synthesis, and in particular relates to a preparation method of prohezidine hydrochloride. Background technique

[0002] The chemical name of chlorhexenidine hydrochloride is 1,3-bis(dichlorobenzylidene amino)guanidine hydrochloride, and the molecular formula is C 15 h 14 Cl 3 N 5 , Slightly soluble in ethanol. Chlorhexenidine hydrochloride is a new type of anticoccidial drug created by American Cyanamid, and it has a better effect on treating coccidiosis in chickens, rabbits and other animals. Experiments on animals such as chickens and rabbits have proved that the drug has the advantages of broad spectrum, high efficiency, low toxicity, small dose, and convenient administration, and has a good development prospect.

[0003] U.S. Patents US3980705, US3941825, etc. have reported the preparation method of prohexenidine hydrochloride, but the products all need to go through a series of ...

Examples

Embodiment 1

[0020] Add 12.56g (0.1mol) of 1,3 diaminoguanidine hydrochloride and 35.2g of methanol into the three-necked flask, start stirring and heat to 50°C to dissolve completely; slowly adjust the pH to 1.5 with 30% methanol hydrochloride ; Control the stirring speed at 80 rpm, and quickly drop 53.45g of p-chlorobenzaldehyde-methanol solution with a mass concentration of 55% at 50°C; after the dropwise addition, reflux for 1 hour, recover methanol by distillation, and add 70ml of deionized Make a slurry with water, filter, wash twice with water, and dry at 105°C to obtain 36.92g of pure product of prohexenidine hydrochloride, the HPLC purity is 99.3%, and the yield is 98.82% (calculated as 1,3 diaminoguanidine hydrochloride ).

Embodiment 2

[0022] Add 12.56g (0.1mol) of 1,3 diaminoguanidine hydrochloride and 37.7g of methanol into the three-neck flask, start stirring and heat to 45°C to dissolve completely; slowly adjust the pH to 2 with 35% methanol hydrochloride ; Control the stirring speed at 80 rpm, and quickly dropwise add 61.6g of p-chlorobenzaldehyde-methanol solution with a mass concentration of 50% at 45°C; after the dropwise addition, reflux for 1.5 hours, recover methanol by distillation, and add 70ml of deionized Make a slurry with water, filter, wash twice with water, and dry at 105°C to obtain 36.43g of pure product of prohexenidine hydrochloride, the HPLC purity is 99.04%, and the yield is 97.34% (calculated as 1,3 diaminoguanidine hydrochloride ).

Embodiment 3

[0024] Add 12.56g (0.1mol) of 1,3 diaminoguanidine hydrochloride and 43.96g of methanol into the three-necked flask, start stirring and heat to 55°C to dissolve completely; slowly adjust the pH to 1.8 with 40% methanol hydrochloride ; Control the stirring speed at 80 rpm, and quickly dropwise add 60.75g of p-chlorobenzaldehyde-methanol solution with a mass concentration of 53% at 55°C; after the dropwise addition, reflux for 2 hours, recover methanol by distillation, and add 70ml of deionized Make a slurry with water, filter, wash twice with water, and dry at 105°C to obtain 36.51g of pure product of prohexenidine hydrochloride, the HPLC purity is 99.14%, and the yield is 97.63% (calculated as 1,3 diaminoguanidine hydrochloride ).

technical field

[0001] The invention belongs to the technical field of veterinary drug synthesis, and in particular relates to a preparation method of prohezidine hydrochloride. Background technique

[0002] The chemical name of chlorhexenidine hydrochloride is 1,3-bis(dichlorobenzylidene amino)guanidine hydrochloride, and the molecular formula is C 15 h 14 Cl 3 N 5 , Slightly soluble in ethanol. Chlorhexenidine hydrochloride is a new type of anticoccidial drug created by American Cyanamid, and it has a better effect on treating coccidiosis in chickens, rabbits and other animals. Experiments on animals such as chickens and rabbits have proved that the drug has the advantages of broad spectrum, high efficiency, low toxicity, small dose, and convenient administration, and has a good development prospect.

[0003] U.S. Patents US3980705, US3941825, etc. have reported the preparation method of prohexenidine hydrochloride, but the products all need to go through a series of ...

Examples

Embodiment 1

[0020] Add 12.56g (0.1mol) of 1,3 diaminoguanidine hydrochloride and 35.2g of methanol into the three-necked flask, start stirring and heat to 50°C to dissolve completely; slowly adjust the pH to 1.5 with 30% methanol hydrochloride ; Control the stirring speed at 80 rpm, and quickly drop 53.45g of p-chlorobenzaldehyde-methanol solution with a mass concentration of 55% at 50°C; after the dropwise addition, reflux for 1 hour, recover methanol by distillation, and add 70ml of deionized Make a slurry with water, filter, wash twice with water, and dry at 105°C to obtain 36.92g of pure product of prohexenidine hydrochloride, the HPLC purity is 99.3%, and the yield is 98.82% (calculated as 1,3 diaminoguanidine hydrochloride ).

Embodiment 2

[0022] Add 12.56g (0.1mol) of 1,3 diaminoguanidine hydrochloride and 37.7g of methanol into the three-neck flask, start stirring and heat to 45°C to dissolve completely; slowly adjust the pH to 2 with 35% methanol hydrochloride ; Control the stirring speed at 80 rpm, and quickly dropwise add 61.6g of p-chlorobenzaldehyde-methanol solution with a mass concentration of 50% at 45°C; after the dropwise addition, reflux for 1.5 hours, recover methanol by distillation, and add 70ml of deionized Make a slurry with water, filter, wash twice with water, and dry at 105°C to obtain 36.43g of pure product of prohexenidine hydrochloride, the HPLC purity is 99.04%, and the yield is 97.34% (calculated as 1,3 diaminoguanidine hydrochloride ).

Embodiment 3

[0024] Add 12.56g (0.1mol) of 1,3 diaminoguanidine hydrochloride and 43.96g of methanol into the three-necked flask, start stirring and heat to 55°C to dissolve completely; slowly adjust the pH to 1.8 with 40% methanol hydrochloride ; Control the stirring speed at 80 rpm, and quickly dropwise add 60.75g of p-chlorobenzaldehyde-methanol solution with a mass concentration of 53% at 55°C; after the dropwise addition, reflux for 2 hours, recover methanol by distillation, and add 70ml of deionized Make a slurry with water, filter, wash twice with water, and dry at 105°C to obtain 36.51g of pure product of prohexenidine hydrochloride, the HPLC purity is 99.14%, and the yield is 97.63% (calculated as 1,3 diaminoguanidine hydrochloride ).

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