SK283686B6 - Process for purification, regeneration and recyclation of 1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2- oxapropane dichloride - Google Patents

Abstract

Disclosed is a purification process for 1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2- oxapropane dichloride (HI-6), which consists in that monohydrate HI-6 reacts with water-free methanol and is subsequently distilled, preferably in the reduced pressure, the released crystalline water is removed in the form of aseotropic mixture with organic solvent. The process for regeneration consists in that HI-6 reacts with water and ethanol producing related monohydrate, which reacts with the water-free methanol and subsequently by distillation the released crystalline water is removed in the form of aseotropic mixture with organic solvent, preferably in the reduced pressure, whilst the process is preferably repeated until the required purity of the product is reached. The said processes are preferably realised with current effect of ultra-sound waves.

Description

Technical field

The present invention relates to a process for the purification, recovery and recycling of 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride (hereinafter referred to as HI-6) of the general formula C ₁₄ H ₁₆ Cl ₂ N ₄ O ₃ .

BACKGROUND OF THE INVENTION

Mass-produced 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride (HI-6) of the structural formula ## STR3 ##

CONH _W is used as a cholinesterase reactivator (Hagedorn S, Gundell WH, J. Hoose, Jenter C .: Arzneim. Forsch. 26, 2055, 1976, Rousseaux C, Dua AK: Can. J. Physiol. Pharmacol. 67, 1183 , 1989). Since it is a relatively complicated organic molecule containing reactive functional groups, the stability of the substance is strongly dependent on purity (min. 99.7%). The shelf life of medicinal products containing this substance in the solid state is limited, even if stored for a long time at a reduced temperature of about 6 ° C. At present, the expiry date of such preparations stored at 6 ° C is 5 years. The stability of the substance is fundamentally influenced by the amount of impurities contained therein, whether they originate from incomplete purification during manufacture or if they arise from spontaneous intra- or intermolecular storage reactions. Crystalline water could also be a source of instability as HI-6 is produced and used as a monohydrate.

Purification of HI-6 is accomplished by multiple crystallizations from aqueous ethanol by adding ethanol to the aqueous solution of HI-6 until crystallization begins, with considerable losses due to the removal of impurities and HI-6 in this solvent system. similar solubility. This results in a low efficiency of the individual crystallizations and the associated economic complexity of the process. Indeed, to achieve the desired purity of the substance (99.7% HI-6), it is usually necessary to repeat the crystallization up to nine times. This complicates the manufacturing process and increases the cost of the HI-6 substance considerably.

SUMMARY OF THE INVENTION

The method of purifying 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride (HI-6) is based on 1- (2-hydroxiyiminomethylpyridinium) -3- (4-carbamoylpyridinium) monohydrate The -2-oxapropane dichloride is treated with anhydrous methanol, followed by removal of distilled crystalline water as an azeotropic mixture with an organic solvent by distillation, preferably under reduced pressure.

The method of regenerating HI-6 is by treating 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride with water and ethanol to give the corresponding monohydrate, which is treated with anhydrous methanol and subsequently The crystalline water released in the form of an azeotropic mixture with an organic solvent is preferably removed by distillation, preferably under reduced pressure.

The method of recycling HI-6, which comes mainly from expired preparations, consists in that 1- (2-hydroxyiminomethylpyridinium) -3- (4

-carbamoylpyridinium) -2-oxapropane dichloride is treated with anhydrous methanol, after cooling, the HI-6 crystals are filtered off, the mother liquor is mixed with ethanol, the water together with ethanol is distilled off preferably under reduced pressure to give an additional fraction of 1- (2-) crystals. hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride (HI-6), which is treated with water and ethanol to give the corresponding monohydrate, which is treated with anhydrous methanol, and then the azeotropic water released is removed by distillation mixtures with an organic solvent, preferably under reduced pressure, the process is preferably repeated until the desired purity of the product is achieved.

The organic solvent used is preferably ethanol.

Said HI-6 purification, recovery and recycling process is preferably carried out in conjunction with ultrasonic waves.

Accordingly, the disadvantage of the prior art is to eliminate the process of purifying ethanol by precipitation of an aqueous solution with a process whereby HI-6 is treated with an organic solvent in which it is soluble, preferably methanol. By disrupting the crystalline lattice, crystalline water is released into the solvent, thereby changing the solubility and crystallizing the HI-6. Moreover, this process crystallizes in anhydrous form, since this form of said compound is almost insoluble in organic solvents, unlike organic impurities which remain dissolved and can therefore be easily removed.

The water from the mother liquors can be removed by distillation, e.g. with ethanol, chloroform, dichloromethane, trichlorethylene, toluene, tetrahydrofuran, dimethoxyethane, isopropanol, propanol, ethylene glycol monomethyl ether, xylene, dioxane, benzene, butanol or a combination of two or more of these solvents without any other solvent to obtain 6. The choice of the solvent consists in its assessment in terms of sorption properties, in terms of properties of the azeotropic mixtures formed, in terms of cost and its environmental acceptability.

Thus, the main significance of this process lies in the very simple method of purifying HI-6, which provides high yields and can be used in the production of a highly pure substance with a substance content of about 99.9% already after the triple operation. The process of the invention can also be advantageously used for the recovery and recycling of a substance from expired formulations containing both HI-6 monohydrate and anhydrous HI-6. If ultrasonic waves are used in the above operations, pure HI-6 in micronized form is completely free of crystalline water in a single operation.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 part HI-6.H ₂ O was mixed with 30 parts methanol and heated to 60-64 ° C with stirring. A colorless substance starts to crystallize from the still hot solution. 10 parts of ethanol 99.9% are added to the mixture and 10 parts of distillate are distilled off at 2 kPa. After cooling, anhydrous HI-6 was filtered off.

Yield: 95-99%, UV spectrum identical to HI-6.H ₂ O. Melting point: not melting.

Example 2 parts of HI-6.H ₂ O are mixed with 40 parts of methanol and the mixture is heated to 60-64 ° C with stirring. A colorless substance starts to crystallize from the still hot solution. 5 parts of dry toluene are added to the mixture and 20 parts of distillate are distilled off at 20 mbar. After cooling, anhydrous HI-6 was filtered off.

Yield: 95-99%, UV spectrum identical to HI-6.H ₂ O. Melting point: not melting.

Example 3 parts of HI-6.H ₂ O (monohydrate) from the expired formulation are mixed with 40 parts of methanol and heated to 60-64 ° C. After cooling, the crystals are filtered off, the mother liquor is mixed with 10 parts of 99.9% ethanol and 20 parts of distillate are distilled off at 2 kPa. After cooling, another portion of the crystalline mass is filtered off. Recrystallization is accomplished by dissolving HI-6 in water to form a 30% solution, which is precipitated with an excess of 96% ethanol. Crystallize HI-6.H ₂ O, which is dissolved by boiling in methanol and repeat the procedure until the purity of the product meets the required criteria (determination of HI-6 content by HPLC).

Example 4 Part HI-6 is dissolved in water to give a 30% solution which is precipitated with an excess of 96% ethanol. Crystallize HI-6.H ₂ O, which is dissolved at 60-64 ° C in methanol. After addition of 10 parts of ethanol 99.9%, 20 parts of distillate are distilled off from the mixture while hot at a pressure of 2 kPa. By cooling, crystallization is complete and the crystals are filtered off. To obtain the desired product purity, repeat the procedure.

Example 5 parts of HI-6.H ₂ O are mixed with 30 parts of methanol and the mixture is heated to 60-64 ° C in an ultrasonic bath (300 W, 20 kHz) with stirring. A colorless substance starts to crystallize from the still hot solution. 10 parts of ethanol 99.9% are added to the mixture and 10 parts of distillate are distilled off at a pressure of 2 kPa. The operation is carried out in an ultrasonic bath of the given parameters. After cooling, the anhydrous micronized HI-6 was filtered off.

Yield: 95 - 99%, UV spectrum identical to HI-6.H ₂ O. Melting point: not melting.

Example 6 parts of HI-6.H ₂ O are mixed with 30 parts of methanol and the mixture is heated to 60-64 ° C with stirring. 10 parts of 99.9% ethanol are added to the mixture and the mixture is quenched to -20 ° C in an ultrasonic bath (300 W, 20 kHz). 10 parts of distillate are distilled off at a pressure of 0.5 kPa and a temperature of -15 ° C. Crystals of micronized HI-6 are filtered off. Yield: 90 to 95%, UV spectrum identical to HI-6.H ₂ O. Melting point: not melting.

Example 7 parts of HI-6.H ₂ O are mixed with 40 parts of methanol and the mixture is heated to 60-64 ° C with stirring. A colorless substance starts to crystallize from the still hot solution. 5 parts dry toluene, 5 parts dry chloroform and 2 parts ethanol 99.9% are added to the mixture, and 30 parts distillate are distilled off at 2 kPa. After cooling, anhydrous HI-6 was filtered off.

Yield: 95-99%, UV spectrum identical to HI-6.H ₂ O. Melting point: not melting.

Industrial usability

The process can be used to purify the newly synthesized HI-6 or to recover and recycle HI-6, for example, from unused expired formulations containing it.

Claims (6)

PATENT CLAIMS Process for the purification of 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride, characterized in that to 1- (2-hydroxiiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane monohydrate The dichloride is treated with anhydrous methanol, followed by removal of the crystalline water released as an azeotropic mixture with an organic solvent by distillation. Method for the regeneration of 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride, characterized in that on 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane the dichloride is treated with water and ethanol to give the corresponding monohydrate, which is treated with anhydrous methanol, followed by removal of the crystalline water released as an azeotropic mixture with an organic solvent by distillation. 3. A process for recycling 1- (2-hydroxyiminomethylpyridinium) -3- (4-carbamoylpyridinium) -2-oxapropane dichloride derived mainly from expired preparations, characterized in that 1- (2-hydroxyiminomethylpyridinium) -3- (4- carbamoylpyridinium) -2-oxapropane dichloride is treated with anhydrous methanol, after cooling, the crystals are filtered off, the mother liquor is mixed with ethanol, water and ethanol are distilled off to give an additional crop of 1- (2-hydroxyiminomethylpyridinium) -3- (4-) crystals. carbamoylpyridinium) -2-oxapropane dichloride treated with water and ethanol to give the corresponding monohydrate, treated with anhydrous methanol, followed by distillation of the liberated crystalline water as an azeotropic mixture with an organic solvent, preferably repeated until does not achieve the desired purity of the product. 4. The process of claim 10 wherein the solvent is ethanol. 5. A method according to claim 1, under reduced pressure. 6. The method of claim 1, rotating under the action of ultrasonic waves. any one of claims 1 to 3, wherein the organic process of claims 1 to 4, wherein any one of claims 1 to 5 is carried out by distillation, wherein the process is carried out