CS215095B2 - Process for preparing 2,6-dihydroxymethylpyridine bis (N-methylcarbamate) - Google Patents

Abstract

The invention relates to a process for the production of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate), which is carried out by reacting 2,6-dihydroxymethylpyridine hydrochloride with methyl isocyanate in a tertiary base, tetrahydrofuran, acetonitrile or in a halogenated hydrocarbon, in the presence of at least one equivalent, calculated as the hydrochloride, of a tertiary amine, preferably a trialkylamine or a cyclic tertiary amine, substituted on nitrogen by an alkyl group with 1 to 4 carbon atoms, the reaction mixture is evaporated and the crude product obtained is recrystallized first from water, then from a mixture of methanol or ethanol and water, prepared in a ratio of 1:1 to 1:2, this mixture being used in a four- to six-fold amount, calculated as the recrystallized product, and the obtained product is dried at a temperature of 50 to 100 °C. 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) is widely used in medicine to treat vascular diseases

Description

The invention relates to a process for the production of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate).

2.6-Dihydroxymethylpyridine-bis(N-methylcarbamate) has been widely used in medicine in recent years to treat vascular diseases (Prodectin ^R , Anginin®, Sospiten ^R , Chlesterinex ^R ).

Several methods for the production of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate) are known, all of which have in common that 2,6-dihydroxymethylpyridine is always used as the starting material.

According to Austrian Patent Specification No. 258,953, 2,6-dihydroxymethylpyridine is reacted with methylamine and phosgene. The reaction is carried out in a solvent in the presence of a tertiary amine as a catalyst, at room temperature at most.

According to Austrian Patent No. 258,954, 2,6-dihydroxymethylpyridine is reacted in a solvent with N-methylcarbamic acid chloride or with N-methylcarbamic acid ester at a temperature of 0 to 150 °C. In the first case, a tertiary base is used as a catalyst, in the second case sulfuric acid, toluenesulfonic acid or a metal alkoxide.

According to Austrian Patent No. 258,955, 2,6-dihydroxymethylpyridine is first reacted with an aryl ester of chloroformic acid in a solvent in the presence of a tertiary base as a catalyst, at a temperature of 0 to 100 °C, and the resulting 2,6-dihydroxymethylpyridine aryl ester of formic acid is then reacted with methylamine in a solvent at a temperature of 0 to 100 °C.

In the process according to Belgian Patent Specification No. 753 2.9, 2,6-dihydroxymethylpyridine is reacted in trichlorobenzene at a temperature of 80 to 90°C with N-methylcarbamic acid phenyl ester in the presence of sodium acetate.

French patent application No. 1,396,624 describes a method in which

2,6-dihydroxymethylpyridine with methyl isocyanate in a solvent and in the presence of a tertiary amine as a catalyst.

A similar process is also described in Japanese Patent No. 7 286/49. Unlike the process described in the cited French patent, water is used as the solvent and sodium hydroxide as the catalyst.

In the described methods, 2,6-dihydroxymethylpyridine bis(N-methylcarbamate) is obtained from the reaction mixture by distilling off the solvent in vacuo and recrystallization from methanol.

After evaluating all these methods, it can be clearly stated that the method according to French patent specification No. 1,396,624 seems to be the most suitable for industrial use. The advantage of this method is that 2,6-dihydroxymethyl ypridine is esterified in a single step with methyl isocyanate, which is produced on a large industrial scale and is easily available. The reaction is simple to carry out, the yield is good and the product obtained in this way contains a minimum of impurities. The use of the method according to Japanese patent specification No. 7,286/49, although it seems relatively simple, is not practical, since according to our own tests, a significant amount of by-products, especially monocarbamate, is formed during it.

According to the technical literature, the most suitable method for the production of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) on an industrial scale is therefore the following method (French patent specification δ. 1 396 624, example 1): 2,6-dihydroxymethylpyridine is dissolved in about ten times the amount of pyridine and left to stand at room temperature for 2 hours with methyl isocyanate added in a 1.5-fold excess. In order for the reaction to be complete, the mixture is then boiled for 3 hours. The pyridine is distilled off in vacuo and the residue is recrystallized from methanol. According to the cited patent specification, the product is obtained in approximately quantitative yield with a melting point of 134 °C in this way.

According to the cited French patent specification, benzene, toluene, chlorobenzene, acetonitrile, chloroform, tetrahydrofuran or pyridine are used as solvents. If necessary, it is also possible to work with a catalyst. Tertiary amines such as trimethylamine, triethylamine, N-alkylpiperidines and pyridine are suitable as catalysts.

From the knowledge of the cited literature, it may seem that, given the availability of the corresponding starting materials 2,6-dihydroxymethylpyridine and methyl isocyanate, it was easy to solve the industrial production of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) and, since the literature does not contain further references, the expert must assume that the product produced and purified in this way can be processed into tablets without further difficulties by known methods.

In contrast, considerable difficulties arise in practical implementation. In each of the known processes, one starting material is 2,6-dihydroxymethylpyridine, although the methods for industrial production known from the literature (see Japanese Patent No. 14,222/43) yield the hydrochloride of this compound. Two methods are known for releasing the base from the hydrochloride: the base can be released either by means of an ion exchange resin or by means of a concentrated alkali metal hydroxide solution. According to Japanese Patent No. 14,222/43, the base is released by means of an alkali metal hydroxide and the ion exchange resin method is not feasible. The base is released by adding a concentrated sodium hydroxide solution after the concentrated 2,6-dihydroxymethylpyridine hydrochloride solution has been clarified and cooled. According to the description, a large part of the base is separated out and can be filtered off. The portion that remains in the aqueous solution due to the good solubility of the base in water can be obtained by extraction with ethyl acetate. The second product obtained in this way can only be used further after recrystallization from methanol. According to the patent specification, the yield is 90%. Although the yield of this method is good, its industrial application is not easy. A total of ten different technological processes are required to release the base and separate it. Filtration of a highly concentrated solution also causes difficulties and reduces the amount of base obtained (in the interest of a good yield, it must be extracted several times, yet the 90% yield stated in the patent specification cannot be achieved in reproduction experiments).

During processing, drying the base filtered off from the aqueous solution presents difficulties because it is decomposable. However, any residual water content remaining is decomposed by the isocyanate used as a reactant (Houben-Weyl, l'ethoden der organisehen Chemie, 8, 131).

Further difficulties arise in the production of tablets from the active substance 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) obtained in the described manner. The mentioned patent documents describe only the production of the active substance, the preparation of medicinal preparations is not mentioned. The active substance obtained according to the mentioned patent documents and recrystallized from methanol is very loose, its particle size is uneven; the powdery substance has a low bulk density and cannot be easily tableted. In these cases, it is usually wet granulated, the active substance is hoinogenized with fillers and adhesion-enhancing agents, moistened and kneaded. The pasty mass is then granulated and dried. The dried material is regranulated, mixed with excipients required for tableting and finally tableted.

When the product recrystallized from methanol according to the cited patents is moistened for granulation, a strong heat development occurs during the preparation of the mass, whereby the material is cementitiously sintered, which prevents further processing. Sintering can be prevented by using a larger than usual amount of wetting agent, but new difficulties arise in the preparation and drying of the granulate. Tablets with suitable disintegration properties can therefore only be produced in this way by time-consuming and expensive processes.

When investigating this abnormal behavior of the active substance, it has now been found that 2,6-dihydroxymethylpyridine-bis(N^methylcarbamate) can bind two moles of water in the form of crystal water. This was proven by thermogravimetric measurements, but it is also indicated by the strong development of tppla when kneading the active substance with water. The capture of crystal water also causes difficulties arising during tableting, appreciably strong development of heat during kneading and cement-like sintering, and poor disintegration properties of the finished tablets.

It is known that one of the conditions for good tabletability and suitable disintegration properties of tablets is the amount of water absorbed by the starch used as an additive, which can be adjusted by appropriate drying of the granulate. The necessary moisture content (based on starch 15 to 20%) cannot be obtained in this case by simple drying, since during drying the water adsorbed by the starch escapes faster than the water of crystallisation of the active substance. Therefore, the disintegration properties of the tablets are poor.

According to our own tests, a more favorable product from the point of view of tableting cannot be obtained in a way different from the literature data, i.e. by recrystallization from water.

In experiments carried out in the preparation of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) from 2,6-dihydroxymethylpyridine hydrochloride and methyl isocyanate, it has now been found that it is not necessary to release 2,6-dihydroxymethylpyridine from its acid addition salt and to isolate the base when a tertiary base is used as a catalyst in a greater than molar amount. In this way the reaction proceeds more rapidly and 2,6-dihydroxymethylpyridine hydrochloride is also suitable for further reaction. It has further been found that by recrystallizing crude 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) from a four to fivefold amount of a mixture prepared in a ratio of 1 : 1 to 1 : 2 of C, - alcohol and water and drying the product obtained at 50 to 100 ° C, a material is obtained which, after mixing with excipients, can be directly tableted without granulation. This finding is surprising, since neither during crystallization from alcohol nor during crystallization from an alcohol-water mixture, the composition of which differs from the composition mentioned above, it was possible to obtain a product suitable for tableting.

The essence of the method for producing 2,6-dihydroxymethylpyridine-bis(N-methylcarbemate) according to the invention consists in reacting 2,6-dihydroxymethylpyridine hydrochloride with methyl isocyanate in a tertiary base, tetrahydrofuran, acetonitrile or in a halogenated hydrocarbon, in the presence of at least one equivalent, calculated as hydrochloride, of a tertiary amine, preferably a trialkylamine or a cyclic tertiary amine, substituted on nitrogen by an alkyl group with 1 to 4 carbon atoms, the reaction mixture is evaporated and the obtained crude product is recrystallized first from water, then from a mixture prepared in a ratio of 1:1 to 1:2 of methanol or ethanol and water, this mixture being used in a four to sixfold amount, calculated as the product to be recrystallized, and the obtained product is dried at a temperature of 50 to 100 °C.

Preferably, crude 2,6-dihydroxymethylpyridine hydrochloride, obtained by hydrolysis of 2,6-diacetoxymethylpyridine and precipitated as hydrochloride, is used as 2,6-dihydroxymethylpyridine hydrochloride, and when recrystallized from a mixture of alcohol and water, a four to six-fold amount of 50% aqueous methanol is used.

The available literature does not provide a clear basis for the expert. According to the general literature of organic chemistry (Houben-Weyl, l'ethoden der organischen Chemie,

8, 129) the reaction between alcohols and isocyanates depends strongly on the catalytic effect. Acidic reacting substances, for example hydrochloric acid, reduce the reaction rate, but at the same time, known acid reacting substances, such as aluminum chloride or zinc chloride, are used as catalysts. Basic reacting substances, for example tertiary amines, trialkylamines, are mentioned as catalysts, but the effect of their acid addition salts, for example hydrochloride, is not known. Based on the organic chemistry literature and the cited patent documents, it must be accepted that 2,6-dihydroxymethylpyridine hydrochloride cannot react with methyl isocyanate and therefore the base must be isolated from the produced acid salt by a very inconvenient procedure, with unclear losses (see Japanese patent document No. 14,223). Therefore, it was not possible to find any information in any professional literature that the tertiary amine mentioned as a catalyst or any of its acid addition salts could have an effect on the reaction of 2,6-dihydroxymethylpyridine hydrochloride with methyl isocyanate.

The process according to the invention also brings other advantages. It has been found that the tertiary base hydrochloride present in a molar amount favorably affects the solubility of the resulting 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) in water and thus the by-products formed during the reaction (2,6-dihydroxymethylpyridine monocarbamate with decomposition products) can be removed from the concentrated aqueous solution by a single recrystallization.

According to one particularly advantageous embodiment of the process according to the invention, the starting material is not pure 2,6-dihydroxymethylpyridine hydrochloride, but a crude product obtained according to Hungarian Patent Specification No. 167,834, Example 10, which also contains sodium chloride and pyridine derivatives containing hydroxyl groups. In this case too, the beneficial effect of the tertiary base hydrochloride can be observed, i.e., by a single recrystallization from water, not only the by-products formed during the reaction with methyl isocyanate but also the impurities introduced with 2,6-dihydroxymethylpyridine hydrochloride or their reaction products with methyl isocyanate can be removed.

The product obtained by recrystallization from water meets the quality requirements for a pharmacologically active substance, but it can be tableted with the difficulties already described.

2,6-Dihydroxymethylpyridine bis(N-methylcarbamate) exhibits solvent polymorphism in crystallographic and X-ray analytical tests.

One polymorphic modification (hereinafter referred to as alpha modification) is obtained by crystallization from water. It crystallizes in longitudinally elongated plates of uneven dimensions, its crystal system is monoclinic. Optically, it is characterized by its low refraction and high birefringence. The extinction angle is 16 to 19°. During drying, the polarization-optical properties of the substance change significantly. The alpha modification is formed when crystals precipitated from any solvent, i.e. other crystal modifications, are additionally treated with water.

Another crystal modification is formed when it is crystallized from alcohol. The crystals also belong to the monoclinic crystal system, but they look different from the alpha modification. They are elongated, fibrous and sometimes form a bundle. Its optical properties are also different. First of all, the extinction angle is very large: 28 to 30°. Solvation also occurs here, but the solvate shell is very strongly bound. The optical properties do not change when dried. This crystal modification is referred to as the beta modification.

If 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) is crystallized, for example, from a mixture prepared from C, - alcohol with water in a ratio of 1:1, another crystal modification is obtained (hereinafter referred to as the gamma modification), the morphological and optical properties of the gamma modification are different from those of the alpha and beta modifications. The crystal system is 2/m holohedral, the extinction angle is 18 to 19°. The refractive index n _alpha is 1.525, n _gamB = 1.442, the birefringence is therefore large.

In appearance, they are small, dense, non-agglomerated, clear individual crystals, having a dimensional ratio of 2:1 and are free of inclusions and mother liquor. The crystals are bounded by a small number of shaped surfaces, their size is 0.1 to 0.3 mm. The densely stacked individual crystals fill the space well. If a product consisting of crystals of the gamma modification is dried, the resulting garnej modification is formed. It can be directly tableted. The existence of the new gamma ₂ modification is proven by the fact that the optical properties of the product differ sharply from the properties of the remaining product. Since water is removed during drying, a change occurs in the structure of the substance. It becomes trigonally symmetrical. When observed with a magnifying glass, mosaic-like, differently oriented groups of crystals can be observed among the previous individual crystals. The refractive indices are close to each other: the refractive index in the longitudinal direction ( ⁿ alpha^ ^is '•'similar to the other two refractive indices ^ ⁿ beta ^and gamma^' ^dvo 3 ^loni 3® much smaller than in the modifications already described. Under the microscope, the product is practically opaque, spontaneous polarization occurs. The gamma ₂ modification cannot be produced by heating the alpha or beta modification.

This finding is surprising, since there is no mention in the literature of crystal polymorphism of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) and nowhere is it stated that this polymorphism is of decisive importance for tabletability.

Table 1 shows the data of various crystal modifications of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate).

The results of X-ray diffraction measurements are shown in Table 2.

The thermogravimetric curves are shown in the attached drawings in Fig. 1, 2, 3 and the X-ray diffractograms in Fig. 4, 5, 6 and 7.

The individual images represent:

Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Thermogravimetric curves of crystal modifications alpha and beta, thermogravimetric curve of crystal modification gamma, thermogravimetric curve of crystal modification gamma ₂ , X-ray diffractogram of crystal modification alpha, X-ray diffractogram of crystal modification beta, X-ray diffractogram of crystal modification gamma, X-ray diffractogram of crystal modification gan^·

Crystal modifications

alpha beta gamma, gamma ₂ Production crystallization from water or action by water crystallization from alcohol crystallization from a mixture of water and alcohol of a specified ratio drying 1 at 50-100 °C Crystals lengthwise- bundle, fibrous, clear, individual isometric or (morphology- n plates, internal brush-like or prism, size a little bit longitudinally through- ky) spines labile, outline indeterminate needle-shaped, size varies greatly uniform grain, grain size 0.1 mm drawn crystals, outline and size as 1 Crystal system monoclinic monoclinic monoclinic, (holohedral class 2/m) triangular Optical properties extinction angle ^alpha ⁼ = 16 - 19° ^c alpha = 28 - 30° = 18 - 19° variably oblique Optical character negative negative negative transparent only at the edges, opaque Refractive index alpha ^{= 1} >47 gamma = ¹ > ⁵⁹ alpha ^{= 1.46} gamma = ^1.6 ° alpha ^{= 1.442} gamma ^{= 1.525} alpha = ^1.550 gamma ^{= 1.545} Value Δ= -0.11 to -0.12 Δ = -0.13 to -0.14 Δ= -0.083 Δ= -0.005 birefringence (large) (large) (medium-sized) (very small) DTK I. 78.5 °C 4.4% II. 102.5 °C 8.0% 12.4% 62°C 11% I. 86 °C 6% II. 102 °C 7% III. 114 °C 4.8% 19.8% practically stable up to melting point

Table 2

X-ray diffraction values

No. ^d hkl ^(nm) crystal modifications note alpha beta gamma^ gamma ₂ 1 1.18- 1.16 - 100 - 90 2 0.872 90 - 100 - 3 0.712 - 100 - - 4 0.706 - - - 100 5 0.630 50 - 40 - 6 0.590 12 15 35 - 7 0.571 - 0.560 15 50 30 85 basic structure 8 0.497 - 0.462 90 90 80 55 basic structure 9 0.445 - 0.458 - 100 40 100 10 0.418 - - - 40 11 0.395 45 60 60 - ,2 0.385 - 80 - 55 13 0.373 30 40 70 - 14 0.358 - 25 - .00 15 0.338 90 - 80 - 16 0.296 - - - 15

The method for producing directly tablettable 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) consists in reacting 2,6-dihydroxymethylpyridine hydrochloride in an organic solvent, in the presence of at least an equivalent amount of tertiary base, calculated as hydrochloride, with methyl isocyanate, the reaction mixture is evaporated and the crude product obtained is recrystallized from water and then from a mixture prepared from C, - alcohol and water in a ratio of 1: 1 to 1: 2, and the obtained 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) is dried at 50 to 100 °C.

According to the invention, for example, 2,6-dihydroxymethylpyridine hydrochloride is mixed with an organic solvent, a tertiary base is added in at least an equivalent amount, based on the hydrochloride, and then methyl isocyanate in a twofold molar excess. The reaction temperature of the mixture is initially expediently as high as ambient temperature, then the mixture is heated to boiling. After the reaction is complete, the volatile components are evaporated. The dry residue is recrystallized from water and the recrystallization is repeated from a mixture prepared from a C^-C-j alcohol and water in a ratio of 1:1 to 1:2. The obtained

2,6-dihydroxymethylpyridine bis(N-methylcarbamate) is present in a crystal modification of gamsj that has not been described in the literature.

Pure or crude 2,6-dihydroxymethylpyridine hydrochloride may be used. It is possible to use hydrochloride containing 20% organic or inorganic impurities.

As organic solvents, tertiary bases can be used, for example trialkylamine, preferably triethylamine, and also tetrahydrofuran, acetonitrile, chlorinated hydrocarbons, for example chloroform or carbon tetrachloride, or mixtures of the solvents mentioned. The amount of organic solvent used is not critical. However, if the tertiary amine used as reagent is also used as solvent, a larger than equivalent amount is naturally required.

Methyl isocyanate is expediently used in a larger amount than the equivalent amount, preferably in a two to fourfold excess.

The reaction can be carried out at a temperature of 0°C up to the boiling point of the reaction mixture./It is expedient to start at a lower temperature, about 0°C to ambient temperature, and as the reaction progresses, the reaction mixture is slowly heated up to the boiling point of the reaction mixture.

The reaction time depends on the reaction temperature. Typically, the reaction time is one to ten hours.

When recrystallizing from water, the amount of water is chosen so that the solubility of the substance does not cause any unnecessary losses (about two to three times the amount of water). The amount of water may also depend on the purity of the starting substance. If a heavily contaminated starting substance is used, it is advisable to recrystallize the final product from a larger amount of water.

To produce the gamma ₁ modification of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) according to the invention, a mixture of C, - alcohol and water in a ratio of 1:1 to 1:2 is used. Methanol, ethanol, propanol, but also mixtures thereof can be used as alcohol. Usually, four to five times the amount of aqueous alcohol is used, based on the amount of the substance to be recrystallized.

The directly tablettable modification gammag is prepared by heating the modification gamma^. It is dried expediently at a temperature of 50 to 100°C until constant weight.

The advantages of the method according to the invention can be summarized as follows:

- the yield of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate), based on 2,6-dihydroxy methylpyridine hydrochloride, is improved by 15 to 20%;

- the resulting tertiary base hydrochloride creates exceptionally favorable crystallization conditions; practically, a product meeting the requirements of pharmacological purity can be obtained after just one crystallization from water; ,

- by recrystallization from a water-alcohol mixture of a given composition and drying, a directly tablettable crystalline modification, the gamag modification, can be produced. This is of great importance from a production-technical and, above all, economic point of view, since the preparations are pharmacologically important and are produced in considerable quantities.

The invention is explained in more detail in the following examples.

The purity of the substances prepared according to the examples was checked by thin-layer chromatography and UE-spectrophotometry. Thin-layer chromatography was carried out on activated silica gel layers with a mixture prepared from ethyl acetate, chloroform and ethanol in the ratio 6:2:1, developed with iodine vapor. The R^ value of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) is 0.4. UF-spectrophotometric measurements were carried out in ethanolic solution at 165 to 175/263 nm (Rj ^ _ffl ).

The degree of purity of the produced substance, its active ingredient content, was determined by titration with a 0.05 N solution of perchloric acid to crystal violet.

For crystallomorphological and crystallooptical measurements, important for tabletability, a polarizing microscope (Leitz: "Panphot" and Zeiss: "Polmi A" was used, for imaging DTA and DTO curves (Fig. 1, 2, 3) a differential thermogravimeter (according to Erdey-Paul) and for imaging X-ray diffractograms (Fig. 4, 5, 6, 7) an X-ray diffractometer ("Kristalloflex 4" by Siemens) was used.

Example

a) 15.7 g (0.1 M) of 2,6-dihydroxymethylpyridine hydrochloride are suspended in 176 ml of acetonitrile and then 20.8 ml (0.15 M) of triethylamine are added. Then 13 ml (0.22 M) of methyl isocyanate are added dropwise to the reaction mixture at 20 to 25 °C. The reaction mixture is stirred at 20 to 30 °C for one hour and then boiled for 3 hours. The solvent is then distilled off under reduced pressure. 35 to 40 g of a gray, crystalline mass, a mixture of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate) and triethylamine hydrochloride, remain. The product is dissolved in 80 ml of boiling water, the solution is clarified by boiling with 2 g of activated carbon for 30 minutes and then filtered. The crystalline slurry is then stirred at 0 to 5 °C for three hours and then filtered. The filtered substance is dried at 50 to 60 °C.

23.3 g of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate) are obtained (94.4% of theoretical yield). The product melts at .34 to 135°C, the content of pure substance, determined by UF-spectrophotometry, is 99.8%. The product is uniform according to thin layer chromatography.

b) 23.3 g of the product obtained in the described method are dissolved in a mixture prepared from 46.6 ml of water and 46.6 ml of methanol while boiling the mixture. When everything is dissolved, the solution is allowed to cool slowly with stirring without external cooling. Crystallization occurs at 48 to 50 °C. When the temperature of the mixture drops below 35 °C, it is cooled by external cooling to 0 to 5 °C and the mixture is left to stand at this temperature for about 8 hours. The product is then filtered and dried at 50 to ,00 °C. 22.65 g of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) is obtained, which meets the requirements for pharmacological quality.

The yield of recrystallization is 95.7%. The product obtained is a crystalline modification of gamma^, suitable for direct tableting. The content of pure substance, determined by UF-spectrophotometry, is 99.9%.

Example 2

The procedure is as described in Example 1, except that tetrahydrofuran is used as the solvent instead of acetonitrile. The mixture is boiled for 5 to 6 hours instead of 3 hours. The mixture is worked up and crystallized as described in Example 1. 23.15 g (93.7% of theory) of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate) are obtained, which melts at 134 to 136 °C. The active substance content, determined by UF spectrophotometry, is 99.7%. The product is uniform according to thin layer chromatography and can be directly tableted.

Example 3 g of crude 2,6-dihydroxymethylpyridine hydrochloride (produced according to Hungarian Patent Specification No. 167,834, purity 91.7) is suspended in .60 ml of acetonitrile. 20 ml of triethylamine and 20 ml of methyl isocyanate are added dropwise to the suspension. The reaction mixture is stirred for one hour at 20-30 °C, then heated to boiling within one hour and boiled for three hours. It is then evaporated to dryness under reduced pressure. The 38 g of product obtained is recrystallized from 76 ml of water as described in Example 1.

24.4 g of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate) is obtained, which melts at

134 to 136°C. The content of pure substance, determined by UF-spectrophotometry, is 100%. With regard to the purity of the starting compound, the yield is 92.2% of theory.

The product is recrystallized from methanol-water as described in Example 1b) and then dried. A crystalline modification suitable for direct tableting is also obtained with a similar yield. The quality is the same as that of the product crystallized from water.

Example 4

5.25 g (0.03 M) of 2,6-alpha-hydroxymethylpyridine hydrochloride are dissolved in 25 ml of pyridine and reacted with 5.3 ml (0.09 M) of methyl isocyanate as described in Example 1. The reaction mixture is worked up as described in Example 1. 7.65 g (94.0% of theoretical yield) are obtained.

2,6-dihydroxymethylpyridine-bis(N-methylcarbamate), which melts at 135 to 137 °C. The product has a 99% active substance content, determined by UF-spectrophotometry, and is uniform according to thin layer chromatography.

Example 5

The procedure described in Example 1 is followed, except that 200 ml of carbon tetrachloride is used as the solvent instead of acetonitrile. 23.5 g of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate) is obtained, the physical constants and degree of purity of which are identical to those of the product obtained according to Example 1.

Example 6

The procedure described in Example 1 was followed, except that instead of triethylamine, 14.8 ml (0.12 mol) of N-methylpiperidine was used as the tertiary amine. The mixture was worked up and crystallized as described in Example 1. 24 g (97%) of 2,6-dihydroxymethylpyridine-bis(N-methylcarbamate) with a melting point of 134-136 °C was obtained.

The active substance content, determined by UF spectrometry, was 99.6%. The product was uniform according to thin layer chromatography.

Example7

The procedure was as described in Example 1, except that instead of triethylamine, 24.4 ml (0.14 mol) of diisopropylethylamine was used as the tertiary amine. The mixture was worked up and crystallized as described in Example 1. 23.65 g (95.7%) of 2,6-dihydroxymethylpyridine bis(N-methylcarbamate) with a melting point of 133.5 to 137 °C was obtained. The active substance content, determined by UF spectrometry, was 99.5%. The product was uniform according to thin layer chromatography.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of 2,6-dihydroxymethylpyridine bis (N-methylcarbamate) comprising reacting 2,6-dihydroxymethylpyridine hydrochloride with methyl isocyanate in a tertiary base, tetrahydrofuran, acetonitrile or a halogenated hydrocarbon, in the presence of at least one equivalent, calculated on hydrochloride, a tertiary amine, preferably a trialkylamine or a cyclic tertiary amine substituted on the nitrogen with an alkyl group and 1 to 4 carbon atoms, the reaction mixture is evaporated and the crude product obtained is recrystallized first from water, then from 1: 1 to 1 1: 2 methanol or ethanol and water are used in quantities of four to six times, based on the recrystallized product, and the product obtained is dried at a temperature of 50 to 100 ° C. 2. A process according to claim 1 for the preparation of 2,6-dihydroxymethylpyridine bis (N-methylcarbamate), characterized in that the crude 2,6-dihydroxymethylpyridine hydrochloride used is crude 2,6-dihydroxymethylpyridine hydrochloride obtained by hydrolysis of 2,6-diacetoxymethylpyridine and precipitated as the hydrochloride. 3. The process of claim 1, wherein four to six times 50% aqueous methanol is used in the recrystallization from an alcohol / water mixture. 6 sheets of drawings