HU191618B - Process for production of 2,6-bis/hydroxi-methil/piridin - Google Patents

Abstract

2,6-Bis-(hydroxymethyl) -pyridine is prepd. by hydrolysis of mixts. contg. at least 50 wt.% 2,6-bis(chloromethyl) -pyridine with other halogenated pyridine derivs., pref. 2-(chloromethyl) -6-(dichloro-methyl)-pyridine and 2-methyl-6-(dichloromethyl) -pyridine in the 4-6 fold amt. of water based on the dry amt. of the mixt. with not more than 1.2 fold wt. of sodium-hydrogen-carbonate, in the presence of a 0.1-0.1 fold amt. of an inert organic solvent forming an azeotropic mixt. with water boiling above 80 deg.C. The reaction mixt. is boiled, extracted with an inert, water immiscible organic solvent and concentrated opt. before or after neutralization with an amt. of HCl equiv. to the NaHCO3 and/or Na2CO3 content of the reaction mixt. 2,6-Bis-(hydroxymethyl) -pyridine is sepd. from the mixt. now contg. only sodium-chloride as inorganic salt either as pure cpd. or as a mixt. with sodium-chloride. Pure 2,6-bis-(hydroxymethyl) -pyridine can be obtd. from the mixt. with NaCl by forming a concn. aq. sodium-chloride soln., and/or the mother liquor can be returned as diluent to the beginning of the process.

Description

The present invention relates to a novel process for the preparation of 2,6-bis (hydroxymethyl) pyridine starting from a mixture containing 2,6-bis (chloromethyl) pyridine. The target compound is an important intermediate in the preparation of 2,6-bis (methylcarbamoyloxymethyl) pyridine (Prodeetin) for the treatment of arteriosclerosis.

Several processes are known for the preparation of 2,6-bis (hydroxymethyl) pyridine (hereinafter BHMP) starting from 2,6-bis (chloromethyl) pyridine (hereinafter BCP). These include, for example, the methods described in Hungarian Patent Nos. 167,834 and 170,496, and the solution disclosed in Japanese Patent Application Publication No. 103 983/78, which is hereby incorporated by reference.

Using the methods described in the cited Hungarian patents, starting from BCP of different purity, they can produce BHMP economically on an industrial scale. However, the process has the disadvantage that BHMP is obtained from BCP via an intermediate compound, 2,6-bis (acetoxymethyl) pyridine. Although this compound is not isolated, its production requires expensive auxiliaries, the regeneration of which and the utilization of the resulting mother liquors are economically important and difficult to solve, especially from an environmental point of view.

In this respect, the process described in Japanese Patent Application Publication No. 31034/80 appears to be advantageous. According to this, pure BCP is hydrolyzed to BHMP in water in the presence of alkali metal carbonates or bicarbonates in near theoretical yields.

One-step aqueous-acid hydrolysis is also disclosed in Japanese Patent Laid-open Nos. 14 020/65 and 77 334/75, but basic hydrolysis commonly used for aromatic and heterocyclic chloromethyl compounds can be used to prepare the target compound [Houben-Weyl: Methoden derorganischen Chenüe, IV., 5/4. 134 (1960). However, these methods were unsuitable for industrial applications due to long reaction times, side reactions or corrosive media such as aqueous hydrochloric acid. This is evidenced by the data of Comparative Example 2 of Japanese Patent Application Publication No. 31 034/80.

The process described in Japanese Patent Application Laid-Open Publication No. 31 034/80 is simple, the yields given are satisfactory, but their industrial realization is difficult according to the technology disclosed. The process described and described in detail in the examples is based on pure BCP. It is prepared by chlorination of 2,6-dimethylpyridine. However, the chlorination reaction does not produce a uniform product, but leads to the formation of chlorinated derivatives to varying degrees (see, for example, U.S. Patent No. 174,824). Although pure BCP can be isolated from the resulting mixture, for example by the method described in U.S. Patent No. 179,849, the isolation will in any case result in additional work and loss of material. This is all the more disadvantageous because the chlorinated pyridine derivatives are very irritating and it is advisable to minimize their operations or, if possible, to purify them.

A further major disadvantage of the process disclosed in Japanese Patent Application Publication No. 31 034/80 is the separation of BHMP. BHMP is isolated by evaporation of the reaction mixture to dryness and extraction due to the good water solubility of BHMP. According to Example 1 of the application, BCP can be hydrolyzed to BHMP by almost quantitative, optimally 96-98% conversion by gas chromatography, but only about 65% of the resulting BHMP can be recovered by processing the resulting reaction mixture. The remaining 35%, taking into account the BHMP's heat sensitivity, is lost. This is confirmed by our own experiments, which show that the aqueous solution of BHMP decomposes on evaporation, and even under certain conditions, at temperatures above 130-140 ° C, the decomposition may increase to explosion. Difficult to extract BI-MP from. Also, the cxtraction must be performed from a mixture of BHMP and an inorganic salt in a ratio of nearly 1: 1. Thus, the industrial realization of these processes is difficult and impractical because of the yields of up to 65% due to degradation and explosion during evaporation and problems resulting from extraction and their combined effect. Yields further deteriorate when calculated, as realistically, for the BCP content of the starting mixture containing chlorinated red din derivatives.

In summary, reviewing the known procedures, it has been found that in the literature so far, BHMP has been produced in one step only from pure BCP in an industrially difficult manner with a loss of about 35%. Up to now, BHMP has been obtained from blends containing BCP, i.e. pure BCP, by two-step synthesis. The cost-effectiveness of the two-step process is unsatisfactory and serious environmental problems need to be addressed in its industrial implementation.

The present invention is based on the discovery that, under appropriate conditions, mixtures containing at least 50% by weight of BCP can be hydrolyzed with aqueous sodium n-bicarbonate solution to BHMP and the hydrolyzate, preferably after neutralization with hydrochloric acid, is substantially pure or optionally low in sodium. mixed with chloride, a very good yield can be obtained.

According to the present invention, at least 50% by weight of 2,6-bis (1-dichloromethyl) pyridine and optionally other halogenated pyridine derivatives, in particular 2-methyl-6- (dichloromethyl) pyridine (DCP) are used. ) and 2- (chloromethyl) -6- (dichloromethyl) pyridine (TCP) with a water content of 4-6 times the dry weight of the mixture, sodium bicarbonate up to 1.2 times and 0.01 The mixture is boiled with an inorganic organic solvent which is water-miscible and water-miscible and has a boiling point higher than 80 ° C, is extracted with a water-immiscible inorganic solvent and, optionally, sodium bicarbonate. and / or before or after neutralization of the sodium carbonate content with an equivalent amount of aqueous saline solution - concentrate the 2,6-bis (hydroxyethylethyl) pyridine from the mixture containing only sodium chloride as the inorganic salt. or pure and mixed with sodium chloride and optionally recovering the pure 2,6bis (hydroxymethyl) pyridine from the sodium chloride mixture to form a saturated aqueous solution and / or recycling the mother liquor, if desired, at the beginning of the process.

Sodium bicarbonate, preferably 0.9 to 1.2 times the dry weight of the mixture to be hydrolyzed, is preferably used in the process of the invention.

The inert organic solvent which is miscible with water and forms an azeotropic mixture is preferably propanol or butanol.

The inorganic water-immiscible inorganic organic extractant is preferably chloroform.

Preferably, the solution is concentrated to 35-65% of its original volume before or after neutralization.

If the mixture is to be neutralized after hydrolysis, the amount of sodium bicarbonate and sodium carbonate remaining in the solution after hydrolysis is determined by analytical methods and then neutralized with an equivalent amount of aqueous hydrochloric acid; preferably a 1: 1 dilute aqueous hydrochloric acid solution is used. The resulting mixture will have a pH of 7-7.5.

According to the present invention, BHMP can advantageously be obtained from the BCP hydrolyzate in two ways. In one method, the optionally neutralized and chloroform-extracted hydrolyzate is evaporated, preferably to about 40% of its original volume, the sodium chloride precipitated at a temperature above 60 ° C and a 1 / 20th volume of the filtrate to the still warm solution. water is added and then pure BHMP which is excellent for cooling is removed.

Alternatively, the hydrolyzate, optionally neutralized and extracted with chloroform, preferably to about 50% by volume, is evaporated, the solution is cooled to below 20 ° C and the activating sodium chloride-mixed BHMP is filtered off.

In the first case, at least 80% of the theoretically generated BHMP is obtained in a purity of 93-99%. In the second case, 85-95% of the theoretically calculated BHMP is obtained, mixed with 10-25% sodium chloride.

In both cases, further evaporation of the mother liquors using either of the two recovery methods mentioned above can be used to isolate further BHMPs of the same quality as the previously isolated product. Thus, BHMP, in a total yield of 90% to 95% based on the BCP content of the chlorinated pyridine derivative, can be clearly isolated.

Pure BHMP can be sold on its own or as an intermediate in the manufacture of 2,6-bis (hydroxymethyl) -pyridine bis (N-methylcarbamate), while BHMP containing sodium chloride can be directly used without further purification for the synthesis of said therapeutic compound. course. If necessary, the BHMP may be purified by dissolving 3 to 6 times the amount of BHMP in sodium chloride mixed with boiling water, if necessary by purification and / or filtration and cooling.

The recognition underlying the present invention is surprising considering the prior art. Indeed, it has been expected in the literature that, due to their behavior similar to benzyl halides, derivatives of haloalkylpyridines will be more readily hydrolyzed by a single carbon atom. Namely, in the literature, for the -CH ₂ Cl group, the -CHCl 1 group hydrolyzes one order faster to the corresponding aldehyde. For example, in an aqueous solution of potassium carbonate, but in some cases in pure water, conversion to the aldehyde occurs at room temperature or reflux jllonbcn-WcykMethoden dérorganchen Chemie, 5/4, (1960), 691; and 7/1 (1954) 211-214]. If, therefore, the hydrolysis of the DCP, BCP and TCP mixture of is carried out as detailed above manner, it would be expected that the first DCP and Groups TCP -C11C1 ₂ is hydrolyzed to the aldehyde, and then to or at most slightly parallel happen _-CH2 C1 hydrolysis of group I to alcohol. If this were the case, the aldehyde derivatives formed more rapidly during the second but essentially the reaction of the main product would have the potential for a number of side reactions under alkaline conditions. Thus, they could be oxidized to acids, dehydrated to unsaturated compounds, and acids could be formed by the Canizzaro reaction. Thus, it would be expected from the literature to produce, besides BHMP, a reaction mixture containing an optionally equivalent amount of 2-methyl-6-formylpyridine and 2-hydroxymethyl-o-formylpyrldine and their degradation products. It will be apparent to those skilled in the art that separating such a mixture and recovering the BHMP of the main product from it at 10-50% contamination is not economically feasible. However, such a mixture of uncontrolled composition cannot be used without purification to produce a final product marketed as a medicament.

The previously cited Japanese Patent Application Publication No. 31 034/80 also suggests that only pure BCP can be produced by hydrolysis of BHMP, since neither the description nor the examples indicate that the product mixture can be used as starting material. .

In contrast, it has been found that by hydrolyzing a mixture of chlorinated pyridine derivatives according to the present invention, BCP is virtually completely hydrolyzed to BHMP, while impurities and non-hydrolyzed chlorinated pyridine derivatives can be completely removed by extraction.

It is further appreciated that BHMP can be isolated as an inorganic salt from a solution containing only sodium chloride, depending on the composition of the solution, completely floated or with little (5 to 25% by weight) sodium chloride in Levert form. In contrast, Japanese Patent Application Laid-Open Publication No. 31 034/80 states that BHMP is obtained from sodium bicarbonate or sodium carbonate, and that the specification does not disclose any information on the beneficial behavior of a mixture of BHMP and sodium chloride. could have inferred.

In terms of industrial feasibility3

The use of an organic solvent which is immiscible with water and has a boiling point higher than 80 ° C with water is only a significant discovery. It has been found that halogenated pyridine derivatives are highly sublimated and blocked in the refrigerator, which can lead to dangerous overpressure in the apparatus. The solvents used in the process of the invention continuously dissolve these substances deposited by sublimation and thus secure the reaction. Japanese Patent Application Laid-Open Publication No. 31 034/80 mentions that the aqueous reaction medium may optionally contain methanol, that is, a chemically similar solvent to that used by us, but that methanol serves to homogenize the reaction mixture and is not suitable for sublimation. to trip; does not form an azeotropic mixture with water. The use of larger amounts of methanol results in the formation of methyl ether.

The main advantages of the process according to the invention compared to the known methods are as follows:

1. The preparation of pure BHMP does not require the production of pure BCP, but may also be used as a starting material for the mixture of 2,6-dimethylpyridine chlorinated residues after removal of the underchlorinated products. This is very advantageous from the point of view of economy and mainly of occupational safety.

2. Non-hydrolyzed and other impure pyridine derivatives can be recovered by extraction and then converted into partially halogenated or fully reduced pyridine derivatives by known methods and thus reused as starting materials. This option also serves environmental purposes by avoiding the destruction of highly irritating and dangerous halogenated pyridine derivatives.

3. The recovery of BHMP from the hydrolyzate was accomplished by large-scale industrial processes, with very good partial evaporation and filtration. This avoids the risk of explosive evaporation to dryness and makes it extremely difficult for large quantities of materials to achieve perfect extraction.

Due to the above-listed advantages, the process of the present invention can hydrolyze BCP-containing mixtures to BHMP in a yield greater than 90% of BCP, under conditions that eliminate the hazards of previous processes, occupational safety and environmental concerns.

Hydrolysis of BCP to BHMP was followed by gas chromatography. Measurements were conveniently performed on an OW 101 (Applied Science Laboratories, Inc., USA) column at 130 ° C, and the reaction was considered complete when the total amount of BCP and 2-chloromethyl-6-hydroxymethylpyridine formed temporarily was 2%. less than 98% of the BCP was hydrolyzed.

The amounts of sodium bicarbonate and sodium carbonate in the aqueous solution were determined by titration with potentiometric endpoint titration with hydrochloric acid. The BHMP content was determined by UV photometry and the sodium chloride content by argentometry.

Further details of the present invention are illustrated by the following examples, without limiting the invention to the examples.

Example 1

250 ml of a chloroform solution of chlorinated pyridine derivatives (dry substance content: 100 g, dry matter composition: 67 g BCP, 25 g DCP and 8 g TCP) are evaporated under reduced pressure to remove chloroform. To the residue were added 500 ml of water, 113.6 g of sodium bicarbonate and 5 ml of propanes. The mixture was refluxed for 7 hours. According to gas chromatography, about 98-99% of the BCP is hydrolyzed. The mixture was cooled to room temperature, extracted with chloroform (3 x 150 mL), and the sodium phase bicarbonate and sodium carbonate were determined in the aqueous phase. The volume of the aqueous phase is 600 ml, containing 1.3% w / v sodium bicarbonate and 2.1% w / v sodium carbonate. To neutralize this, 64 mL of 1: 1 dilute hydrochloric acid was used. After neutralization, the pH of the solution is 7.6. The aqueous solution is concentrated under reduced pressure to 250 ml (40% of its original volume), the desired material (sodium chloride) is filtered off at a temperature above 60 ° C and the filtrate is cooled to + 5 ° C to + 10 ° C. After a few hours of standing, the precipitated BHMP is filtered off and dried. 45.2 g of a white crystalline material are obtained, having a BHMP content of 96% by weight and containing 3.5% by weight of sodium chloride. Converted to 100% pure BHMP, the primary product was obtained in 82% yield. The mother liquor contains an additional 6.1 g of BHMP. From this, about 4 g can be recovered using the method described above. Thus, the total yield, calculated on pure product, is 89.5%.

Further processing of the mother liquors obtained in the exemplary process provides additional BEMP. Thus, in continuous production, the yield can be improved to 91-94%. Molar extraction (1 hour solution in 1 cm cuvette): 624. For the hydrochloride of the product: 494. Measurements were made at 269 nm in n-aqueous HCl.

Example 2

113.6 g of sodium bicarbonate are dissolved in 500 ml of water and the mixture is heated to reflux. While refluxing, 250 ml of the chloroformated pyridine derivative of chloroform described in Example 1 are added at a rate as chloroform distils off. After the system was chloroform-free, 5 ml of butanol was added and the mixture was refluxed for 7 hours. Then, as in Example 1, 48.3 g of white crystalline material was obtained, containing 95.8% by weight of BHMP and 4% by weight of sodium chloride. Primary product yields 37.3 BHMP calculated on pure material.

191,618

Example 3

The procedure of Example 1 was followed, but the concentration was 50% of the volume of the aqueous solution. The evaporated mixture was cooled to 5-10 ° C and the precipitated crystals were filtered and dried. 58.8 g of white crystalline material are obtained, containing 81 wt.% BHMP and 19 wt.% Sodium chloride. The yield is 90% based on pure primary product. The product is mixed with sodium chloride,

The resulting 240 ml mother liquor had a BHMP content of 0.95%, equivalent to an additional 2.28 g. The first product and the second product together weighed 49.9 g, 94.2% of the total yield.

Example 4

The procedure of Example 1 is followed, but upon completion of the hydrolysis, the sodium bicarbonate and / or sodium carbonate is not neutralized but the solution is concentrated to 40% by volume under reduced pressure. After evaporation, the mixture was neutralized with 64 ml of a 1: 1 dilute aqueous hydrochloric acid solution based on a predetermined sodium bicarbonate and sodium carbonate content, followed by filtration at 60 ° C as in Example 1, and processing the filtrate.

46.4 g of crystalline material are obtained, containing 95% by weight of BHMP and 6.5% by weight of sodium chloride. As a primary product, BHMP is obtained in a yield of 81.5% based on the BCP reacted.

Example 5

300 ml of chloroform solution of chlorinated pyridine derivatives (108.8 g dry matter, 85.5 g BCP dry matter, 20.8 g DCP and 2.5 g TCP), 440 ml of water according to Example 2, and 130 g of sodium bicarbonate are added. After chloroform removal, 5 ml of butanol was added and the mixture was refluxed for 7 hours. Work-up as in Example 1 gave 80.4 g of crystalline material containing 75% by weight of BHMP and 25% by weight of sodium chloride. The BHMP was obtained as a primary product in 89.3% yield based on the BCP reacted.

Example 6

Dissolve 100 g of BHMP / sodium chloride mixture (77.4 g of BHMP and 25.6 g of sodium chloride) in 100 ml of hot water and concentrate to 110 ml under reduced pressure. The precipitated residue was filtered at 70-80 ° C, 5 ml of water was poured into the still warm filtrate and cooled. The precipitated BHMP was filtered off, washed with 30 ml of ice water and dried. 72.9 g of BHMP are obtained, containing 96.6% by weight of BHMP and 3.1% by weight of sodium chloride. The purification loss is 9%.

Comparative Example 1

The purpose of the experiments was to reproduce Example 1 of Japanese Patent Application Publication No. 31 034/80 for a starting mixture containing 75% BCP. Two experiments were performed:

(a) the amount of sodium bicarbonate was calculated on the actual BCP tarpalot;

b) the amount of sodium bicarbonate was calculated for the total dry matter (BCP + DCP + TCP).

(a) Experiment

A mixture of chlorinated pyridine derivatives (75% by weight BCP, 20% by weight DCP and 5% by weight TCP) was boiled as described in 5 # aqueous sodium bicarbonate solution containing 18.5 g of sodium bicarbonate and then After charcoal clarification and filtration, the slurry was evaporated to dryness under reduced pressure. 27.0 g of brown material were obtained, which formed a hard, sticky mass. This was scraped off and triturated and extracted with 20 times ethyl acetate at reflux. BHMP is soluble in 18 times ethyl acetate at boiling point, and 226 times at + 5 ° C. Insoluble in ethyl acetate 13.75 g with a BHMP content of 2.88 wt. 8.96 g of a substance with a BHMP content of 99.54% by weight, precipitated from ethyl acetate at + 5 ° C. Evaporation of the ethyl acetate to dryness yielded 3.12 g of an oily product (dark brown) having a BHMP content of 84 wt.

The measured BCP can theoretically produce 13.92 g of BHMP.

In our experiment: quantity yield (G) (%) first product: 8.96 64.35 in the salt mass: 0.39 2.84 dissolved in ethyl acetate left: 2.62 18.82 11.97 86.01

That is, about 14% of the BHMP is degraded during hydrolysis and processing. As the first product, 64.35% of the calculated BHMP was recovered, and as a second product, an additional 1-1.5 g of ethyl acetate mother liquor was obtained.

7-10% can be recovered. Thus, even in the optimum case, only 75% yield of BHMP could be produced.

(b) experiment

Experiment a) was carried out, but for hydrolysis

A 5% aqueous solution of sodium bicarbonate containing 23.5 g of sodium bicarbonate was used. Workup of the hydrolyzate as described in Experiment a gives 8.96 g of crude BHMP with a BHMP content of 98.7%. Based on the BHMP content of the mother liquors and the salt weight, the loss of hydrolysis was 14%.

191,618

Comparative Example 2 G pure BHMP (content: 99%) was hydrolyzed according to Example 1 of the Japanese Patent Application, but instead of evaporation to dryness and ethyl acetate extraction as described in Example 1 of the present invention.

30.5 g of BHMP were obtained with a sodium chloride content of 5%. The first product thus obtained was 84% of the calculated production, as opposed to 65% in the Japanese publication.

Comparative experiments show that the hydrolyzate, which has been evaporated to dryness according to Japanese Patent Application No. 31 034/80, is a very hard, concentrated substance which needs to be rubbed and crushed for ethyl acetate extraction. This cannot be solved under operating conditions. By extraction with ethyl acetate and evaporation of the solvent used for the extraction, BHMP was produced in a total yield of only about 75%, in an uneconomical manner, with significant loss of solvent. Thus, the known process for converting non-pure BCP to BHMP cannot be used commercially on an industrial scale.

Claims (6)

A process for the preparation of 2,6-bis (hydroxymethyl) pyridine by hydrolysis of 2,6-bis (chloromethyl) pyridine in the presence of an alkali metal hydrogencarbonate at elevated temperature, and isolating the product obtained by treating at least by weight 2,6-bis (chloromethyl) pyridine and optionally other halogenated pyridine derivates, in particular 2-methyl-6- (dichloromethyl) pyridine and 2- (chloromethyl) -6- (dichloromethyl) ) -pyridine containing 4 to 6 times the dry weight of the mixture, up to 1.2 times sodium bicarbonate and 0.01 to 0.1 times water miscible and boiling in water greater than 80 ° C boiling with an inorganic organic solvent which forms an azeotropic mixture, extracting the mixture with an inert organic solvent immiscible with water and optionally containing an equivalent amount of sodium bicarbonate and / or sodium carbonate before or after neutralization with aqueous hydrochloric acid, concentrate and recover the 2,6-bis (hydroxymethyl) pyridine from the mixture containing only sodium chloride as the inorganic salt, pure or by stirring with sodium chloride, if necessary. from the mixture to form a saturated aqueous solution of sodium chloride to yield pure 2,6bis (hydroxymethyl) pyridine and / or 1q of the mother liquor if desired. as a diluent, it is led back to the beginning of the process. 2. Process according to claim 1, characterized in that sodium hydrogencarbonate is 0.9 to 1.2 times the dry weight of the mixture. 3. Process according to claim 1 or 2, characterized in that the water-miscible and azeotropic inert organic solvent is propane or butanol. is ¹ 4. Process for preparing a process according to any one of claims 1 to 3, characterized in that chloroform is used as the water-immiscible inorganic organic extraction agent. 5. A process according to any one of claims 1 to 4, wherein the solution is concentrated after neutralization at a volume of 35 to 65% of its original volume. 6. A process according to any one of claims 1 to 4, wherein the solution is concentrated to 35-65% of its original volume prior to neutralization. L Refer to Figures 1-6. Process according to any one of claims 1 to 3, characterized in that the 2.63 g of a mixture of bis 7 (hydroxymethyl) pyridine and sodium chloride is dissolved in 3 to 6 volumes of hot water and, if desired, clarified, filtering off the bis (hydroxymethyl) pyridine which is excellent for cooling. f. 1-7. Process according to any one of claims 1 to 3, characterized in that the hydrolysis of 2,6-bis (chloromethyl) pyridine is effected by the continuous addition of a solution of chloroform in boiling aqueous sodium bicarbonate solution and by continuous distillation of chloroform.