DE2460039A1 - Hydroxymethyl-pyridines prepn. - by treating acetoxymethyl-pyridines with methanol in the presence of base in anhydrous medium - Google Patents

Abstract

Hydroxymethyl-pyridines (e.g. 2,6-bis-hydroxymethyl-pyridine) are prepd by treating acetoxymethyl-pyridines with at least an equivalent amt of methanol (calculated on the basis of the number of acetyl gps) in the presence of base (pref. a volatile base, esp. NH3 or an org. tertiary base, or NaOH in anhydrous medium at a temp. between 0 degrees C and the b. pt of the reaction mixts the prod opt being isolated in the form of a salt. Hydroxymethylpyridines are useful as intermediates for pharmaceuticals, esp. cardiovascular agents (e.g. 2,6-dihydroxymethylpyridine bis(-N-methlcarbamate)). The process gives good yields and is suitable for large-scale use.

Description

METHOD OF PREPARING HYDROXYMETHYL PYRIDINES The invention relates to a process for the production of hydroxymethyl pyridines by methanolysis of acetoxymethyl pyridines.

The hydroxymethyl pyridines are important starting products for production of numerous medicines, particularly those affecting the heart and blood circulation.

So is z. B. 2,6-dihydroxymethyl-pyridine-bis (N-methyl-carbamate) as an important one Diseases of the blood vessel system known (cf. Negwer, Organischchemische Arzneimittel und their Synonyma. Akademie-Verlag Berlin, 1971, compound no. 1488) According to a method known from the literature for the production of hydroxymethylpyridines, those from alkylpyridines are relatively simple Acetoxymethylpyridines obtainable are hydrolyzed to the corresponding hydroxymethyl compounds. For the hydrolysis, concentrated hydrochloric acid or alkalis, especially aqueous alkali solutions, are used in the equivalent excess amounts, at least in a 20-30% excess. So z. B0 according to Japanese Patent No. 14 222/43 (Chem. Abs.

70, 19944c) worked in such a way that the 2,6 diacetoxymethyl pyridine is hydrolyzed by boiling for one hour with concentrated hydrochloric acid solution that is used in about 30% strength, however. The hydrolysis product is then concentrated in vacuo) and the residue becomes the of the hydroxymethyl pyridine precipitated with ethyl alcohol and. The base required for further processing is then filtered off by dissolving the in water, releasing the base with concentrated alkalis, filtering and extracting in 36% yield (calculated on the acylated starting material). Kato and coworkers (Chem. Abs, 59, 559b (1963)) worked in a similar way and obtained 2,6-dihydroxymethylpyridine in 40% yield.

According to other authors, an acylated derivative of 5-ethyl-2-hydroxymethyl-pyridine is used boiled with an approximately three-fold excess of aqueous sodium hydroxide solution. By Extracting with dichloromethane gives the hydroxymethyl derivative in 75% yield (O.S. Bullitt et al., J. Am. Chem. Soc. 76, 1370 (1954)).

JA Berson and Mi-tarbw (J. Am. Chem. Soc., 77, 1281 (1955)) an aqueous potassium hydroxide solution for the hydrolysis of the acylated derivative of 4-hydroxymethylpyridine used. That 4-hydroxymethyl-pyridine was then extracted by chloroform won, yields were not specified.

According to the method of N. Eiming et al. (Acta Chim. Scand. 11, 6590 (1958) is the 2-acetoxymethyl - pyridine-3-acetate with a twofold equivalent Amount of ethanolic sodium hydroxide solution boiled for 2 hours. The hydrolyzate is mixed with water, concentrated, acidified, then made alkaline again and The hydroxymethylpyridine derivative is extracted overnight with ether.

81% yield obtained.

For hydrolysis of the important from a therapeutic point of view Diacetoxymethyl-pyridine was only used in the literature in the Japanese cited above Patent specification or

This paper describes the method carried out with hydrochloric acid. There is no information on the hydrolysis of these compounds carried out in an alkaline medium. This condition can be attributed to the difference in solubility of the mono- and dihydroxymethyl-pyridines. It has been found that, while the pyridiny compounds containing a hydroxymethyl group can be obtained from aqueous solutions by extraction and / or salting out in a more or less short time, the dihydroxymethyl derivatives can only be obtained from aqueous-alkali solutions by lengthy ones Extraction of very concentrated (at least 50%) solutions and only isolate X1 senr low yields. Because of the particularly good solubility of the bases, it is more advantageous to use the products in the form of to isolate, but even in this case - calculated on the base - not even 40% yields are achieved.

According to the known process, the hydrolysis of acetoxymethyl-pyridines carried out with acids or bases used in excess by boiling at 80 to 100 ° C.

Work is always carried out in the presence of water. Among those Under certain circumstances, both acetoxymethyl and hydroxymethyl pyridines can decompose suffer. It is known that the alcohols in the presence of Acids or bases are converted into unsaturated compounds by the action of heat (cf. S. Patai: The Chemistry of the Hydroxyl Group. Interscience Publ., London 1971). Such reactions are also in the case of the hydroxyalkyl pyridines known (C.B. Bachmann etc.: Am. Chem, Soc. 70, 2381 [1948]; B. Emmert etc .: Ber. 72, 1188 [1939]).

Under the known reaction conditions and especially during the are mainly composed of evaporation of the reaction mixture the circumstances for such decomposition reactions are extremely favorable. The presence of By-products formed in this way can particularly occur in the hydrolysis of diacetoxymethyl derivatives be detected. These substances can easily polymerize and then stay as practically indelible brown impurities in the desired product. The processes can take place in the specified orders of magnitude - and that means quantities of a few kilograms - can actually be clearly reproduced. The aua these Compound-made drugs come in relatively large doses (1 to 2 g daily) and widely used, so the dihydroxymethyl-pyridines must be used Quantities of several tons are produced daily.

however, the methods described in the literature apply to such masses practically not reproducible. E.g.

in hydrochloric acid hydrolysis according to the cited Japanese patent When working with quantities of 10 kg, the decomposition of the product during the evaporation process so extensively that pure product can hardly be isolated.

the Execution of the known methods also presents serious technological difficulties. The hydrolysis with hydrochloric acid can can only be carried out with great difficulty, since the boiling and evaporation of the concentrated aqueous hydrochloric acid solutions attack and destroy all apparatus materials except for the glass.

The cooking of alkaline reaction mixtures can indeed be carried out in iron apparatus, but from the point of view of the chen realization disadvantageous that the hydroxymethyl derivative can only be obtained by lengthy extraction lasting 10 to 25 hours. The extraction and working up of the extract are made more difficult by the fact that some of the alkali acetates formed from the acetic acid formed by hydrolysis and neutralized by the excess alkali used get into the organic phase due to their good solubility, where they can cause further decomposition due to their basic nature . These difficulties also arise in the case of the alkaline hydrolysis of the monoacetoxymethyl derivatives known from the literature en to a greater extent in the hydrolysis of the diacetoxymethyl derivatives. Another disadvantage of the known processes arises from the fact that water enters the reaction mixture during hydrolysis or work-up. The hydroxymethylpyridines formed are soluble in water. In the case of nonohydroxymethyl-pyridines, the hydroxymethyl compound can still be obtained economically by long extraction, but the dihydroxymethyl-pyridines, which are even more soluble in water, can only be obtained with great losses, at most in 40% yield.

The presence of water is also disadvantageous because the hydroxymethylpyridines are reacted with Insowaneton or chlorocarbonic acid esters to produce the carbamic acid esters mentioned, which are used as medicaments will. Since these compounds are recommended against water, the hydroxymethyl pyridines must be completely dried beforehand. In view of the large amounts of substance and the heat sensitivity of the hydroxymethylpyridines, this is a technologically difficult task.

Another disadvantage of the known method is.

that this can only be carried out with purified acetoxymethyl pyridines. The acetoxymethyl-pyridines are therefore by distillation or their sparingly soluble salts, eg. B. cleaned via the picrates or oxalates. Ss found that the distillation required to isolate these compounds - which must be carried out at pressures below 1 mmHg and at temperatures v;) n 150 to 200 ° C - is a dangerous operation which cannot be carried out at all with the large amounts of substance mentioned. namely found that the decomposition of the acetoxymethylpyridines under the action of heat occurs even with the distillation carried out below 1 mmHg and about 150 ° C. and - presumably as a result of'Polymerisationsreaktionen - can be increased to the point of explosion. On the other hand, the purification of acetoxymethyl-pyridines via their insoluble salts is of technological importance because of the salts to be used and because of the inclusion of further operational steps. point of view uneconomical.

From the above it appears that the known methods for Conversion of acetoxymethylpyridines into the corresponding hydroxymethyl derivatives can only be used to a very limited extent in operational wet conditions.

When studying the reactions of acetoxymethyl pyridines in aqueous media surprise the wise found that the hydroxymethyl-pyridines in aqueous methanol Presence of catalytic amounts of a basic substance even at room temperature in a few hours practically quantitative yields can be produced. When examining the reaction conditions, it has been found that the reaction is practically only in plays from methanol in dreser way; with higher alcohols the reaction is slightly slower. For example, in the case of 2,6-diacetoxymethylpyridine this reaction takes place in methanol of ammonia under certain conditions q1 (antitativ in 5 hours. The same reaction proceeds about 200 times more slowly in ethanol and does not take place at all in isopropanol. In anhydrous, non-alcoholic solvents the situation is similar to that of higher alcohols Solvents, with the exception of methanol, the long reaction times required by increasing the temperature or the amount of the alkaline substance present, even in the best ball - such as when used before ethanol - could only be reduced by about half. However, since there was no water in the reaction mixture, it had to be assumed that the hydroxymethyl derivative was not formed by hydrolysis but by plethanolysis. Accordingly, methyl acetate and the corresponding hydroxymethyl pyridine are formed as methanolysis products from the acetoxymethyl pyridines in methanol under the catalytic action of basic substances. The methyl acetate could be detected in the reaction mixture and also determined quantitatively. It was found that the amount of methyl acetate formed is equi valent to the amount of acetoxymethyl groups present in the pyridine derivative. Such alcoholysis does not take place with higher alcohols - presumably as a result of steric hindrance.

This great difference in the reactivity of the acetoxymethylpyridines - that they react quantitatively in methanol in a short time, while practically no reaction takes place in ethanol in the same time - was very surprising, since such differences in the reactivity of the pyridine derivatives were previously unknown . The invention / is based on the surprising finding that the acetoxymethyl-pyridines exclusively with methanol in anhydrous media in of basic catalysts at temperatures between 0 ° C. and the boiling point of the reaction mixture, advantageously at room temperature, can be alcoholysed in a very short time with almost quantitative yield.

The invention is therefore a process for the preparation of hydroxymethyl-pyridines from acetoxymethyl-pyridines, which is characterized in that the ace-oxymethyl-pyridines are in of bases in anhydrous media with a, a0 calculated the acetyl groups, treated at least equivalent amount of methanol at temperatures between 0 ° C and the boiling point of the reaction mixture and, if desired, the hydroxymethylpyridine obtained or a salt thereof is isolated from the reaction mixture appropriately worked so that one z. B. 2,6-Diacetoxymethyl-pyridine dissolves in ten times the amount of methanol, then this solution is mixed with a methanolic solution of sodium hydroxide and the mixture is advantageously stirred at room temperature. After the end of the methanolysis - the reaction can be followed well by thin layer chromatography, the methanolic solution is neutralized with methanolic hydrochloric acid, the precipitated sodium chloride is filtered off and the filtrate is evaporated to dryness. The contaminated with a little sodium chloride of 2,6-dihydroxymethylpyridine is obtained as a powdery crystalline residue. B. triethylamine used, then after the end of the methanolysis, the reaction mixture can immediately to dryness The residue obtained in such cases is a pale colored oil which, if the base present is volatile, crystallizes spontaneously and in other cases can be made to crystallize by stirring with petroleum ether; the hydroxymethylpyridine obtained can be isolated directly or by filtering off the petroleum ether solution.

When using tertiary bases it is not necessary to crystallize the evaporation residue, since the tertiary base remaining as an impurity is used in the further processing of the product for the production of the therapeutically valuable carbamic acid esters mentioned above, e.g. B. by reaction with methyl isocyanate does not disturb sX but rather acts as a catalyst. The distillation residue can therefore be used immediately after determining the product content the further implementation can be used. Methanolysis catalyzed by sodium hydroxide can be particularly advantageous the processing of reaction mixtures containing at least 50% 2,6-diacetoxymethylpyridine, in addition to other acylated pyridine derivatives, which can be obtained from 2,6-lutides by acetylating the N-oxides (cf. Kato and colleagues: Chem. Abstr . 59, 559b [1963]). The 2,6-diacetoxymethylpyridine hydrochloride obtained in this way also contains about 10-20% sodium chloride, which, however, does not interfere with the further reactions, so the crude product obtained can be used immediately without any purification.

The amount of base to be used in the ethanolysis, the reaction time and the temperature can vary depending on the structure of the to be methanolysed Acetoxymethyl-pyridins, its quality - whether it is a pure product or is a reaction mixture - and determined by the nature of the Baze used will. The disruptive decomposition reactions already mentioned and known from the literature do not occur with this procedure even if one is in the interest of acceleration the reaction works at higher temperatures or with larger amounts of the base.

When using pure starting materials you can according to the invention Process hydroxymethylpyridine derivatives of 95-100% purity (spectrophotonetrically determined) obtained in yields of 95 to 99%.

In the methanolysis of the above-mentioned reaction mixture containing 2,6-diacetoxymethylpyridine - calculated on the actual diacetoxymethylpyridine content of the mixture - the usual when using pure starting materials can also be used can be achieved. The use of anhydrous media and Amount of bases as well as the short reaction time is the advantage of the process according to the invention thanks to that also under Conditions and at higher temperatures decomposition neither of the acetoxymethylpyridine starting material nor of the hydroxymethylpyridine end product can occur. The methanolysis is practically quantitative. The reaction mixture can be worked up in a very simple manner1 one only has to remove the solvent from it. Since that arhaltene hydroxymethyl-pyridine will continue to work in all cases, it is a very important advantage of the.

Process according to the invention that by removing the solvent obtained crude end product without any further purification for further reactions can be used.

From the point of view of Execution is one of the most important advantages of the process, that the methanolysis can also be carried out with non-isolated icetoxymethylpyridines and so the purification of this substance, which is difficult to carry out in practice, is no longer necessary.

It is clear from the above that these products cannot be manufactured in large quantities by the known processes or by any combination of known processes. By contrast, the method according to the invention is the cal production of hydroxymethyl pyridines with a simple technology and with good yields.

The process according to the invention is illustrated by the examples below illustrated in more detail.

Example 1 24.55 g (0.11 mol) of 2,6-diacetoxymethylpyridine are in the solution of 8.0 g (0.2 mol) of sodium hydroxide in 223 ml of anhydrous methanol Stirred room temperature for 3 hours. The pH of the solution is adjusted with methanolic Hydrochloric acid set to 1 and the mixture cooled to 10 ° C orbit. The -decorated Sodium chloride is removed by filtering and the filtrate is evaporated to dryness.

18.70 g of 2,6-dihydroxymethylpyridine hydrochloride are obtained as a white crystalline residue obtained with about 7% sodium chloride content; M.p. 151-154 OC.

According to the spectrophotometric determination, the product contains 93.6% pure compound, in addition to sodium chloride. The yield calculated for the pure compound is 96.6% Mixture of 112 ml of anhydrous methanol and 112 ml of acetonitrile in methanolysed by sodium hydroxide in the manner described in Example 1. After the reaction has ended and the pH has been adjusted, the reaction mixture is worked up according to Example 1. 19.5 g of 2,6-dihydroxymethylpyridine hydrochloride contaminated by an inorganic salt are obtained; M.p .: 150-154 ° C.

The pure compound content, determined spectrophotometrically, is 95.8%.

The tWf the pure compound calculated yield 97% Example 3 4.46 g (0.02 mol) of 2,6-diacetoxymethylpyridine are dissolved in 44.6 g of anhydrous methanol; the solution is mixed with 0.28 ml (0.2 g = 09002 mol) of triethylamine and boiled for 3 hours. The reaction mixture is evaporated to dryness in vacuo, the 2.82 g of colorless oil obtained as residue are stirred with 10 ml of petroleum ether and the precipitated crystalline 2,6-dihydroxymethyl filtered off pyridine and dried. The yield is 2.69 g (96.7% of theory) The product melts at 113-114 ° C; the pure compound content, determined by spectrophotometry, is 99.6%. Example 4 4.46 g (0.02 mol) of 2,6-diacetoxymethylpyridine are dissolved in 44.6 ml of anhydrous methanol and mixed with 4.2 ml (3, 01g = 0.03 mol) triethylamine stirred at Ranim temperature for 8 hours.

2.64 g of 2,6-dihydroxymethylpyridine are obtained; M.p .: 114-116 OCa The yield is 95.0%. Content of pure compound: 99.8%. Example 5 Es Example 3 is followed9 but instead of triethylamine an equivalent is used Amount of piperidine used. After a reaction time of 5 hours, 2.71 g of 2,6-dihydroxymethylpyridine are obtained obtained of 99.6% purity; M.p .: 114-115 ° C.

Yield 97.4% of theory

Example 6 Example 4 is followed, but instead of triethylamine an equivalent amount of methylamine in ethanolic solution is used The reaction takes 7 hours at 25 tC0 2.72 g of 2,6-dihydroxymethyl pyridine hold, m.p. 112-114 ° C.

Yield: 97.9% of theory

Example 7 8.76 g (0.05 mol) of 2-methyl-6-acetoxymethyl-pyridine become in 88 ml of anhydrous methanol with 6.25 ml (0.045 mol) of triethylamine at 25 ° C. Stirred for hours. The reaction mixture is removed by evaporation in vacuo from the solvent free. There are in this way 6.32 g of 2-methyl-6-hydroxymethyl-pyridine of 95.8% purity obtained.

The calculated yield for the pure compound is 98.3% of theory.

Example 8 15.1 g (0.1 mol) of 4-acetoxymethyl-pyridine are used in 75 ml of anhydrous methanol dissolved, and the solution is with 12.5 ml (0.09 mol) of triethylamine offset. The reaction milk is boiled for 3 hours, then to dryness in vacuo evaporated. 10.54 g of pale yellow crystalline product are obtained as residue, its pure compound content, determined by gas chromatography, is 98.2%.

Yield: 96.7% of theory

Example 9 24.55 g (0.11 mol) of 2,6-diacetoxymethyl-pyridine are in 110 ml of anhydrous methanol are dissolved, then the solution is diluted with 16.2 ml with ammonia saturated, anhydrous methanol (3.4 g NH3 0.2 mol) was added. The reaction mixture is left to stand at room temperature for 24 hours.

then freed from the solvent by evaporation. The crude product obtained is stirred with 30 ml of ether and the precipitated 2,6-dihydroxymethylpyridine is isolated by filtration. Yield: 13.4 g (96.3% of theory) The product melts at 111-113 ° C; the spectrophotometrically determined content of pure compound is 97.8%. Example 10 g crude 2,6-diacetoxymethyl-pyridine - which was prepared according to Japanese patent specification No. 14 222743 and contains 60% 2,6-diacetoxymethyl-pyridine in addition to 3-acetoxy-2,6-lutidine, 2-methyl-6-formyl- pyridine diacetal and 2-acetoxymethyl-3-acetoxy-6-methyl-pyridine - are dissolved in 1500 ml of anhydrous methanol, then after adding the solution of 50 g of sodium hydroxide in 500 ml of anhydrous methanol, stirred for 5 hours at 25-30 °. The pH of the mixture is adjusted to 1 with methanolic hydrochloric acid and the precipitated sodium chloride is removed by filtration. The filtrate is freed from the solvent by evaporation in vacuo and the thick dark brown oil obtained as residue is stirred with the mixture of 50 ml of methanol and 50 ml of ethanol. The 2,6-dihydroxymethyl-pgridine hydrochloride separates out in the form of sand-gray crystals; This product is separated off by filtration and dried. 97.2 g of product are obtained which, according to the spectrophotometric determination, contains 85.2% 2,6-dihydroxymethylpyridine hydrochloride and 14.8% sodium chloride.

This product can be used for further implementation without any further purification can be used.

Yield1 the pure compound calculated: 87.6% of theory

Claims (9)

PATENT CLAIMS 1. Process for the production of hydroxymethyl pyridines from acetoxymethyl pyridines, by using the acetoxymethyl-pyridines in von Bassen in anhydrous medine with one calculated on the acetyl groups; at least equivalent Amount of methanol at temperatures between 0 ° C and the boiling point of the reaction mixture treated and, if desired, the hydroxymethylpyridine obtained or a salt d A v o n isolated from the reaction mixture. 2. The method according to claim 1, characterized in that the base is used in amounts below the stoichiometrically equivalent amount, used in catalytic amounts1. 3. The method according to claim 1, characterized in that g e k e n nze i c h n e t, that the base is a volatile base, especially an organic tertiary base or ammonia is used. 4. The method according to claim 1, characterized in that g e k e n nz e i c h n e t, that sodium hydroxide is used as the base. 5. The method according to claim 1, characterized geken nz eichnet that the reaction at temperature. 6. The method according to claim 1, characterized g e k e n nz e i c h n e t that the methanol is mixed with an anhydrous non-alcoholic solvent begins. 7. The method according to claim 1, characterized g e k e n nz e i c h n e t that the hydroxymethylpyridine derivative obtained is isolated in the form of the hydrochloride. 8. The method according to claim 1, characterized in that g e k e n n z e i c h n e t that one uses 2,6-diacetoxymethyl-pyridine as a starting material. 9. The method according to claim 1, characterized geken nz eichnet s that at least 50% 2,6-diacetoxymethyl pyridine containing neutral and anhydrous reaction mixture in of 0.9 molar equivalents of sodium hydroxide temperature treated with methanol and the resulting 2s6-dihydroxymethyl-pyridine optionally in the form Hydrochloride isolated.