CS207355B2 - Method of making the 2,6-diacyloxymethylpiridines - Google Patents

Abstract

Prepn. of 2,6-bis (acryloxymethyl) pyridines of formula (I) (where R1 and R2 are H or 1-4C alkyl comprises reacting a 2,6-bis(halomethyl)-pyridine (II) with >=1 equiv. of R1COOH and >=1 equiv. of a tert. amine in an organic solvent at a temp. between 0 degrees C and the reflux temp. Cpds. (I) are inters for cardiovascular drugs, e.g. 2,6-bis (methylcarbamoyl-oxymethyl) pyridine. The process gives high yields (e.g. 982-98%) without the formation of difficult-to-separate by-products. Except for (I; R1 = R2 = Me), cpds. (I) are new. The reaction can be effected in an inert solvent or pref. in excess of one or both reactants. The tert. amine is pref. NEt3 or N-methylpiperidine. (II) is pref. 2,6-bis (chloromethyl) pyridine.

Description

(54) A method for producing 2,6-diacyloxymethylpyridines

(AND)

The present invention relates to a process for the preparation of 2,6-diacyloxymethylpyridines of the formula I:

R-jOC-O-CH ₂ wherein R 1 and R 8 are identical radicals denoting hydrogen or C 1 -C 4 alkyl.

Compounds of formula (I) are except for an acetyl derivative in which R 1 and R 8 are methyl compounds and valuable intermediates in the manufacture of a number of drugs affecting blood circulation and cardiac activity, such as pyridinol carbamate.

So far, according to the literature, only 2,6-dimethylaminopyridine has been used to prepare pyridinolkabjemyu.

For the preparation of 2,6-diacetoxyethylpyridia, only one method is known from the literature in which 2,6-lithium dihydroxy is converted to an N-oxide which is converted into acetic anhydride to 2-ene-6-methoxyethoxymenylpyridine, from which, after re-formation of the N-oxide and acetylation, 2,6-dimethyloxyeenhypyridium is obtained (OH Bullitt, Am. Soc., 6, 1370 (1954)); V. Boschelheide: Am. Soc., £ 6, 1286 (1954). E. Ochei: J. Org. Chem., £ 8, 535 (1953); S. Ginsburg: Am.

72, 481 (1957); V.T.T. Soc. 80, 6590 (1958); Tetsuzo Kato: C. A, 22, 559 (1963); Japanese Patent Specification No. 14,222/43, C.A. 70, 19,444 (1969).

In these processes, many different by-products are formed in a large amount in the acylation reaction, which can only be partially removed from the 2,6-dimethoxyethyl pyridine. Attempts made to industrialize this process have led to the applicant's patent application no.

RI-557 under the new process for the preparation of the methoxymenomethylpyridines, but even with this improved process, only a mixture containing 75-80% 2,6-diacetoxymethylpyridine with a maximum yield of 89.5% can be obtained (see Example 2). For further processing - for example for the preparation of the aforementioned pyridinolkabbamane - it is possible. this product . Suitable, but the yield is relatively low, so that the yield of pyridinococbaamane, based on 2,6-lutidine, is approximately 15%.

However, the synthesis of 2,6-diacyloxymethyypyridines via N-oxide formation is in no way applicable, for example. 2,6-diformylmethyppyidin cannot be prepared by this procedure. Also, no references can be found in the literature for the preparation of longer alkyl chain compounds.

One method is known from the literature for the preparation of monoalkoxyoxyethylpyridines (T. Kato et al., J. Pharm. Soc. Japan, 75, 1228 (1955)), whereby 2-chloromethylpyridio is heated in a pressure tube for 8 hours. 190 ° C with anhydrous sodium acetate in glacial acetic acid. Yield data are not given in the cited source.

Synthesis used by the author · Kato is very widespread in preparative organic chemistry (Houben-Weyl: Methoden der organischen Chemie, IV. Ed., 8, 541) as a result. For example, p-nitrobenzylchlorinium, e.g. which, in terms of reactivity, is closest to chloromethylpyrrine, by reaction with molten sodium acetate in boiling acetic acid over a period of 8 to 10 hours with p-nitrobenzyl acetate in 78 to 82% yield (Org. Synt. СоШ.

St. III, 650).

Compared to p-nitnobenzylchloride, the pyridine derivatives thus behave in a similar manner, since they can only be induced to undergo the reaction under substantially more environmental-friendly conditions. In literature was not nale-. zen reference to similar reactions of dichloi-m-thylpyridines.

Due to the extreme reaction conditions, the process is industrially impracticable because it requires use. anhydrous basic acetates to react. These salts are strongly. hygroscopic and can be dehydrated by melting · immediately before use. Owing to the presence of the basic salts, the reaction proceeds in a heterogeneous system, and therefore the resolution of the basic acetates to the desired fineness is essential. The dewatering of the dewatered melt under absolutely dry conditions is non-ventilating on an industrial scale.

Of the other esterification methods commonly used in organic chemistry, one more process is known for the preparation of iiacyloxyeeelhropyrimines. According to him,. by reaction of 2,6-dihydroxymethylpridine with triethoxylbtozoic chloride. trimtthoϊybtozoane 2,6-dihydryeymehpyridine (see Belgian patent specification 812,127) ·

However, this procedure is not applicable to the present case, since 2,6-dihydropylethylpyridines can only be prepared by hydrolysis of 2,6-diacenoxyethylpyridine.

From literature it is thus only known method for producing _{2,6-dihldroxyeeelvУppridinž>} and acylating _2> 6-N-lžtidnn nxiiž. However, this method is not applicable in general, but rather. is known only for acetyl derivatives and industrially acceptable only with poor yield. In addition, only the preparation of monoobetooylmethyppyrides can be found in the literature. This process is not useful in the industrial process and high yields cannot be expected.

In the experimental acylation of 2,6-dimethyl-pyridine, in particular with regard to the possibility of converting it to 2,6-diacttoxleylpyridine, it has now surprisingly been found that from 2,6-dichloro-pyridine. In the presence of at least the eonary moiety of the lower tertiary bases with lower biphatic carbonic acids, 2,6-diaclloxyethylcyclopyridine is formed with virtually an internal yield.

Accordingly, the present invention provides a process for the preparation of 2,6-diacyloxymethylpyridines of formula (I),

R.OC-CH ₂

CH ₂ -O-COR ₂ (I)

wherein and R 8 are the same and represent hydrogen or C 1 -C 4 alkyl.

The compounds of the formula I are prepared according to the invention from pyridine derivatives of the formula II,

X - CH ₂ wherein X is a halogen atom, by reacting the compounds of formula II in the presence of organic solvents with at least a molar amount, calculated on halogen, a trialkylamine, preferably triethylamine or a cyclic amine, preferably Nmeethyppyidine , and aliphatic carboxylic acids having 1 to 4 carbon atoms at elevated temperature, preferably at the boiling point of the reaction mixture, whereupon the product obtained is isolated from the mixture.

Indeed, the invention is surprising since it has not been expected from the literature that 2,6-di-methylmethylpyridio exhibits a greater reactivity than, e.g., p-oitrobenzyl chloride.

Nevertheless, 2,6-diacethoxymenylpyrido is formed under more gentle reaction conditions and in a higher yield than, for example, p-nitrobenzyl acetate and p-oitrbosyl chlorosu. This observation is surprising in particular because, in reaction with sodium acetate, 2 - [beta] - [beta] - [beta] - [beta] - [beta] - is substantially less reactive than p-oitrsbeozyl chlorine.

It is also surprising that the 2,6-diacylorylmethylpyridines obtained according to the invention are obtained practically without by-products in quantitative yield, since the formation of quaternary salts from 2,6-Sichlsrrettylpyrimis and tertiary amines used in excess could also be expected from the literature. Auuor I. Stuchlik (Chem. Listy, 50, 662 (1956)). has shown that the corresponding quaternary salt is formed from benzyl chlorosulfuric acid at 70 to 75 ^° C within 5 hours in 91% yield.

The process according to the invention is carried out by dissolving 2,6-sulfonyl fluoride in an organic solvent and then reacting it with at least equivalent masculinity, calculated on the halogen-tertiary amine and an aliphatic carboxylic acid having 1 to 4 carbon atoms. The reaction proceeds practically in a few hours. In most cases (depending on the type of solvent used), the tertiary amine salt precipitates during the reaction, which is then removed by filtration. The filtrate contains practically only 2,6-Silcylsonylene-pyrimidine in the dissolved state. The solvent is removed from the filtrate under atmospheric pressure or under vacuum. The crude product obtained is practically pure 95 to 100% of 2,6-silcylsulphonylenedioxy. The yield is 95 to 99% of the theoretical yield.

Any organic solvent which does not react with the reactants under the reaction conditions may be used as the organic solvent. Suitable solvents include, for example, ethyl acetate, butyl acetate, benzene, toluene, xylene, cyclohexane, Si-propyl ether, tetrahydrofuran and the like. It is also expedient to use mixtures of solutions.

According to one preferred embodiment of the process according to the invention, one reactant or a mixture of constituents simultaneously serves as the reactant. In this case, however, the tertiary amine and / or the aliphatic carboxylic acid must be used in excess. When reactants or mixtures of both are used as reactants, the reaction time is shorter and the isolation of the product is thereby facilitated. In this case, the reaction mixture is poured on ice upon completion of the reaction and the product is extracted from the aqueous solution with a solvent, such as a chlorinated hydrocarbon, preferably chloroform. The rosppuSiSlo is then denied. In this way, a product of 96-100% purity is obtained with a 95-99% yield.

207355 4

As tertiary amines, trialkymines and / or heterocyclic amines, e.g.

triethylamine or N-mehehlpippridine.

The reaction is carried out at the boiling point of the reaction mixtures. In the case of suitably selected reaction components, the reaction is carried out at relatively low temperatures; only the reaction time is correspondingly longer. It is therefore preferable to proceed at a boiling point near the boiling point, since the reaction will take place within a few hours.

The advantage of the process according to the invention is that by using a very simple technology it is possible to practically limit the yield of such a pure product, and that it can be subjected to further reactions without any purification, e.g. hydrolysis to 2,6-ditydroxymethylthylpiperidine described in Maara Patent Application No. RI. -533. The process according to the invention is also advantageous from an industrial point of view, since the preparation of diacyloxymethylpyridines does not have to be based on pure diethyl ether pyridine. For example, a crude product obtained by chlorinating 2,6-lutidine containing 85% 2,6-dictopetyl-pyridyl may also be used. From this product, pure diacetoxymethylpyridine can be obtained in 90 to 99% yield based on 2,6-dichloroethylpyridine content. A further advantage of the process according to the invention is that it can also obtain diacylo-α-β-β-idines whose synthesis has not yet yielded in another way, e.g. using other methods to obtain only an extremely low yield.

In general, a generally usable and good yield yielding a synthesis, which is very economical to realize on an industrial scale, has been produced by a process for the preparation of dilcyloxymethylcyclylidines according to the invention.

The structure of the newly prepared compounds was demonstrated by infrared spectroscopy, elemnary analysis, as well as by comparison with other reference substances obtained using other methods. Purity obtained Friday was checked by ultraviolet spectroscopy, gas ctromaloorrhea, and titoometric procedures.

The process according to the invention is further explained in the examples below.

In the examples, the gas ctromalographs were scanned at a temperature of 100 to 200 ° C in a 2.4 m long 3 mm silicon glass column, the carrier gas containing 1% OV-17 distributor liquid and the column was loaded with a chromium-Q-support.

Thin layer chromatography was performed using sillkignl G (Merek) on 0.25 mm thin layers, using a 50:50 mixture of chloroform and ethyl acetate as the eluent, and iodine vapor developers.

SpicCficlá extinction dilcntoxlmen-2,6-tlpi ^г makes drivers 383 = (269 · nm).

Example 1

5.28 g (0.03 moles) of 2,6-dimethylethylpyridine are dissolved in 50 ml of ethyl acetate and 3.43 ml (0.06 moles) of glacial acetic acid and 8.32 ml are added to the solution while stirring. ml (0.06 mol) of triethylamine. The reaction mixture was heated and boiled under reflux for 12 hours. · Approximately 15 to 20 minutes after the start of boiling, trichloromethyl chloride begins to precipitate. Mon. at the end of this reaction time, the mixture is cooled to about 20 ° C and the precipitated salt is filtered off. The filtrate was evaporated to dryness.

6.55 g of 2,6-dimethoxymethylpyridine are obtained in the form of a pale yellow oil. The pure substance was found to be 94.2% by spectroscopy, corresponding to 92.3% of the theoretical yield. The product can be further processed immediately.

Fractionation of the crude product under a pressure of 5 torr yielded a clear oil at 166-168 ° C after a 10% loss by purification, with a UV-spinotrophomeomeric content of pure substance of approximately 93.8 µm = 1.4966 .

Example 2

3.52 g (0.02 mol) of 2,6-dichloromethylpyridine are dissolved in 35 ml of glacial acetic acid and treated with 5.06 ml (0.044 mol) of N-methylpiperidine. The reaction mixture was boiled at 116-118 ° C for 12 hours. It is then evaporated to 13 to 15 ml and diluted with 30 ml of water. The pH of the solution is adjusted to 8 with solid potassium carbonate. It is then extracted with 3x10 ml of chloroform. The chloroform phases were combined, clarified with 0.20 g of activated carbon and evaporated to dryness after filtration. 4.40 g of a pale yellow oil are obtained with a content of 96.9% of 2,6-diacetoxymethylpyridine corresponding to 95.5% of the theoretical yield. The product is suitable for further processing.

Example 3

17.61 g (0.1 mol) of 2,6-dichloromethylpyridine are dissolved in 88 ml of glacial acetic acid and treated with 41.5 g (0.3 mol) of triethylamine. The reaction mixture is boiled for 5 hours and then evaporated to approximately 60 to 70 ml. After dilution with 200 ml of water, the pH of the solution was adjusted to 8-9 with solid potassium carbonate. The solution was extracted with 4x50 ml of chloroform, the chloroform phases were combined, clarified with 2 g of activated carbon and then evaporated.

22.10 g of a pale yellow oil are obtained which contains 98.2% of 2,6-diacetoxymethylpyridine corresponding to a yield of 97.4%. The product is suitable for further processing.

Example 1 a d 4 <

Dissolve 9.28 g (0.03 mol) of 2,6-dichloromethylpyridine in a mixture of 3.43 ml (0.06 mol) of glacial acetic acid and 53 ml of triethylamine. The reaction mixture was boiled for 5 hours. Crystallization starts already with heating. After this time, the reaction mixture was evaporated to dryness. The thus obtained mixture of crystals and oil was dissolved in 50 ml of chloroform, washed with 3 x 25 ml of water and dried over anhydrous sodium sulfate. After filtration, clarification and evaporation, 6.27 g of a yellow oil is obtained. The product contains 96.1% 2,6-diacetoxymethylpyridine corresponding to 93.8% of the theoretical yield. The product is suitable for further processing.

Example 5

5.30 g (0.02 mol) of 2,6-dibromomethylpyridine are dissolved in 53 ml of glacial acetic acid and treated with 8.30 ml (0.06 mol) of triethylamine. The reaction mixture is boiled for 7 hours, then evaporated to about 15 ml and diluted with 30 ml of water. The pH of the solution was adjusted to 8 with solid potassium carbonate and the solution was extracted with 3x20 ml of chloroform. The combined chloroform phases were washed with water until neutral, dried over anhydrous sodium sulfate and clarified with 0.2 g of activated carbon. After filtration, the solvent was removed. 4.20 g of a pale yellow oil are obtained which contains 97.4% of 2,6-diacetoxymethylpyridine corresponding to a yield of 94.2%.

Example 6

10.56 g (0.06 mol) of 2,6-dichloromethylpyridine are dissolved in 53 ml of formic acid and treated with 25.0 ml (0.18 mol) of triethylamine. The mixture was boiled for 6 hours, then evaporated to about 40 ml and poured into 120 ml of water. The pH of the solution was adjusted to 8 with solid potassium carbonate and the solution was extracted with 3x50 mL of chloroform. After combining and clarifying the chloroform phases, the solvent is removed. 11.5 g of a pale yellow oil are obtained which contains 97.1% of 2,6-difluoromethylpyridine corresponding to a theoretical yield of 95.5%. The crude product is fractionated in vacuo. Boiling point: 130 to 132 ° C / 3 torr; - 1,5145. The fractionated product shows a degree of purity of 99.7% and is practically pure as shown by gas chromatography and thin layer chromatography.

ab

Analysis for C 8 H 9 NO 4 (mol. Calculated: 55.38% C, found: 55.28% C, weight: 195.18)

H, 4.65; N, 7.18.

% H, 4.59;% N, 7.20.

55,34%

4.65% 7.27%

32.79% 0

32.70% O

32,68%

2,6-Dimethyl-non-ethylpyridine is a novel compound.

Example 7

10.56 g (0.06 mol) of 2,6-dicymeromethylpyridine are dissolved in 106 ml of toluene and 9.85 ml (0.132 mol) of n-propionic acid and 18.3 ml (0.132 mol) of triethylamine are added. The solution was then boiled for 11 hours. The salt formed during cooking is filtered off and the filtrate is washed with water, then with 5% sodium bicarbonate solution and finally with water until a gentle reaction. The solution was dried over anhydrous sodium sulfate and clarified. and finally filters. After evaporation under reduced pressure, 14.70 g of crude product are obtained which contains 95.5% of 2,6-di-n-propionylmethiphyrdine, which corresponds to a theoretical yield of 93.1%. The crude product is fractionated under a pressure of 5 torr. . . The main fraction distilled at 167-169 ° C shows a degree of purity of 99.8%. n? ⁵ = 1.4889.

The product is virtually pure, as shown by gas chromatography and chromattgraff on a thin film.

AAsolution for calculated:

C ₁ H ₄ N ₁ O ₄ . (Mol. Weight: 251.28)

% C, 62.14;% H, 6.82;% N, 5.57.

62.07% C,

62,11%

6.90% H,

6.81%

5.50% N,

5,54%

25.47% 0

25,50% 0

25,59%

2,6-di-n-propionylinethylpyridine is a novel compound.

Example 8 g of crude 2,6-SicУlormet) yllpyгiSins (i.e. the product obtained - chlorováním'2,6-lutidine and obs85% pure substance) were rozpuutí in 440 ml of concentrated acetic acid and treated with 207 ml _β hrtellylteminu reaction. the mixture is boiled for 6 hours, then evaporated under reduced pressure to half its volume and poured onto 1000 ml of water. The aqueous solution was extracted with 4x100 mL of chloroform. The chloroform phases were combined and washed at first with a 5% solution. acid carbonate! sodium and then water. The solution was then dried over anhydrous sodium sulfate, clarified with charcoal, and then the solvent was removed. 106-110 g of an oil are obtained, which contains up to 90% of 2,6-sitethoxymethylpyrrine corresponding to a yield of more than 95%.

The crude 2,6-Sitcetoxymethylpyrrine thus obtained can be immediately further processed, for example, hydrolyzed to 2,6 &apos;

Claims (3)

SUBJECT OF THE INVENTION CH ₂ -O-COR 2 (I 1. A process for the preparation of 2,6-Sitcyloxymethylpyrimans of the general formula I wherein R 1 and R 8 are the same and include hydrogen or C 1 -C 4 alkyl from the pyridine derivatives of formula II wherein X is halogen, wherein the pyridine derivatives of formula II wherein X is as defined above; reacted in the presence of an organic solvent with at least a molar amount calculated on halogen, a trialkylamine, preferably triethylamine, or a heretocyclic amine, preferably N-methylpyridine, and an aliphatic carboxylic acid having 1 to 4 carbon atoms at the boiling point of the reaction mixture; from the mixture. 2. A process according to claim 1 for the preparation of 1,6-diformylmethylpyridine, characterized in that 2,6-dichloromethylpyrrolidine is reacted with formic acid. 3. A process according to claim 1 for the preparation of 2,6-di-n-propionylmethylpyridine, characterized in that 2,6-dichloromethylpyridine is reacted with n-propionic acid.