HU186424B - Process for selective reducing pyridine derivatives containing dichloromethyl side chain - Google Patents

Abstract

The present invention relates to 2-methyl-6-dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine or 2,6-bis (dichloromethyl) pyridine or a mixture of two or all of these, in particular 2,6- the major in the chlorination of dimethylpyridine. by selective dehalogenation of dichloromethyl side-chain components in a reaction mixture containing the above-mentioned compounds by reduction with zinc or iron and, if desired, 2,6-dihydroxymethylpyridine or the resulting 2-methyl-6-methylpyridine. for the conversion of chloromethylpyridine to 2,6-bis (chloromethyl) pyridine, characterized in that the reduction is carried out in the presence of water and a C 1-4 aliphatic alcohol. For example, 2,6-bis (chloromethyl) pyridine is an important intermediate in the preparation of 2,6-dihydroxymethylpyridine bis (N-methylcarbamate) (Prodectin) for the prevention and treatment of atherosclerosis. 186424 -1-

Description

The present invention relates to a process for the preparation of 2-methyl-6-dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine or 2,6-bis (dichloromethyl) pyridine, or a mixture of two or all of them, in particular 2,6- is formed by the chlorination of dimethylpyridine. by weight reduction of zinc or iron in the reaction mixture containing a mixture of the compounds listed above, and optionally the resulting 2,6-bis (chloromethyl) pyridine

For the conversion of 2,6-dihydroxymethylpyridine or the resulting 2-methyl-6-chloromethylpyridine to 2,6-bis (chloromethyl) pyridine, characterized in that the reduction is carried out in the presence of water and a C 1-4 aliphatic alcohol.

An important intermediate of 2,6-bis (chloromethyl) pyridine is, for example, the preparation of 2,6-dihydroxymethylpyridine bis (N-methylcarbamate) (Prodectin) for the prevention and treatment of atherosclerosis.

The present invention relates to a process for the conversion of dichloromethyl side chain pyridine derivatives to chloromethyl side chain derivatives by selective reduction to provide 2,6-bis (chloromethyl) pyridine and / or 2-methyl-6-chloromethylpyridine.

For example, 2,6-bis (chloromethyl) pyridine is an important intermediate in the preparation of 2,6-dihydroxymethylpyridine bis (N-methylcarbonate brown) (Prodectin) used to prevent and cure atherosclerosis, but can also be used directly in, for example, cruise ships. 2-methyl-6-chloromethylpyridine, similarly to the dyeing agent, because it inhibits algae formation, algae degeneration and snail deposition (Japanese Patent Application Publication No. 58 122/74).

For 2,6-dimethylpyridine, for example, the starting material for the preparation of 2,6-bis (chloromethyl) pyridine (Hungarian Patent No. 174,824).

One of the indirect processes for the preparation of 2,6-bis (chloromethyl) pyridine is Bem economical and is therefore not feasible industrially.

In all cases, 2,6-bis (chloromethyl) pyridine is commercially prepared by chlorination of 2,6-dimethylpyridine or a mixture of 2,6-dimethylpyridine and 2-methyl-6-chloromethylpyridine (e.g. Japanese Patent Specification No. 73.44,843; Japanese Patent Application Publication No. 89,265/80; Hungarian Patent Application No. 174,824). A common feature of all known processes is that they cannot carry out selective chlorination of 2,6-dimethylpyridine and thus process the reaction mixture to give a mixture of different degrees of chlorination of 2,6-dimethylpyridine. The composition of the chlorinated mixture ranges over a relatively wide range, as follows: 1-8% by weight of 2,6-dimethylpyridine, 24-45% of 2-methyl-6-chloromethylpyridine, 8-12% of 2-methyl -6-dichloromethylpyridine, 34-45% 2,6-bis (chloromethyl) pyridine (target product), 10-18% 2-chloromethyl-6-dichloromethylpyridine, 0-4% 2,6-bis ( dichloromethyl) pyridine.

Hungarian Patent Application No. 179,849 provides a process which can be used commercially for the separation of the mixture obtained during the chlorination of 2,6-dimethylpyridine and for the isolation of the various chlorinated 2,6-dimethylpyridine derivatives. The purpose of vacuum distillation separation (French Patent No. 1 394 362) and extraction purification combined with fractional crystallization (Japanese Patent Nos. 73,448 43 and 74,543 74) is to isolate 2,6-bis (chloromethyl) pyridine. All chlorination processes are applicable not only to the pure 2,6-dimethylpyridine, but also to the chlorination, i.e. recycling, of the mixture of 2,6-dimethylpyridine and the underchlorinated 2-methyl-6-chloromethylpyridine which can be regenerated by the above separation methods. However, other derivatives formed during the chlorination process, such as 2-methyl-6-dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine and 2,6-bis (dichloromethane) pyridine, would be it is possible that these can be added with metals such as zinc, iron, nickel, etc. 2,6-dimethylpyridine in hydrochloric acid and the resulting 2,6-dimethylpyridine is re-chlorinated in Japanese Patent Application Publication No. I49 365/80). Other hydrogenation, such as metal hydride, electrolytic or contact catalytic hydrogenation, is uneconomical and in these processes, the total reduction can be achieved. A further disadvantage of total reduction is that the metabolite to be reduced also contains a relatively large amount of 2, 6-bis (k) -methyl) pyridine, so that the valuable target compound is reduced back to the starting material, see Japanese Patent Publication No. 49,365/80. 1 and 2). It should be noted that the dehalogenation of 2-methyl-6-dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine and 2,6-dichloromethylpyridine to relatively cheap 2,6-dimethylpyridine is not only economical, but environmental considerations also make it necessary. These substances are highly toxic and, when burned, also produce significant amounts of hydrochloric acid gas.

It is clear from the above that the key issue for the economical preparation of 2,6-bis (chloromethyl) pyridine is the reaction of unreacted 2,6-dimethylpyridine and by-products 2-methyl-6-chloromethylpyridine, 2-methyl-6 dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine and 2,6-bisex (dichloromethyl) pyridine. 2,6-Dimethylpyridine and 2-methyl-6-chloromethylpyridine can be re-chlorinated following known separation procedures, 2-methyl-6-dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine and 2-methyl-6-dichloromethylpyridine. However, 6-bIB2, - (dichloromethyl) pyridine has been reported in the literature to date only

It was utilized by complete reduction to 2.6-dimethylpyridine.

Our goal was to convert 2-methyl-6-dichloromethylpyridine to 2-methyl-6-chloro-methylpyridine and to 2-chloro-methyl-6-dichloroethyl-pyridine and 2,6-bis (dichloromethyl) pyridine.

The selective dehalogenation of 2.6-bis (chloromethyl) -pyridine is solved.

The present invention is based on the discovery that the side chain is highly chlorinated 2,6-dimethylpyridine derivatives such as 2-methyl-6-dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine and 2,6-bis (dichloroethyl) -pyridine in a mixture of metals with a C1-C4 aliphatic alcohol selectively containing metals with a monochloromethyl side chain, such as 2-methyl-6-chloromethylpyridine and 2,6-bis (chloromethyl) pyridine dehalogenated.

The present invention thus relates to a process for 2-methyl-6-dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine or 2,6-bis (dichloromethyl) pyr

-2186424 for the selective dehalogenation of dichloromethyl side-chain components in a mixture of two or three of them, or mixtures thereof of two or all of them, in particular in the reaction mixture containing by weight with 2,6-dimethylpyridine, by reduction with zinc or iron; the reduction is carried out in the presence of water and a C 1 -C 4 alcohol.

C 1-4 aliphatic alcohols are preferably methyl alcohol, ethyl alcohol or isopropyl alcohol. The fastest and most selective reaction is provided by methyl alcohol containing 10-30% v / v water. The alcohol-water mixture may be diluted with an ethylene indifferent but not halogenated solvent, such as acetone, benzene, tetrahydrofuran, if necessary.

Zinc or iron is preferably used in a finely powdered form, zinc being most preferred and most economical.

The reaction may be carried out at a temperature between room temperature and the boiling point of the solvent mixture, but preferably at about the boiling point.

The discovery of the present invention is surprising because pyridine derivatives containing a monohalomethyl side chain, like benzyl chloride, have substantially greater reactivity than compounds containing a highly halogenated side chain, such as dichloromethyl or dibromomethyl. The reductive dehalogenations of hitherto known acidic media (mostly hydrochloric acid or acetic acid) in Borane are converted very rapidly to methylcarbonate from the dihalomethyl group and the reaction cannot be stopped at the monohalomethyl compound. However, in our own experiments, it has been found that the reaction cannot be carried out in alkaline media such as methyl alcohol or ethyl alcohol and metal sodium because the chloromethyl group is converted relatively quickly into meloxymethyl or eloxymethyl groups such as 2-methyl-6-meloxymethylpyridine or methyl alcohol. bis (methoxymethyl) pyridine is formed.

The reaction can be carried out using pure water and metal, but such a solution cannot be used at industrial scale. The reaction time is several days, the utilization of the metal is very poor, and neither the starting materials nor the products are soluble in water. By using pure alcohol, the selectivity is reduced.

Although the process of the present invention is also applicable to isolated 2,6-dimethylpyridine derivatives containing a highly chlorinated side chain, it is predominantly 2-methyl-6-dichloromethylpyridine and its primary commercially available preparation, as described in Hungarian Patent No. 179,849.

Fractions containing 2-chloromethyl-6-dichloromethyl-pyricine may be used.

The process of the present invention provides utilization of 2-methyl-6-dichloromethylpyridine, 2-chloromethyl-6-dichloromethylpyridine and 2,6-bis (dichloromethyl) pyridine, which is otherwise wasteless. 2-Methyl-6-dichloromethylpyridine can be used to obtain 2-methyl-6-chloromethylpyridine in good yield,

Mixed with 2.6-dimethylpyridine in known manner

It can be chlorinated to 2.6- (chloromethyl) -pyridine. 2-Chloromethyl-6-dichloromethyl-pyridine; and or

2,6-Bis (dichloromethyl) pyridine b.c. according to the process of the present invention gives an excellent yield of 2,6-dichloromethylpyridine which is either directly used or can be converted to the valuable 2,6-dihydroxymethylpyridine in a known manner.

The process is easy to apply on an industrial scale. The excipients used are inexpensive. easily accessible and manageable. The reaction is carried out and the processing can be carried out in standard apparatus. The reaction powder is neutral in reaction powder, so that no known corrosion problems occur.

Based on the above, to ensure cost efficiency. In addition, the invention is also significant from an environmental point of view, since there is no need to dispose of large amounts of by-products which are harmful to health, as they can be utilized economically by the process according to the invention.

The following examples illustrate the process of the invention in more detail.

Example 1

Dissolve 10.0 g of 2-chloromethyl-6-dichloromethylpyridine in 40 ml of methanol and 10 ml of water and reflux for 2 hours after adding 2 g of zinc powder. Thereafter, at 1 hour intervals, while maintaining reflux, 0.5 g portions of zinc were added to the reaction mixture in portions of 0.5 g, and the mixture was cooled, filtered and the filtrate evaporated to methyl alcohol-free. To the residue was added 40 in. Hydrochloric acid, and the resulting solution was extracted with chloroform (1 x 50 and 2 x 25 mL). The combined chloroform portions are freeze-dried after drying. There are obtained 7.46 g of 2,6-bis (chloromethyl) pyridine having a content of 95.2% by weight of the halide.

Yield: 84.9% based on the active ingredient content of the product.

Example 2

Dissolve 5.0 g of 2-chloromethyl-6-dichloromethylpyridine in 45 ml of ethyl alcohol and 5 ml of water, add 0.75 g of zinc powder and heat to boiling. After refluxing for 2 hours, an additional 2.5 g of zinc powder is added in 0.5 g increments every 2 hours. After the reaction time, the mixture was refluxed

Work up as in Example 1 to give 3.58 g of 2,6-bis (chloromethyl) pyridine having a content of 96.1% by gas chromatography. Yield: 82.3% based on product active ingredient.

Example 3

In the same manner as in Example 2 but using butyl alcohol instead of ethyl alcohol, the resulting 2,6-bis (chloromethyl) pyridine weighs 3.62 g and contains 83.2%. It contains 2-chloromethyl-6-dichloromethylpyridine as its main impurity. Yield based on active ingredient content: 72.0%

Example 4 2-Chloromethyl-6-dichloromethyl-pyridine (g) was dissolved in a mixture of methyl alcohol (35 ml) and water (15 ml), and iron powder (0.75 g) was added and the mixture was heated to reflux. In 0.5 g increments, an additional 4 g iron powder is added at 1.5 hour intervals. After the reaction time, the mixture was worked up as described in Example 1 to give 3.70 g of 2,6bis (chloromethyl) pyridine having an active ingredient content of 91.1%.

Production is 80.6% of theory.

Example 5

5.28 g of 2-methyl-6-dichloromethylpyridine. Dissolve in a mixture of 25 ml of ethyl alcohol and 5 ml of water. A total of 3.0 g of zinc powder is added in 0.5 g increments at 1.5 hour intervals. After addition of the last portion of zinc powder, the mixture was refluxed for an additional 2 hours, after which the filtrate was cooled and filtered to evaporate to methyl alcohol-free. The residue was diluted with water (30 mL), adjusted to pH 7.5-8 with 10% aqueous potassium bicarbonate solution, and the precipitated zinc salt was filtered off. The filtrate was extracted with chloroform (3 x 20 mL) and the combined chloroform fractions were dried to remove solvent. 3.48 g of an oil are obtained having a gas chromatography composition of 71.6% of 2-methyl-6-chloromethylpyridine, 23.7% of 2,6-dimethylpyridine, 4.7% of 2-methyl-6-dichloromethylpyridine. .

Yield 67.1% based on 2-methyl-6-chloromethylpyridine.

Example 6

100 g of crude 2-chloromethyl-6-dichloromethyl-pyridine, prepared as described in Example 9 of Hungarian Patent No. 179,849, containing 4.3% of 2-methyl-6-dichloromethyl-pyridine, 2.1 % 2,6-bis (chloromethyl) pyridine, 85.2% 2-chloromethyl-6-dichloromethylpyridine and 8.4% 2,6-bis (dichloromethyl) pyridine.

Dissolve 100 g of the substance in 500 ml of a 4: 1 mixture of ethyl alcohol and water. The solution was heated to 50 ° C and 10 g of zinc powder was added with stirring. The mixture is heated to reflux and then an additional 40 g of zinc powder is added in 5 to 5 g increments at 1.5 hour intervals. After the addition of the final portion of the powder, the mixture was refluxed for an additional two hours, then cooled and filtered. The filtrate was concentrated under reduced pressure to remove methyl alcohol and 400 ml of water, 30 ml of concentrated hydrochloric acid and 200 ml of chloroform were added to the thick paste thus obtained. After stirring for 10 minutes, the phases are separated. The chloroform phase is dried and the chloroform is distilled off. 67.3 g of 2,6-bis (chloromethyl) -pyridine are obtained, the content of which by gas chromatography is 98.7%. Yield is the starting material

The content of 2,6-bis (chloromethyl) pyridine, 2-chloromethyl-6-dichloromethylpyridine and 2,6-bis (dichloromethyl) pyridine is 84.8% of theory.

The aqueous phase was adjusted to pH 5 with 20% aqueous sodium hydroxide solution, the precipitated inorganic salt was filtered off and the filtrate was extracted with chloroform (3 x 40 ml). The combined chloroform phases are evaporated. 10.2 g of an oily substance are obtained, consisting of 37.2% of 2,6-dimethylpyridine and 58.2% of 2-methyl-6-chloromethylpyridine.

Example 7

The starting material used is the crude product prepared as described in Example 9 of Hungarian Patent No. 179,849, consisting of: 2.1% 2-methyl-6-dichloromethylpyridine, 1.9% 2,6-bis (chloromethyl) pyridine; 71.9% 2-chloromethyl-6-dichloromethylpyridine, 24.1% 2,6-bisBz (dichloromethyl) pyridine. Dissolve 100 g of the above compound in 350 ml of methanol and 150 ml of water. At intervals of 1.5 hours, a total of 60 g of zinc powder is added in 4 g increments while the mixture is refluxed.

After the reaction time, the mixture was cooled and filtered, and the filtrate was evaporated to anhydrous melyl alcohol. To the residue were added water (400 ml), concentrated hydrochloric acid (40 ml) and chloroform (200 ml). After separation of the chloroform portion, the aqueous portion is extracted with 2 x 100 mL chloroform. The chloroform phases are combined, 54 ml of concentrated hydrochloric acid are added and the mixture is evaporated under reduced pressure as a solvent. The resulting solid was stirred with acetone and filtered. 77.4 g of 2,6-bisBz (chloromethyl) pyridine hydrochloride 48 are obtained with an active ingredient content of 96.9%. Yield is the starting material

Taking into account 2,6-bis (chloromethyl) pyridine, 2-chloromethyl-6-dichloromethylpyridine and 2,6-bis (dichloromethyl) pyridine malalm: 78.3%. 5

Claims (4)

Claims A process for the preparation of 2-methyl-6-dichloromethylpyridine, 2- 10-chloroethyl-6-dichloromethylpyridine or 2,6-bis (dichloromethyl) pyridine or a mixture thereof, or in all three, in particular 2,6-dinethyl. Pyridine chlorination, in its main mass, in a reaction mixture containing the mixture of the above compounds to dehalogenate the dichloromethyl side-chain components to a selective monochloromethyl derivative by reduction with zinc or iron, characterized in that the reduction is in the presence of water and a C 1-4 aliphatic alcohol. carried out. The method of claim 1, wherein the C 1-4 aliphatic alcohol is methyl alcohol, ethyl alcohol or isopropyl alcohol. The method of claim 1 or 2, wherein the reduction is carried out in the presence of water containing from 10 to 30% by volume of aliphatic alcohol. 4. Referring to 1-3. Method according to any one of claims 1 to 3, characterized in that the reduction is carried out at a temperature between room temperature and the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture. without drawing The Director of Economic and Legal Publishing is responsible for publishing 87.2505.66-4 Alföldi Printing House Debrecen - Responsible manager: István Benkő CEO