JPS609026B2 - Method for producing sulfur-containing pyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new and advantageous process for the preparation of 2-methyl-3-hydroxy-4-ethylaminomethyl-5-methyl-mercaptomethyl-pyridine (1) and its acid addition salts.

Said compounds exhibit valuable pharmacological properties.

Therefore, they can be used as pharmaceutical agents. In particular, they show favorable effects on brain waves. Several methods are known for the preparation of said compounds, however these methods have various disadvantages. On the one hand, they do not produce pure products, and on the other hand, the yields are unsatisfactory. It has now been found that said compounds are obtainable in particularly high yields and in high purity by the novel process of the invention. The subject of the present invention is to prepare pyridine derivatives of the general formula 0, in which X is O or S and R is alkyl or pendyl having 1 to 4 carbon atoms, or salts of said compounds with ethylamine. 2-methyl-3-hydroxy-4-, characterized in that the base (1) obtained is converted by treatment with an acid into one of its physiologically acceptable acid addition salts.
This is a method for producing ethylaminomethyl-5-methylmercaptomethyl-pyridine (1) and its acid addition salt.

One of the starting materials, namely 2-methyl-3-hydroxy-
4-Hydroxymethyl-5-methylmercaptomethyl-pyridine (b) (wherein X is O and R is day) is known. Other compounds of formula 0 may also be used, such as those of formula D (
In the formula, × is ○ and R is day)
2-methyl-3-hydroxy-4- by reacting with C12
by known methods such as forming chloromethyl-5-methylmercaptomethyl-pyridine and then reacting with an alcoholate or mercaptide of the formula R-X-Na (e.g. sodium methylate, sodium hydrogen sulfide or sodium benzylmercaptide). can be manufactured.
Due to its low boiling point, the reaction of the compound of formula 0 with ethylamine is suitably carried out under pressure (less than about 10 tons), optionally with the addition of an inert gas such as nitrogen or argon. .

Inert solvents may also be present, e.g. methanol,
An alcohol such as ethanol, propanol, isopropanol or butanol. The reaction temperature is about 20
qo to about 250 C, preferably 13,000 or less, to 230 C is appropriate. Base obtained as desired (1
) can be converted into the corresponding acid addition salt by reaction with an acid by conventional methods.

Acids that produce physiologically acceptable salts may be used in this reaction. i.e. inorganic acids such as sulfuric acid,
Hydrohalic acids such as nitric acid, hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid or sulfamic acids are used, as well as organic acids, especially aliphatic, cycloaliphatic, araliphatic and aromatic acids. or polycyclic mono- or polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, bivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid , malic acid, < enoic acid, gluconic acid, ascorbic acid,
Benzoic acid, salicylic acid, 2-phenylpropionic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalene mono and disulfonic acids may also be used. If desired, the free base of a compound of formula 1 can be liberated from its salt by treatment with a strong base such as, for example, sodium or calcium hydroxide or sodium or calcium carbonate.

The process according to the invention produces the compounds of base (1) and their acid addition salts in extremely high yields and in extremely pure form (virtually free of by-products). The compounds thus obtained can be converted directly into conventional pharmaceutical preparations without further purification. Example 1 2-methyl-3-hydroxy-4 in methanol 750 units
A solution of 150 ml of methoxymethyl-5-methylmercaptomethyl-pyridine is heated with liquid ethylamine to 14,000° C. for 6 hours in a submerged autoclave.

The mixture was concentrated, 300' of ethanolic hydrochloric acid was added to the residue, the mixture was cooled and the resulting 2-methyl-3-hydroxy-4-ethylaminomethyl-5-
The methylmercaptomethyl-pyridine dihydrochloride is filtered off with suction and washed with a small amount of methanol and ether (
Melting point 23800). Example 2 In an autoclave with a rope pestle, a mixture of 1.8 g of liquid ethylamine and 1.8 g of methanol was mixed with 2-methyl-3
-Hydroxy-4-hydroxymethyl-5-methylmercaptomethyl-pyridine 1k9.

After applying 1 ton of nitrogen pressure in the autoclave, the mixture is heated to 150° C. for 6 hours under pressure. The mixture is cooled, concentrated, the residue is dissolved in isopropanol and concentrated again. The crude base obtained is dissolved in methanol, the solution is treated with charcoal and filtered.
Add hydrochloric acid to the filtrate until pH 1.5. The dihydrochloride crystallizes out on cooling (melting point 238° C.). Example 3 A mixture of 2-methyl-3-hydroxy-4-mercaptomethyl-5-methylmercaptomethyl-pyridine 645, ethanol 2, and ethylamine 2' is heated to 150 oo for 6 hours in a sealed tube.

The mixture is concentrated and the residue is chromatographed on silica gel with chloroform/methanol/ethyl acetate (7:2:1) to give 2-methyl-3-hydroxy-4-ethylaminomethyl-5-methylmercaptomethyl-pyridine ( Melting point ~6500). Example 4 2-methyl-3-hydroxy-4,5-bis-(
A mixture of methyl mercaptomethyl)-pyridine, 690 parts, isopropanol, 2 parts, and ethylamine, 2 parts', is heated to 220:00 for 6 hours.

The mixture is concentrated and chromatographed on silica gel to give 2-methyl-3-hydroxy-4-ethylaminomethyl-5-methylmercaptomethyl-pyridine (melting point 64-65oo) Example 52-Methyl-3-hydroxy-4 -benzylmercaptomethyl-5
-Methylmercaptomethyl-pyridine is treated analogously to Example 4 to give the same final product.

Claims (1)

[Scope of Claims] 1 Formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein X is O or S and R is H, alkyl or benzyl having 1 to 4 carbon atoms) A 2-methyl- 3-Hydroxy-4-ethylaminomethyl-5-methylmercaptomethyl-pyridine (
I) and its acid addition salt production method.