DE1695402A1 - Process for producing a sulfur-containing pyridine derivative - Google Patents

Description

(previously: M 73 338 IVd / 12p)

E. M e r c k January 10, 1970

Darmstadt

Process for the preparation of a sulfur-containing pyridine derivative

The present invention relates to a new process for the preparation of a sulfur-containing pyridine derivative of the formula I.

CH ₂ OH

and its salts.

Compound I is known as a therapeutic agent for treatment of cerebral regression processes, nervous states of exhaustion in involutional age, developmental inhibitions in childhood and other cerebral insufficiencies.

Various processes for the preparation of the disulfide I are already known:

According to German patents 1,135,460 and 1,197,455, the compound can be aue a salt of 4ι5-bis-brominmethyl-3-hydroxy-2-methylpyridine by reaction with an alkali oxanthate and subsequent treatment with bases or duroh reaction with an inorganic disulfide. According to other acquaintances

109812/1822

In the process (German patents 1,222,062 and 1,227,908), the disulfide I is obtained by oxidation of 2-methyl-3-hydroxy-4-hydrox-methyl-5-mercaptomethyl-pyridine or by reacting the corresponding 5-halomethyl compound with a disulfide, wherein the hydroxyl groups in the starting materials z. B. are protected by acyl, and by subsequent cleavage of the Protecting groups. A process is also known in which the compound I can be obtained by treating 5-chloromethyl-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine with thiourea, alkali and an oxidizing agent (Spanish patent 305 156). According to a Japanese publication, the disulfide can also be obtained by alkaline treatment of 3-hydroxy-4-hydroxymethyl-2-methyl-5-thiocyanatomethyl-pyridine or by the action of thiourea, potassium iodide or ammonium rhodanide on 2-methyl-3-hydroxy-4-hydroxymethyl-5-thiosulfatomethyl-pyridine obtained in acidic solution (Vitamines / Kyoto /, Vol. 30, No. 6, Page 431 (1964)). From the Japanese patent application 1966-19097 a method has also become known, according to which from 2-methyl-3-hydroxy-4-hydroxymethyl-5-thiosulfatomethyl-pyridine by reaction with an alkali hydrogen sulfide or a lower one Alkyl mercaptan salt the compound I is formed.

Of the known processes for the preparation of the disulfide I, only a few are suitable for practice, since the yields, for. T. are low and, moreover, the cleaning of the end products often causes difficulties. The main disadvantage of the majority of the known processes is that the end product is obtained in impure form. Since the disulfide I is used as an active ingredient in pharmaceuticals, it is essential to produce a pure compound that is as free as possible from toxic by-products. A further disadvantage is in most known manufacturing method, that by the use of sulfides or Mercaptansalzen, especially when working in an acidic solution, such as in the method of Japanese Patent Application 1966-19097 _t a considerable odor nuisance occurs.

1 0 9 8 12/1822

It has now been found that after a new technically easy-to-use process, the compound I in excellent Yield and largely free of impurities can be produced.

The present invention relates to a new process for the preparation of the sulfur-containing pyridine derivatives of the formula I, which consists of a 2-methyl-5-alkali thiosulfatomethyl pyridine compound of formula II

• R ₁ O
CH ₂

R _Q 0 -f> Τ »CH ₉ -S-SO ^ -M

^ I Il * · s

wherein

H * and Rp are the same or different and

Hydrogen, acyl or together that

Radical C ^ mean,

^R 4

R, and R. are identical or different and

Hydrogen or lower alkyl or together a lower alkylidene group mean or with one another to form a 5- or 6-membered hydrocarbon ringes are connected and

M is an alkali metal, preferably sodium or potassium,

treated with an acidic agent and then the reaction mixture to a neutral or possibly weak

109817/1822

adjusts to acidic or weakly alkaline pH. If desired, the compound obtained can be used in catfish known per se in their acid addition salts or quaternary ammonium salts are converted

It is surprising that the disulfide I from the Bunte salt II can be produced by simple acid treatment. From the literature it is known that a Bunte salt under the action no disulfide results from acid. (Cf. Journ. Chem. Soc. 1962, Page 2172, last paragraph). It was therefore not foreseeable that the disulfide I by the process of the present Invention can be obtained in high yields and in pure form.

In the starting materials II of the process according to the invention, the radicals R ₁ and R ₂ denote hydrogen or else acyl, in particular lower acyl, such as acetyl, propionyl, butyryl. R * and / or R ^ can mean hydrogen or, for example, methyl, ethyl, n-propyl, isopropyl or butyl, so that the radicals RJ and R ₂ together represent a methylene, ethylidene, n-propylidene, isopropylidene, Represent butylidene, pentylidene, hexylidene, heptylidene, octylidene or nonylidene radical. In addition, the radicals R 1 and R 4 can also be linked together to form a 5- or 6-membered ring, preferably a cyclopentane or cyclohexane ring. Starting materials II in which R 1 and R _{2 are} H and M are particularly preferred. The starting compounds II can be prepared, for example, by reacting the corresponding 5-halomethylpyridine compounds with alkali thiosulphate. It is not necessary to use the starting products prepared in this way Rather, these can also be converted directly into the end product I or its salts in a solution by adding an acidic agent according to the process of the invention.

109817/18 2

169S4Ü2

In the process according to the invention, inorganic or organic acids, for example hydrogen halide, can be used as acidic agents acids such as hydrochloric acid, hydrobromic acid, Hydriodic acid or sulfuric acid, phosphoric acid, Perchloric acid, mono- or disulfonic acids, e.g. B. benzenesulfonic acids and p-toluenesulfonic acid can be used. Furthermore can optionally also acidic salts or Lewis acids, e.g. B. zinc chloride or aluminum chloride can be used. Are preferred strong mineral acids, especially hydrohalic acids, hydrochloric acid being the most suitable.

In general, it is best to use the acidic compound, in particular the acid, in a concentration of about 5 to 20 percent by weight. to use. The response times for optimal Implementation depend on the acidic compound used and, above all, on the temperature used. In general it has proven to be useful to keep the acidic compound on for a period of 10 minutes to several hours to let the starting products II act. At higher temperatures, e.g. B. at reflux temperature, is the reaction time shorter, longer at low temperatures. Appropriately is carried out at higher temperatures, especially at the reflux temperature, in order to shorten the reaction time. For example, a very pure end product is obtained high yield if the starting materials II for about 15 to minutes with dilute hydrochloric acid, in particular with about 2 - 3 η hydrochloric acid boils under reflux. A quantitative conversion can also be achieved, for example, by a five-hour treatment the starting products with about 4 η hydrochloric acid at 80 °. At a At an even lower temperature of about 60 °, a reaction time of about 18-20 hours is sufficient to achieve a higher temperature Exploit. Hydrobromic acid is advantageously used in a concentration of about 8 percent by weight. z. B. for a time of about 15 to 45 minutes at a higher temperature, preferably at the boiling point, applied. When using sulfuric acid has an acid concentration of 15 to 25 percent by weight. as

10981? / 1822

~ ⁶ ~ 16954Q2

proven favorable. For p-toluenesulfonic acid, one is recommended Acid concentration of about 15 percent by weight. and refluxing for about 1 1/2 to 3 hours.

By taking samples and titrating with n / 10 iodine solution, the point in time at which the sales are optimal can be determined. Then the reaction mixture is on a weakly acidic, neutral or weakly alkaline pH. This happens e.g. B. by adding alkaline compounds, such as an alkali or alkaline earth metal hydroxide, e.g. B. Potassium, Sodium, calcium hydroxide or an alkaline salt, e.g. B. an alkali or alkaline earth carbonate or bicarbonate such as sodium, potassium or calcium bicarbonate or by adding ammonia. Appropriately, the mixture is on a pH value between 4 and about 9 to 10 is set. The desired end product of the above formula I precipitates here and can be separated in the usual way. At a more alkaline pH, however, the end product partially reverts to Solution. Therefore, a pH range of about 4-8, especially an approximately neutral pH of 6.5-8, is preferred for the precipitation. The final product can, if desired, by recrystallization from a suitable solvent, for example n-butanol or dimethylformamide / water, can be further purified.

If appropriate, the disulfide I prepared by the new process can also be converted into an acid addition salt in a manner known per se or a quaternary ammonium salt can be converted. Physiologically acceptable acid addition salts are obtained, for example by adding inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, Nitric acid or organic acids such as alkyl sulfonic acids, e.g. B. methanesulfonic acid, or p-toluenesulfonic acid to the free base X. Quaternary ammonium salts are obtained by adding alkyl halides, such as methyl iodide or ethyl bromide of the compound I. Optionally, the base can also be liberated from an undesired acid addition salt of the compound I and if desired, these are converted into another acid addition salt.

109817/182 2 ORIGINAL INSPECTED

~ ⁷ ~ 1695 /, 0 2

example 1

A solution of 124 g of sodium thi ο sulfate in 500 ml of water is added with stirring to a suspension of 93.5 g of 5-chloromethyl-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine in 500 ml of water. After 1-1 1/2 hours heating at 6O ⁰ C 200 ml of concentrated HCl are added. The reaction mixture is then refluxed for 1/2 hour. After cooling, the pH of the solution is adjusted to 6-7 with dilute NaOH, the precipitated bis - ^ - hydroxy-4-hydroxymethyl-2-methyl-pyridyl- (5) -methyl7-disulfide is suctioned off and washed with water and acetone » Yield 92 g (= 100 % of theory), mp 222 ° C. (decomposition).

Example 2

23.2 g of 5-bromomethyl-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine are suspended in 70 ml of water, a solution of 24.8 g of sodium thiosulphate in 130 ml of water is added and the mixture is set to 40 for 1 1/2 hours - 45 ° C heated. Then 50 ml of concentrated HCl are added; then the mixture is refluxed for 1/2 hour. After cooling, the pH of the solution is adjusted to 6.5 and the precipitated bis-ZB-hydroxy ^ -hydroxymethyl-2-methyl-pyridyl- (5) -methyl7-disulfide is suctioned off. Yield 17 g, P. 220-222 ⁰ G (decomposition).

Example 3

5 g of 3-hydroxy-4-hydroxymethyl-2-methyl-pyridyl- (5) -methylthio sulfate sodium are refluxed in 50 ml of 4N H ₂ SO ^ for 30 minutes and neutralized after cooling. The precipitated bis- / 3-ky ^drox y-4-hydroxymethyl-2-methylpyridyl- (5) -methyl7-disulfide is then filtered off with suction. Yield 2.97 g (93 % of theory), mp 220-222 ° C. (decomposition) ¹ .

'109817/1822

- ⁸ - ■ 1 B 9 ό /: U 2

Example 4

10 g of 3-hydroxy-4-hydroxymethyl-2-methyl-pyridyl- (5) -methylthio sulfate sodium are refluxed with 100 ml of 2N HBr for 30 minutes and then neutralized. Yield 4.6 g (= 72 % of theory) bis - ^ - hydroxy ^ -hydroxymethyl ^ -methylpyridyl- (5) -methyl7-disulfide _r F. 220 - 222 ⁰ C (decomposition)

Example 5

5 g of 3-hydroxy-4-hydroxymethyl-2-methyl-pyridyl-C5) -methylthio sulfate sodium are refluxed in 50 ml of 15 % strength aqueous p-toluenesulfonic acid for 2 hours and then neutralized. Yield 2.85 g ( »89 $ of theory) of bis- / 3-hydroxy-4-hydroxymethyl-2-methyl-pyridyl (5) -methylj-disulfide, mp 220-222 ⁰ C (decomposition).

Example 6

6 g of 2-methyl-3-acetoxy-4-acetoxymethyl-pyridyl (5) -methylthiosulfate sodium (prepared by reacting the corresponding 5-bromomethyl-pyridine compound with sodium thiοsulfate) are dissolved in 60 ml of 2N hydrochloric acid for 1/2 hour on Boiled under reflux and then neutralized with 2N sodium hydroxide solution. The precipitated Bi s- ^ j-hydroxy ^ -hydroxymethyl-2-methyl-pyridyl- (5) methyl7-disulfide is filtered off with suction. Yield 2.8 g (= 85% of theory), mp 220-222 ⁰ C (decomposition).

Example 7

24 g of sodium thi ο sulfate are dissolved in 200 ml of water, then with 22.8 g of 4 ^f , 5 ^f -isopropylidene-3-chloromethyl-5-hydroxy-4-hydroxymethyl-6-methyl-pyridine (P. 100 ⁰ C) ^{added and heated to 60 °} C. for 2 hours with stirring. The solution is mixed with 50 ml of concentrated hydrochloric acid and then refluxed for 30 minutes. After cooling down, the pH

1 0 9 8 1 ^{2/1 8 2 2 WCC3INAL INSPECTE} °

the solution adjusted to 6-7 with dilute sodium hydroxide solution and the precipitated bis- £ 5-hydroxy-4-hydroxymethyl-2-methylpyridyl- (5) -metnyl7-disulfide sucked off. Yield 17.3 g, P. 220-222 ° (decomposition). ·

Example 8

5.35 g of 4 ', 5'-cyclohexylidene ^ -chlomethyl ^ -hydroxy ^ -hydroxymethyl-6-methyl-pyridine are suspended in 50 ml of water, then 4.5 g of sodium thiosulfate are added and the mixture is ^{heated to 60 °} C. for 3 hours with stirring . Then 10 ml of concentrated hydrochloric acid are added, then the reaction mixture is refluxed for 30 minutes. After cooling, the acidic solution is extracted with ether to remove the split-off cyclohexanone. The solution is neutralized with dilute sodium hydroxide solution and the precipitated bis- / 3-hydroxyr4-hydroxymethyl-2-methyl-pyridyl- (5) -methy ^ -disulfide is suctioned off. Yield 3.1 g; M.p. 220-222 ° (decomposition).

1 0 9 H 1 ? / 1 8 2 2

Claims (2)

Claims ^R 2 ° - ^ = V-CH ₂ -S-SO ₃ -M (II) RJ and R _{2 are} identical or different and are hydrogen, acyl or together the radical CC mean Rj and R. are the same or different and Hydrogen or lower alkyl or together a lower alkylideral group mean or with each other to form a 5- or 6-membered Hydrocarbon ring connected are and M is an alkali metal, preferably sodium or potassium, ORIGINAL INSPECTED 109812/1822 Untürlayofι i * "· '·' S ι Aba, a No. ι sau 3 - '■ treated with an acidic agent, the reaction mixture is then adjusted to a neutral or optionally weakly acidic or weakly alkaline pH and optionally the end product of the formula I thus obtained is converted into an acid addition salt or quaternary in a manner known per se
Ammonium salt transferred. 2. The method according to claim 1, characterized in that a dilute strong mineral acid is used as the acidic agent will. 3 · Method according to claim 1 and 2, characterized in that
that dilute, preferably 1-4N, hydrochloric acid is used
will. 109812/1822