CA1068710A

CA1068710A - Preparation of 2-methyl-3-hydroxy-4-ethylaminomethyl-5-methylmercaptomethyl-pyridine and its acid addition salts

Info

Publication number: CA1068710A
Application number: CA236,795A
Authority: CA
Inventors: Otto Saiko
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1974-10-02
Filing date: 1975-10-01
Publication date: 1979-12-25
Also published as: CH602650A5; CS188253B2; IE41740B1; IE41740L; ATA746775A; BE833984A; AT350568B; FR2286818A1; LU73493A1; NL7511253A; GB1461068A; YU247075A; SE7511011L; JPS5141364A; ES441425A1; DK442975A; DE2447053A1; FR2286818B1

Abstract

ABSTRACT OF THE DISCLOSURE
2-Methyl-3-hydroxy-4-ethylaminomethyl-5-methylmercapto-methyl-pyridine and its acid addition salts are produced by a novel process involving treating a pyridine derivative of the general formula

Description

la6s7l0 This invention relates to a novel process for the preparation of 2-methyl-3-hydroxy-4-ethylaminomethyl-5-methylmercaptomethyl-pyridine and its acid addition salts.
These known compounds exhibit valuable pharmacological properties and can, therefore, be used as pharmaceuticals.
In particular, they exhibit electroencephalogram-modifying activity. See, U.S. Patents Nos. 3,658,825 issued to G. Schorre et al., April 25, 1972, and 3,759,930 issued to G. Schorre et al., September 18, 1973.
The known processes for the preparation of these compounds have various disadvantages, viz., some do not produce pure products and in some the yields are unsatisfactory.
It has now been found that these compounds can be produced according to the process of this invention in very high yields and in excellent purity.
According to the process of a broad aspect of this in-vention, 2-methyl-3-hydroxy-4-ethylaminomethyl-5-methyl-mercaptomethyl-pyridine (I) and its acid addition salts are prepared by treating a pyridine derivative of the general Formula II

HO ~ H2-S-CH3 II

wherein R is -CH=N-CH2- or -CH2-N=CH-, or a salt thereof, with sodium borohydride, with zinc and an acid, or with hydrogen in the presence of Raney nickel.

~06~7~0 The reduction with sodium borohydrideis carried out in the usual manner, viz., in the presence of an inert solvent, preferably in the presence of water and/or an alcohol, e.g., methanol or ethanol. Reaction temperatures generally are from 0 to 50 C., preferably 10 to 30 C.
In the reduction with zinc and an acid, the zinc is advantageously used in the form of zinc dust. Preferred acids are aliphatic carboxylic acids with up to 4 carbon atoms, especially acetic acid but also formic acid, propionic acid and butyric acid, as well as mineral acids, e.g., hydro-chloric acid and sulfuric acid. This reaction is conveniently conducted at 20 to 100 C., preferably 40 to 70 C.
The hydrogenation with Raney nickel can be conducted in an acidic, neutral or basic range, preferably in the presence of an inert solvent, preferably an alcohol, such as, for example, methanol or ethanol, but also esters, e.g., ethyl acetate, carboxylic acids, e.g., formic acid, acetic acid and propionic acid and ethers, e.g., tetrahydrofuran and dioxane. The hydrogenation is expediently conducted at temperatures of -20 to +150 C., preferably from room temp-erature to +100 C., and at pressures from 1 to 100, preferably 1 to 10 atms.
Of the Schiff's bases of Formula II, 2-methyl-3-hydroxy-4-ethyliminomethyl-5-methylmercaptomethyl-pyridine (IIa) is known and can readily be obtained from 2-methyl-3-hydroxy-4-formyl-5-methylmercaptomethyl-pyridine and ethylamine. See the aforementioned U.S. Patent No. 3,658,825.

The Schiff's base 2-methyl-3-hydroxy-4-ethylidene-aminomethyl-5-methylmercaptomethyl-pyridine (IIb~ is obtain-able in the conventional manner from 2-methyl-3-hydroxy-4-aminomethyl-5-meihylmercaptomethyl-pyridine and acetaldehyde.
In an especially advantageous embodiment of the process, the starting compounds of Formula II are formed in situ from the correspondin~ aldehydçs and the correspond-ing amines and subsequently reduced as described above, without isolation, which overall reaction can be illustrated by the following reaction schemes:

~HO
HO ~ CH - S-CH

~ [IIa]
H3C~" N + CH3CH2NH2 CH 2NH 2 [ H~
HO~ CH2-S-CH3 [IIbl /

H C J` ~ + CH 3CHO

The thus-obtained base of Formula I can, if desired, be converted with an acid in the conventional manner into an acid addition salt thereof, preferably'a physiologically acceptable acid addition salt, unless the salt is formed for isolation, characterization or purification purposes only. For this purpose, there can be used inorganic acids, e.g., sulfuric acid, nitric acid, hydrohalic acids, e-g-~068710 as hydrochloric acid or hydrobromic acid, phosphoric acids,e.g., orthophosphoric acid, sulfamic acid, and organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- and polybasic carboxylic or sulfonic acids, e.g., formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, salicylic acid, 2~phenylpropionic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulfonic acid, ethane-disulfonic acid, 2-hydroxyeth~ne-sulfonic acid, benzene-sulfonic acid, p-toluene-sulfonic acid, naphthalene-mono- and di-sulfonic acids.
The free base of Formula I can, if desired, be liberated from its acid addition salt thereof by treatment with a strong base, e.g., sodium or potassium hydroxide, sodium or potassium carbonate.
The process of aspects of this invention yields the free base I and its acid addition salts in very high yields and in a very pure form practically free from byproducts. The thus-obtained compounds can be worked up directly, without further purification, into the usual pharmaceutical compositions.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative.

Dissolve 22.4 g. of 2-methyl-3-hydroxy-4-ethylimino-methyl-5-methylmercaptomethyl-pyridine (IIa; m.p. 43 C., obtainable from 2-methyl-3-hydroxy-4-formyl-5-methylmercapto-methyl-pyridine and ethylamine) in 100 ml. methanol and add thereto 3.7 g. of sodium borohydride portionwise, with cooling. The reaction mixture thereafter is filtered, the filtrate is acidified with cooling with ethanolic hydrochloric acid, and mixed with ether. The precipitated 2-methyl-3-hydroxy-4-ethylaminomethyl-5-methylmercaptomethyl-pyridine dihydrochloride (I-dihydrochloride) is filtered off with suction, washed with ether, dried and recrystallized from methanol/ether, m.p. 245 C. The product obtained in thin layer chromatographically pure. The yield is quantitative.
The same product is obtained analogously from 2-methyl-3-hydroxy-4-ethylideneaminomethyl-5-methylmercaptomethyl-pyridine (IIb).

Dissolve 19.7 g. of 2-methyl-3-hydroxy-4-formyl-5-methylmercaptomethyl-pyridine in 200 ml. ethanol, add thereto 20 ml. of ethylamine and boil briefly. After cooling, add thereto a further 6 ml. of ethylamine, evaporate the solvent, dissolve the thus-produced crude free base of Formula IIa in 100 ml. ethanol. Introduce into the ethanol solution proportionwise, with cooling, 3.7 g. of sodium borohydride and work the reaction product up as described in Example 1. There is obtained I-dihydrochloride, m.p. 245 C., in an overall yield of 90~.

1(~68710 The same compound is obtained by the reaction of

2-methyl-3-hydroxy-4-aminomethyl-5-methylmercaptomethyl-pyridine with acetaldehyde and subsequent reduction of the crude free base of Formula IIb thus-obtained.

Dissolve 19.7 g. of 2-methyl-3-hydroxy-4-formyl-5-methylmercaptomethyl-pyridine and 26 ml. ethylamine in 200 ml. of methanol, boil for 15 minutes and evaporate the solvent. Dissolve the crude free base of Formula IIa thus-obtained in 650 ml. of acetic acid. Add thereto 32.5 g.
zinc dust within 5 minutes and then heat to 70 C., cool to 40 C., and again add thereto another 32.5 g. of zinc dust.
Again heat to 70 C., cool to 40 C. and add thereto still another 32.5 g. of zinc dust. After briefly heating to 50 C., cool and filter the reaction mixture, acidify the filtrate with ethanolic hydrochloric acid and then evaporate the solvent. The I-dihydrochloride obtained, after the addition of ether, is filtered off with suction and re-crystallized from methanol/ether. The overall yield of product, m.p. 245 C., is 83%.
The same compound is obtained by the reaction of 2-methyl-3-hydroxy-4-aminomethyl-5-methylmercaptomethyl-pyridine with acetaldehyde and subsequent reduction of the crude free base of Formula IIb thus-obtained.

Dissolve 197 g. of 2-methyl-3-hydroxy-4-formyl-5-methylmercaptomethyl-pyridine in 2,000 ml. of methanol, add thereto 195 g. of ethylamine and boil for a few minutes.
Cool and mix with a further 60 g. of ethylamine. The solution thus-obtained is hydrogenated on 40 g. of Raney nickel at 3 atms. and 20 C. for 3 hours. Filter, evaporate the solvent and work up analogously to Example 1. There is obtained I-dihydrochloride, m.p. 245 C., in quantitative yield.
The same compound is obtained by the reaction of 2-methyl-3-hydroxy-4-aminomethyl-5-methylmercaptomethyl-pyridine with acetaldehyde and subsequent reduction of thecrude free base of Formula IIb thus-obtained.
The preceding examples can be repeated with similar suc~ess by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are as follows:

1. A process for the production of 2-methyl-3-hydroxy-4-ethylaminomethyl-5-methylmercaptomethyl-pyridine and its acid addition salts, which comprises treating a pyridine derivative of the formula wherein R is -CH=N-CH2- or -CH2-N=CH-, or an acid addition salt thereof, with sodium borohydride, with zinc and an acid, or with hydrogen in the presence of Raney nickel.

2. A process according to Claim 1, wherein the starting pyridine derivative is treated with sodium borohydride.

3. A process according to Claim 2, wherein R is -CH=N-CH2-.

4. A process according to Claim 1, wherein the starting pyridine derivative is treated with zinc and acetic acid.

5. A process according to Claim 4, wherein R is -CH=N-CH2-.

6. A process according to Claim 1, wherein the starting pyridine derivative is treated with hydrogen in the presence of Raney nickel.

7. A process according to Claim 6, wherein R is -CH=N-CH2-.

8. A process according to Claim 1, wherein the starting pyridine derivative is produced in situ from the corresponding aldehyde and amine and used without isolation or purificaton.

9. A process according to Claim 8, wherein the starting amine and aldehyde are ethylamine and 2-methyl-3-hydroxy-4-formyl-5-methylmercaptomethyl-pyridine.

10. A process according to Claim 9, wherein the pyridine derivative is treated with sodium borohydride.

11. A process according to Claim 10, wherein the reaction is effected in an inert solvent at a temperature of from 0° to 50°C.

12. A process according to Claim 11, wherein the inert solvent is at least one of water, methanol or ethanol, and the temperature is from 10° to 30°C.

13. A process according to Claim 9, wherein the pyridine derivative is treated with hydrogen in the presence of Raney nickel.

14. A process according to Claim 13, wherein the reaction is effected in an inert solvent, at a temperature of from -20° to +150°C, and a pressure of from 1 to 100 atmospheres.

15. A process according to Claim 14, wherein the inert solvent is at least one of methanol or ethanol, the temperature is from room temperature to +100°C, and the pressure is from 1 to 10 atmospheres.