Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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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
R-CH3
HO ~ H2-S-CH3 II
H3C
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.
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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.
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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-
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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.
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EXAMPLE 1
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).
EXAMPLE 2
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~.
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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.
EXAMPLE 3
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.
EXAMPLE 4
Dissolve 197 g. of 2-methyl-3-hydroxy-4-formyl-5-
methylmercaptomethyl-pyridine in 2,000 ml. of methanol,
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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.