Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
108405Z
1 This invention relates to a process for
preparing substituted imidazole compounds which are useful
intermediates in the preparation of compounds having
pharmacological activity. In particular, the invention
relates to a process for preparing 4-(oxy, thio or amino)-
methylimidazoles via displacement of the trisubstituted
phosphonium group from a 4-(trisubstituted phosphonium)-
methylimidazole compound which is represented as follows:
Rl ~H2P (R ) 3 Rl CH2R2
~N R2H ~ ~\ 5
~/ H ~ ~ H + P ~R ) 3
R3 R3
I II
in which Rl is hydrogen or lower alkyl, preferably methyl;
R2 is methoxy, ethoxy, n-propoxy, n-butoxy, i-butoxy,
NCN
2 t-butoxy~ -ScH2cH2NH2' -SCH2CH2NHC~ or -NR R
O NHCH3
where R and R are each hydrogen, lower alkyl or together
with the nitrogen atom to which they are attached form a
piperidine, pyrrolidine or morpholine ring; R3 is hydrogen,
lower alkyl, trifluoromethyl, benzyl, amino or -SR4 where R4
is lower alkyl, preferably methyl, phenyl, benzyl or
chlorobenzyl; R5 is lower alkyl or, preferably, phenyl and X
is halo, preferably chloro or bromo. Preferably, R2 is
~, .
1084052
1 ~NCN
-SCH2CH2NH2 or -SCH2CH2NHC
NHCH3
The 4-(trisubstituted phosphonium)methyl-
imidazole compounds of Fsrmula I are also objects of this
invention.
As used herein, the term "lower alkyl" refers
to groups containing from one to four carbon atoms.
According to the above process, the displacement
~ 5
of a trisubstituted phosphonium group [-P(R )3] of a
compound of formula I is effected by reaction of a compound
of formula I with R2H under basic conditions, that is with
R2H in the form of its anion R2 ~. The anion may be formed
from in situ reaction of a compound of the formula R2H and
a strong base. Among the bases which may be used in the
process of this invention are those which are cap~ble of
removing the proton from a compound of the formula R2H to
form the anion R2 ~ where R2 is defined as above. Such
bases are those having a pKa greater than 12, for example
the alkali metal alkoxides such as sodium methoxide or
ethoxide or the metal hydrides such as sodium hydride
which are preferred. When R2H is itself sufficiently basic,
for example when R2H is piperidine, no additional base need
be used. In those cases where R2H is extremely volatile,
such as when R2 is -NR6R7 and one or both of R6 and R7
are hydrogen, it is preferable that R2H be in the form of
a metalate, for example sodium or lithium metalate, such
as sodium amide. Preferably, a slight excess of R2H is
present.
3~
iO84052
The reaction is carried out in an organic solvent
with solvents such as methanol, ethanol, propanol, butanol,
acetone, acetonitrile, dimethylformamide and dimethylsulfoxide
being preferred. Preferably, the reaction is carried out
at a temperature ranging from about ambient temperature
to the reflux temperature of the solvent used in the
reaction, viz. from about 25C. to about 200C., about
65C. to about 100C. being advantageous, for from about
20 minutes to about 24 hours, advantageously from about
20 minutes to about 3 hours.
Preferably, the reaction mixture is worked up
by dilution with water and removal of the trialkyl- or
triphenylphosphine by-product by filtration. Extraction of
the filtrate when necessary followed by evaporation gives
the compounds of formula II. It is often desirable to
convert the compounds of formula II to the corresponding
salts, preferably hydrochloride salts. Such salts are
prepared by treating a solution of the imidazole of
formula II with an acid or acid solution, for example with
an ethereal or ethanolic solution of hydrochloric acid, and
crystallizing the salt produced from an appropriate solvent.
The 4-(trisubstituted phosphonium)-
methylimidazoles of formula I are prepared from reaction of
a trisubstituted ~-acylvinylphosphonium halide, preferably
bromide or chloride, of the formula
.
(R5)3P ~ Rl where Rl, R5 and X are defined as
~) ,
above with a compound of the formula
--4--
~0t34052
I R3
H2N ~ NH where R3 is defined as above other than
hydrogen, according to the procedure described by Zbiral,
S Synthesis 11:775 (1974) and Zbiral and Hugl, Phosphorus 2:29
(1972). When R3 is hydrogen, the corresponding 4-(trisubstituted
phosphonium)methylimidazoles of formula I are also prepared
by reaction of trichloroacetamidine or formamidine sulfinic
acid with a triphenyl ~-acylvinylphosphonium halide. In
the formamidine sulfinic acid process a base is used,
preferably a non-nucleophilic base such as a tertiary amine.
To prepare the trisubstituted ~-acylvinylphos-
phonium halides not known to the art, a halovinyl alkyl
ketone such as chlorovinyl methyl ketone is treated with a
trialkyl- or triphenylphosphine. When Rl is hydrogen, the
trisubstituted ~-formylvinylphosphonium halides are prepared
by oxidation of a ~-haloallyl alcohol such as ~-chloroallyl
alcohol and treatment of the product thus formed with a
trialkyl- or triphenylphosphine.
The process of this invention provides an
inexpensive, efficient and high yield method for preparing
certain imidazoles useful as intermediates in the
preparation of pharmacologically active compounds. A
further advantage of this process for the conversion of
2.5 compounds of formula I to those of formula II is that the
trisubstituted phosphines, P(R5)3, formed during the
course of the reaction may be easily removed from the
reaction mixture and recycled or otherwise reused.
The imidazole compounds of formula II prepared
by the process of this invention are useful as intermediates
for the production of pharmacologically active compounds
1084052
1 in particular histamine H2-antagonists, for example
N-cyano-N'-methyl-N"-[2-(5-Rl-imidazolylmethylthio)ethyl]-
guanidine and N-methyl-N'-[2-(5-Rl-imidazolylmethylthio)-
ethyl]thiourea compounds. Histamine H2-antagonists act at
histamine H2-receptors which as described by Black et al.
[Nature 236:385 (1972)] may be defined as those histamine
receptors which are not blocked by "antihistamines" such
as mepyramine but are blocked by burimamide. Blockade of
histamine ~2-receptors is of utility in inhibiting the
biological actions of histamine which are not inhibited by
"antihistamines". Histamine H2-antagonists are useful,
for example, as inhibitors of gastric acid secretion.
Conversion of the compounds of formula II to the
pharmacologically active guanidine and thiourea products
can be accomplished in a variety of ways. When R2 is
-SCH2CH2NH2 and R3 is hydrogen, lower alkyl, trifluoro-
methyl, benzyl or amino, the 4-(2-aminoethyl)thiomethyl-
imidazole compound of formula II is treated with methyl
isothiocyanate to give the corresponding N-methyl-N'-
[2-(5-Rl-imidazolylmethylthio~ethyl]thioureas. Reaction
of the same 4-(2-aminoethyl)thiomethylimidazole compound
with N-cyano-N',S-dimethylisothiourea gives the
corresponding N-cyano-N'-methyl-N"-[2-(5-Rl-imidazolyl-
methylthio)ethyl]guanidines. The guanidine products
~ are also prepared by reaction of the 4-(2-aminoethyl)-
_5
thiomethylimidazole with dimethyl-N-cyanoimidodithio-
carbonate and subsequently reacting the resulting
N-cyano-N'-[2-(5-Rl-imidazolylmethylthio)ethyl]-S-
methylisothiourea with methylamine. When R2 is
3~
--6--
108405Z
1 ~NCN
SCH2C~2NHC~ , the guanidine products are prepared
NHCH3
directly by the process of this invention.
When R2 is -SCH2CH2NH2 and R3 is -SR4 where R4
is defined as above, the compounds of formula II are
treated with a reducing agent, for example, with Raney
nickel, to give the corresponding 4-(2-aminoethyl)thio-
methylimidazoles where R3 is hydrogen which are then
converted to the guanidine and thiourea products as
NCN
described above. When R2 is -SCH2CH2NHC \ and R3 is
NHCH3
-SR4, treatment with a reducing agent gives the guanidine
product directly.
When R2 is methoxy, ethoxy, n-propoxy, n-butoxy,
i-butoxy, t-butoxy or -NR R and R3 is -SR4 where R4 is
defined as above, the -SR4 group of the compounds of
formula II is removed as described above and the products
thus formed are then treated with cysteamine to give the
4-(2-aminoethyl)thiomethylimidazole compounds where R3 is
hydrogen which are converted to the guanidine and thiourea
products as previously described.
When R is methoxy, ethoxy, n-propoxy, n-butoxy,
i-butoxy, t-butoxy or -NR6R7 and R3 is hydrogen, the
compounds of formula II are treated with cysteamine to
give the 4-(2-aminoethyl)thiomethylimidazoles which are
then converted to the guanidine and thiourea products
as previously described.
--7--
1084052
1 These thiourea and cyanoguanidine products
prepared from the compounds of formula II are described
in U.S. Patents 3,950,333 and 3,950,353.
The following examples illustrate the invention
but are not intended to limit the scope thereof.
Temperatures are in degrees Centigrade (C.) unless
otherwise indicated.
EXAMPLE 1
Sodium metal (25.3 g., 1.1 mole) was dissolved
in ethanol (2 L). 2-Methylpseudothiourea sulfate (278.3 g.,
1.0 mole) was added and the mixture was stirred for O.S
hour. Then 411 g. (1.0 mole) of triphenyl B-acetyl-
vinylphosphonium bromide was added and the mixture was
heated at reflux for 18 hours, cooled and filtered. The
filter cake was washed with 200 ml. of ethanol. The
filtrate and ethanol wash were combined and evaporated under
reduced pressure to leave a brown residue. Chloroform
(500 ml.) was added to the residue and the mixture was
stirred for a few minutes, then filtered. The filter cake
was washed three times with 150 ml. portions of chloroform
and dried to give 364 g. (75%) of [(2-methylthio-5-methyl-
imidazolyl)-4-methyl]triphenylphosphonium bromide.
Cysteamine (12.23 g., 0.13 mole) was dissolved
in 100 ml. methanol and 46.5 ml. of 25% wt/v sodium methoxide
solution added. After stirring at ambient temperature for
10 minutes, the solid phosphonium salt was added and the
mixture was refluxed for 20 minutes. The solution was
diluted with twice its volume of ice water and stirred.
The precipitated triphenyl phosphine was removed by
filtration. The filtrate was extracted with three 100 ml.
1084052
1 portions of chloroform and the chloroform extracts were
dried and evaporated to dryness to yield 19 g. (86%) of
4-(2-aminoethyl)thiomethyl-5-methyl-2-methylthioimidazole
as a viscous oil.
Treatment of 4-(2-aminoethyl)thiomethyl-5-methyl-
2-methylthioimidazole with ethanolic hydrochloric acid ga~e
the corresponding dihydrochloride salt, m.p. 165 (ethanol-
ethyl acetate).
EXANPLE 2
A solution of 48.3 g. (0.1 mole) of [t5-methyl-
2-methylthioimidazolyl)-4-methyl]triphenylphosphonium
bromide in 250 ml. of methanol was added rapidly at ambient
temperature to a stirred solution of 35 ml. of 25~ sodium
methoxide i~ methanol in 250 ml. of methanol. The mixture
was refluxed for 20 minutes then concentrated to half the
volume. After dilution with 900 ml. of water, the tri-
phenyl phosphine was removed ~y filtration. The aqueous
solution was extracted twice with 150 ml. portions of
benzene and then three times with 250 ml. portions of
chloroform. The chloroform extracts were dried (MgSO4)
and evaporated to dryness to give 13 g. (76%) of
4-methoxymethyl-5-methyl-2-methylthioimidazole.
EXAMPLE 3
Sodium metal (2.3 g., 0.1 mole) was dissolved in
ethanol and 9.5 g. (0.1 mole) of acetamidine hydrochloride
was added with stirring. After 10 minutes 41.1 g. (0.1
mole) of triphenyl ~-acetylvinylphosphonium bromide was
added and the mixture was refluxed for 17 hours. The
mixture was filtered and the filtrate evaporated to dryness
to give a tan solid which was digested with 300 ml. of
_g_
108405Z
1 chloroform. Ethyl acetate (100 ml.) was added and the
precipitate was collected by filtration and washed with
100 ml. of acetone to give 36 g. (80~) of [(2,5-dimethyl-
imidazolyl)-4-methyl]triphenylphosphonium bromide.
When an equivalent amount of [(2,5-dimethyl-
imidazolyl)-4-methyl]triphenylphosphonium bromide is
substituted into the procedures of Examples 1 and 2 for
[(2-methylthio-5-methylimidazolyl)-4-methyl]triphenyl-
phosphonium bromide, 4-(2-aminoethyl)thiomethyl-2,5-
dimethylimidazole and 2,5-dimethyl-4-methoxymethylimidazole
are prepared, respectively.
EXAMPLE 4
(a) Trichloroacetamidine (1.62 g., 0.1 mole)
was dissolved in 20 ml. of dry dimethylsulfoxide and 4.1 g.
(0.1 mole) of triphenyl ~-acetylvinylphosphonium bromide in
40 ml. of dimethylsulfoxide was added in one portion with
stirring. The exothermic reaction mixture gradually
lightened in color and was heated at 100 for 10 minutes.
Evaporation of the solvent gave [(5-methylimidazolyl)-4-
methyl]triphenylphosphonium bromide.
Alternatively, and preferably, the phosphonium
bromide is prepared using trichloroacetamidine by the
following procedures:
Triphenyl ~-acetylvinylphosphonium bromide (8.0 g.,
0.019 mole) was dissolved in a minimum amount of dry
acetonitrile (about 100 ml.) and trichloroacetamidine 14.0 g.,
0.25 mole) was added in one portion. The resulting mixture
was stirred at room temperature and the material which
crystallized out was filtered off to give [(2-trichloromethyl-
5-methylimidazolyl)-4-methyl]triphenylphosphonium bromide.
--10--
1084052
1 This phosphonium salt (15.0 g., 0.027 mole) was
added to 150 ml. of methanol and the resulting mixture was
refluxed for three hours. The mixture was concentrated to
about 15 ml. and the solid material was filtered off to give
[(2-methoxycarbonyl-5-methylimidazolyl)-4-methyl]triphenyl-
phosphonium bromide.
The above prepared phosphonium salt is heated to
its melt1ng point (approximately 170) and held at this
temperature until the evolution of gas is complete. On
cooling, the solid product is triturated with chloroform to
give ~(5-methylimidazolyl)-4-methyl]triphenylphosphonium
bromide.
Triphenyl ~-acetylvinylphosphonium chloride t36 g.,
0.01 mole) and trichloroacetamidine (16.1 g., 0.1 mole) were
stirred in 200 ml. of methanol for one hour. The solution
was heated to reflux, cooled and the methanol evaporated to
leave [(2-methoxycarbonyl-5~methylimidazolyl)-4-methyl]-
triphenylphosphonium chloride. Heating this phosphonium
chloride salt at 170 until evolution of gas is complete,
then cooling and triturating with chloroform gives
[(5-methylimidazolyl)-4-me_hyl]triphenylphosphonium chloride.
(b) Formamidine sulfinic acid (11.0 g., 0.1 mole)
was suspended in 250 ml. of dry dimethylsulfoxide and
2.4 g. (0.1 mole) of sodium hydride was added. After
cessation of hydrogen gas evolution 36.5 g. (0.1 mole) of
triphenyl 3-acetylvinylphosphonium chloride was added
and the mixture was stirred for one hour at ambient
temperature, then heated at 100 for 10 minutes. After
cooling, the dimethylsulfoxide was evaporated and the
3~ residue was dissolved in 300 ml. of 1:1 chloroform-methanol
1084052
1 and the solution filtered. The filtrate was evaporated to
dryness and the residue was recrystallized from chloroform-
acetone to give 20 g. (50%) of [(5-methylimidazolyl)-4-
methyl]triphenylphosphonium chloride, m.p. 223-225.
Alternatively, and preferably, [(5-methylimidazolyl)-
4-methyl]triphenylphosphonium chloride and bromide are
prepared using formamidine sulfinic acid by the following
procedures:
Triphenyl ~-acetylvinylphosphonium chloride (3.65 g.,
0.01 mole) and formamidine sulfinic acid (1.1 g., 0.01 mole)
were dissolved in 50 ml. of dimethylsulfoxide. 1,8-bis-
(nimethylamino)naphthalene ("proton sponge") (Z.14 g.,
0.01 mole) was added and the mixture warmed to 80. After
cooling, evaporating the dimethylsulfoxide, precipitating
the inorganic salts with chloroform, filtering, evaporating
to dryness and recrystallizing the residue from chloroform-
acetone, an essentially quantitative yield of
[(5-methylimidazolyl)-4-methyl]triphenylphosphonium chloride
was obtained.
Triphenyl ~-acetylvinylphosphonium bromide (20.6 g.,
0.05 mole) and formamidine sulfinic acid (6.0 g., slight excess
over 0.05 mole) were dissolved in 100 ml. of dimethylsulfoxide.
1,5-DiazabicyclolS.4.0]undec-5-ene (DBU)(7.6 g., 0.05 mole)
was added dropwise with stirring. The mixture was maintained
2 at 80 for 20 minutes and the dimethylsulfoxide was evaporated
off. The residue was taken up in chloroform and inorganic
salts were removed by filtration. The filtrate was evaporated
to dryness and the residue was recrystallized from chloroform-
acetone to give 1(5-methylimidazolyl)-4-methyl3triphenyl-
phosphonium bromide in 80% yield.
-12-
~08405Z
1 To a sclution of 39~3 g. (0.1 mole) of
[(5-methylimidazolyl)-4-methyl]triphenylphosphonium chloride
in 200 ml. of methanol was added 22 ml. of 25% sodium methoxide
in methanol and the re~ction mixture was refluxed for 1
hour. After cooling, the solution was diluted with three
times its volume of water and filtered to remove triphenyl
phosphine. The filtrate was extracted with four 125 ml.
portions of chloroform and the extracts were dried (MgSO4)
and evaporated to dryness to yield 10.1 g. (80~) of
4-methoxymethyl-5-methylimidazole which was converted to the
corresponding hydrochloride salt as described in Example 1,
m.p. 150.
EXAMPLE S
- Triphenyl ~-acetylvinylphosphonium bromide
(4.11 g., 0.01 mole) was added in one portion to a
stirred suspension of 1.1 g. (0.01 mole) of formamidine
sulfinic acid in 20 ml. of dimethylsulfoxide containing
0.25 g. of sodium hydride. The mixture was stirred at
ambient temperature for 1 hour then at 80 for an additional
hour. A solution of 0.99 g. (0.01 mole) of the sodium salt
of cysteamine, prepared by addition of two equivalents of
sodium methoxide to cysteamine dihydrochloride, in 10 ml.
of methanol was added and the resulting mixture was heated
at 70-80 for 4 hours. The mixture was diluted with twice
its volume of water and the triphenyl phosphine was removed
by filtration. The filtrate was extracted with 100 ml. of
toluene and with two 100 ml. ~ortions of chloroform. The
chloroform extracts were combined, dried (MgSO4) and
evaporated to dryness to give 4-(2-aminoethyl)thiomethyl-
5-methylimidazole.
-13-
~08~1~5Z
1 Alternatively, and preferably, the above described
reaction of triphenyl ~-acetylvinylphosphonium bromide and
formamidine sulfinic acid is carried out using 1,8-bis-
(dimethylamino)naphthalene or 1,5-diazabicyclo[5.4.0]undec-
5-ene by the procedures described in Example 4~b).
EXAM2LE 6
When an equivalent amount of triphenyl
~-ethylcarbonylvinylphosphonium bromide or triphenyl
~-isopropylcarbonylvinylphosphonium bromide is allowed
to react with formamidine sulfinic acid as described in
the procedure of Example 4, [(5-ethylimidazolyl)-4-methyl]-
triphenylphosphonium bromide and [(5-isopropylimidazolyl)-
4-methyl]triphenylphosphonium bromide are prepared,
respectively.
Reaction of [(5-ethylimidazolyl)-4-methyl]-
triphenylphosphonium bromide and [(5-isopropylimidazolyl)-4-
methyl]triphenylphosphonium bromide with cysteamine in the
presence of sodium methoxide or sodium hydride as described
above gives 4-(2-aminoethyl)thiomethyl-5-ethylimidazole and
4-~2-aminoethyl)thiomethyl-5-isopropylimidazole,
respectively.
In a similar manner, the triphenylphosphonium
group of [(5-ethylimidazolyl)-4-methyl]triphenylphosphonium
bromide and r(5-isopropylimidazolyl)-4-methyl]triphenyl-
phosphonium bromide is displaced by reaction with other
nucleophiles by procedures described herein.
EXAMPLE 7
When [(5-methylimidazolyl-4-methyl]triphenyl-
phosphonium bromide is allowed to react with sodium ethoxide
in ethanol, sodium n-propoxide in n-propanol or sodium
t-butoxide in t-butanol according to thQ procedure described
in Example 4(b), the following imidazole compounds are
~084052
obtained:
4-ethoxymethyl-5-methylimidazole
5-methyl-4-n-propoxymethylimidazole
4-t-butoxymethyl-5-methylimidazole.
EXAMPLE 8
Substitution of a salt of a 2-substituted
pseudothiourea listed below:
2-ethylpseudothiourea
2-butylpseudothiourea
2-benzylpseudothiourea
2-phenylpseudothiourea
2-(4-chlorobenzyl)pseudothiourea
in the procedure of Example l in place of 2-methylpseudo-
thiourea sulfate gives the following triphenylphosphonium
bromide compounds:
[(2-ethylthio-5-methylimidazolyl)-4-methyl]-
triphenylphosphonium bromide
l(2-butylthio-5-methylimidazolyl)-4-methyl]-
triphenylphosphonium bromide
[(2-benzylthio-5-methylimidazolyl)-4-methyl]-
triphenylphosphonium bromide
[(5-methyl-2-phenylthioimidazolyl)-4-methyl]-
triphenylphosphonium bromide
[(2-(4-chlorobenzyl)thio-5-methylimidazolyl)-4-
methyl]triphenylphosphonium bromide.
Reaction of a triphenylphosphonium bromide listed
above with cysteamine as described in Example 1 gives the
imidazole compounds listed below:
4-(2-aminoethyl)thiomethyl-2-ethylthio-5-
methylimidazole
-15-
1084~52
1 4-(2-aminoethyl)thiomethyl-2-butylthio-5-
methylimidazole
4-(2-aminoethyl)thiomethyl-2-benæylthio-5-
methylimidazole
4-(2-aminoethyl)thiomethyl-5-methyl-2-
phenylthioimidazole
4-(2-aminoethyl)thiomethyl-2-(4-chlorobenzyl)-
thio-5-methylimidazole.
EXAMPLE 9
Substitution of a salt of a substituted amidine
listed below:
guanidine
propionamidine
valeramidine
2,2,2-trifluoroacetamidine
2-phenylacetamidine
in the procedure of Example 3 for acetamidine hydrochloride
gives the triphenylphosphonium bromides listed below:
[(2-amino-5-methylimidazolyl)-4-methyl]triphenyl-
phosphonium bromide
[(2-ethyl-5-methylimidazolyl)-4-methyl]triphenyl-
phosphonium bromide
[(2-butyl-5-methylimidazolyl)-4-methyl]triphenyl-
phosphonium bromide
[(5-methyl-2-trifluoromethylimidazolyl)-4-methyl]-
triphenylphosphonium bromide
~(2-benzyl-5-methylimidazolyl)-4-methyl]triphenyl-
phosphonium bromide.
Reaction of a triphenylphosphonium bromide listed
above with cysteamine as described in the procedure of
Example 1 gives the following imidazole compounds:
-16-
108405Z
1 2-amino-4-(2-aminoethyl)thiomethyl-5-methyl-
imidazole
4-(2-aminoethyl)thiomethyl-2-ethyl-5-methyl-
imidazole
4-(2-aminoethyl)thiomethyl-2-butyl-5-methyl-
imidazole
4-(2-aminoethyl)thiomethyl-5-methyl-2-trifluoro-
methylimidazole
4-(2-aminoethyl)thiomethyl-2-benzyl-5-methyl-
imidazole.
EXAMPLE 10
To a solution of 9.25 g. (0.1 mole) of
B-chloroallyl alcohol in 100 ml. of benzene is added an
equivalent amount of an aqueous solution of chromic acid-
sulfuric acid (Jones reagent) and the mixture is stirred
at ambient temperature for 1 hour. After filtering, the
layers are separated and the organic phase is washed with
water. Triphenyl phosphine (26.2 g., 0.1 mole) is added
to the benzene solution and it is heated to reflux. The
precipitate which forms upon cooling is collected by
filtration and dried to give B-formylvinylphosphonium
chloride.
When an equivalent amount of B-formylvinyl-
phosphonium chloride is allowed to react with formamidine
sulfinic acid as described in the procedure of Example 4,
(imidazolyl-4-methyl)triphenylphosphonium chloride is
prepared.
Reaction of (imidazolyl-4-methyl)triphenyl-
phosphonium chloride with cysteamine in the presence of
sodium methoxide or sodium hydride as described hereinabove
gives 4-(2-aminoethyl)thiomethylimidazole.
-17-
~(~84~52
1 I~ a similar manner, the triphenylphosphonium
group of (imidazolyl-4-methyl)triphenylphosphonium chloride
is displaced by reaction with other nucleophiles by
procedures described herein.
EXAMPLE ll
Tri-n-butylphosphine (20.2 g., 0.1 mole) is
added to a solution of 10.4 g. (0.1 mole) of chlorovinyl
methyl ketone in 250 ml. of benzene and the mixture is
refluxed for l hour. The mixture is cooled and the
precipitated material is collected by filtration and dried
to give tri-n-butyl ~-acetylvinylphosphonium chloride.
Triethyl ~-acetylvinylphosphonium chloride is
prepared as described above by use of triethylphosphine
in place of tri-n-butylphosphine.
Reaction of an equivalent amount of tri-n-
butyl ~-acetylvinylphosphonium chloride or triethyl
~-acetylvinylphosphonium chloride with formamidine sulfinic
acid as described in the procedure of Example 4 gives
[(5-methylimidazolyl)-4-methyl]tri-n-butylphosphonium
chloride and [(5-methylimidazolyl)-4-methyl]triethylphos-
phonium chloride, respectively.
Reaction of [(5-methylimidazolyl)-4-methyl]tri-
n-butylphosphonium chloride or [(5-methylimidazolyl)-4-
methyl~triethylphosphonium chloride with cysteamine in the
presence of sodium methoxide or sodium hydride as described
hereinabove gives 4-(2-aminoethyl)thiomethyl-5-methyl-
imidazole.
EXAMPLE 12
Sodium amide (0.39 g., 0.01 mole) was dissolved
in 40 ml. of liquid ammonia and 4.11 g. (0.01 mole) of
3~
-18-
1084052
1 [(5-methylimidazolyl)-4-methyl]triphenylphosphonium bromide
was added. The suspension was stirred at -40C. for one
hour and then allowed to warm to room temperature as the
ammonia evaporated. The triphenyl phosphine was extracted
from the residue with benzene and the remaining solids
were taken up in water and extracted with chloroform. The
chloroform extracts were dried and evaporated to give
4-aminomethyl-5-methylimidazole in 70% yield. This amine
was refluxed with a molar equivalent of cysteamine in acetic
acid and treated with hydrochloric acid to give 4-(2-amino-
ethyl)thiomethyl-5-methylimidazole dihydrochloride.
EXAMPLE 13
[(5-Methyl-2-methylthioimidazolyl)-4-methyl]-
triphenylphosphonium bromide (4.83 g., 0.01 mole) was stirred
in 20 ml. of piperidine at room temperature for 30 minutes,
then refluxed for one hour, cooled and filtered. The filtrate
was evaporated under reduced pressure and chromatographed
on a silica gel column using chloroform/methanol as eluant
to yield 5-methyl-2-methylthio-4-piperidinomethylimidazole.
Treating with hydrochloric acid and refluxing the resulting
dihydrochloride salt with one molar equivalent of cysteamine
in acetic acid gave 4-(2-aminoethyl)thiomethyl-5-methyl-2-
methylthioimidazole dihydrochloride.
By the same procedure, using pyrrolidine in place
of piperidine, 5-methyl-2-methylthio-4-pyrrolidinomethyl-
imidazole is prepared.
Similarly, using morpholine in place of piperidine,
5-methyl-2-methylthio-4-morpholinomethylimidazole is prepared.
Converting these pyrrolidine and morpholine
compounds to the dihydrochloride salts and treating with
--19--
1084052
1 cysteamine in acetic acid gives 4-(2-aminoethyl)thiomethyl-
5-methyl-2-methylthioimidazole dihydrochloride.
EXAMPLE 14
Dimethylamine (0.5 g., 0.01 mole) was dissolved
in 35 ml. of tetrahydrofuran, stirred and cooled in an ice
bath while 5 ml. (0.01 mole) of 2M butyl lithium in hexane
was added dropwise with stirring. After stirring the mixture
for 15 minutes in the cold, 3.93 g. (0.01 mole) of [(5-methyl-
imidazolyl)-4-methyl]triphenylphosphonium chloride was added
and the solution allowed to warm to room temperature. After
stirring for two hours at room temperature, the solvents were
evaporated and the residue treated with 50 ml. of water.
Filtration yielded diphenyl phosphine. The aqueous filtrate
was extracted with chloroform, dried and evaporated to afford
4-(N,N-dimethylaminomethyl)-5-methylimidazole. This amine
was then refluxed with a molar equivalent of cysteamine in
acetic acid and treated with hydrochloric acid to give
4-(2-aminoethyl)thiomethyl-S-methylimidazole dihydrochloride.
By the same procedure, using methylamine in place
of dimethylamine, 4-(N-methylaminomethyl)-5-methylimidazole
is prepared. In the same way, using butylamine and
dibutylamine, 4-(N-butylaminomethyl)-5-methylimidazole
and 4-(N,N-dibutylaminomethyl)-5-methylimidazole are prepared.
Refluxing these intermediates with cysteamine by the above
2 procedure and treating with hydrochloric acid gives
4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloxide.
EXAMPLE 15
N-Cyano-N'-methyl-N"-mercaptoethylguanidine
(1.58 g., 0.01 mole) was dissolved in 15 ml. of methanol and
2.3 ml. of sodium methoxide in methanol was added. After
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~o8405Z
1 stirring at room temperature for five minutes, a suspension
of 3.93 g. of [(5-methylimidazolyl)-4-methyl]triphenyl-
phosphonium chloride in 10 ml. of methanol was added. The
solution was heated to reflux. An equal volume of water was
added and most of the methanol was removed by evaporation.
Filtration and water washing afforded triphenylphosphine. The
filtrate was treated with charcoal, filtered and concentrated.
Filtration gave N-cyano-N'-methyl-N"-[2-(5-methyl-4-
imidazolylmethylthio)ethyl]guanidine.
EXAMPLE 16
A mixture of 6.6 g. (0.03 mole) of 4-(2-amino-
ethyl)thiomethyl-5-methyl-2-methylthioimidazole and 6.6.g.
of 50:50 nickel-aluminum alloy in 50 ml. of formic acid
was refluxed for 3 hours. The metals were removed by
L5 filtration and the filtrate was evaporated to dryness. The
residue was dissolved in ethanol and the ethanolic solution
was saturated with hydrogen sulfide then filtered. The
filtrate was saturated with hydrogen chloride. Addition of
ethyl acetate caused precipitation of 4-(2-aminoethyl)-
thiomethyl-5-methylimidazole as the dihydrochloride salt.
In a similar manner, the 2-substituted thio
group is removed from the other imidazole compounds in which
R3 is a substituted thio group prepared hereinabove.
Potassium carbonate (7.75 g.) was added to a
solution of 14.6 g. of 4-(2-aminoethyl)thiomethyl-5-
methylimidaæole dihydrochloride in 120 ml. of water. The
solution was maintained at ambient temperature for 15
mi~utes and 5.15 g. of methyl isothiocyanate was added.
After heating under reflux for 0.5 hour, the solution was
slowly cooled to 5. The product was collected and
- 108405Z
1 recrystallized from water to give N-methyl-N'-[2-(5-methyl-
4-imidazolylmethylthio)ethyl]thiourea, m.p. 150-152.
EXAMPLE 17
4-Methoxymethyl-5-methyl-2-methylthioimidazole
(13.46 g., 0.078 mole) and ca. 25 g. of Raney nickel were
added to 400 ml. of ethanol and the mixture was refluxed
for 3 hours. The mixture was filtered and the filter cake
was washed with 25 ml. of ethanol. The filtrate and
washings were combined and hydrogen sulfide gas was passed
into the solution for 10 minutes. The mixture was filtered
and the filtrate was evaporated to dryness to give 8.63 g.
(88%) of 4-methoxymethyl-5-methylimidazole.
4-Methoxymethyl-5-methylimidazole was converted
to the corresponding hydrochloride salt as described above.
4-Methoxymethyl-5-methylimidazole hydrochloride
(4.9 g., 0.03 mole) an~ 3.4 g. (0.03 mole) of cysteamine
hydrochloride were dissolved in a minimum amount of acetic
acid and the mixture was refluxed for 18 hours. After
cooling in an ice bath, the mixture was filtered to give
5.8 g. (80~) of 4-(2-aminoethyl)thiomethyl-5-methyl-
imidazole dihydrochloride salt.
Similarly, the other imidazoles prepared
hereinabove in which R2 is an alkoxy group and R3 is a
substituted thio group are reacted with Raney nickel
followed by treatment of the product thus formed with
cysteamine in acetic acid to give the corresponding
4-(2-aminoethyl)thiomethyl imidazoles.
(a) A solution of 17.0 g. of 4-(2-a~inoethyl)-
thiomethyl-5-methylimidazole and 11.2 g. of N-cyano-N',S-
dimethylisothiourea in 500 ml. of acetonitrile was refluxed
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for 24 hours. The mixture was concentrated and the
residue was chromatographed on a column of silica gel with
acetonitrile as eluant. The product obtained was
recrystallized from acetonitrile-ether to give N-cyano-N'-
methyl-N"- [2-(5-methyl-4-imidazolylmethylthio)ethyl]-
guanidine, m.p. 141-142.
(b) A solution of 23.4 g. of 4- (2-aminoethyl)-
thiomethyl-5-methylimidazole in ethanol was added slowly to
a solution of 20.0 g. of dimethyl-N-cyanoimidodithiocar-
bonate in ethanol, with stirring at ambient temperature.
Filtration afforded N-cyano-N'-[2-(5-methyl-4-imidazolyl-
methylthio)ethyl]-S-methylisothiourea, m.p. 148-150.
The filtrate was concentrated under reduced pressure and
the mixture was triturated with cold water to give a
solid material which was collected by filtration and
recrystallized twice from isopropanol-ether,
m.p. 148-150.
A solution of 75 ml. of 33% methylamine in
ethanol was added to a solution of 10.1 g. of N-cyano-
N'-[2- (5-methyl-4-imidazolylmethylthio)ethyl]-S-
methylisothiourea in 30 ml. of ethanol. The reaction
mixture was set aside at ambient temperature for 2.5
hours. Following concentration under reduced pressure,
the residue was recrystallized twice from isopropanol-
petroleum ether to give N-cyano-N'-methyl-N"-[2-(5-
methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p.
141-143.
EXAMPLE 18
Using [(2-methylthio-5-methylimidazolyl)-4-
methyl]triphenylphosphonium bromide in place of the
phosphonium compound in the procedure of Example 15
108405Z
1 gives N-cyano-N'-methyl-N"-[2-(2-methylthio-5-methyl-4-
imidazolylmethylthio)ethyl3guanidine. The 2-methylthio
group is removed by refluxing a mixture of the compound
and 50:50 nickel-aluminum alloy in formic acid and working
up by the procedure of Example 16 to give N-cyano-N'-
methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-
guanidine.
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