Note: Descriptions are shown in the official language in which they were submitted.
- ~83E;03
This inven-tion relates -to a new process for -the pro-
duction of mono-, di- and trisubs-tituted guanidines of -the
formula
Rl _ NH - C - NH - R (I)
N
R3
wherein each of Rl, R2, and R3 is hydrogen, an alkyl group 9
including cycloalkyl, having 1 to 6 carbon atoms, a phenyl_
alkyl group of not more than 3 carbon atoms in the alkyl
part, with the proviso that at leas-t one of Rl, R2, and
R shall be different from hydrogen.
Particularly, the compounds of formula I, wherein one
of the substituents Rl, R2, and R3 is a benzyl group or a
phenylethyl group are known and used therapeu-tically, because
they selectively depress sympha-te-tic nerve function and have
little or no effect on the parasymphatetic or central nerve
functions, cf. the British Patent Specification No. 973,882.
According to the said specification, the compounds may
be prepared by the reaction of ammonia or an ammonia deri-
vative or a salt thereof with a S-substituted isothiourea
or a salt thereof, for example as follows:
Rl-NH Rl-NH
C-SR + R2NH ~ C-NHR2 ~ RSH
+ ~ 2 +
XNH2 XNH2
In this scheme, Rl and R2 are as above defined, R is
an alkyl group, generally methyl, and X is an anion.
The foully smelling mercap-tans formed in this process have
to be removed completely, which may prove difficult and any-
way involves a separate purification process.
-- 2 --
.' '' 9~
~83~1~3
In the presen-t process, compounds of -the above formula
I are produced easily and in good yields from substituted
thioureas without formation of thef`oully smelling mercap-
tanes of -the known process.
Thus, according to -the invention, a N- or N,N'-substi-
tuted thiourea or isothiourea, or a salt -thereof, is oxi-
dized to form the corresponding formamidine-sulphonic acid,
which is subsequently reacted with ammonia or an amine to
yield the desired compound of formula I, as illustrated by
the following schemes of reaction, wherein Rl, R2, and R3
are as hereinbefore defined.
Rl_NH Rl_NH
CS + 3 H22 ~----~ C-S03H -~ 3 H20
R3-NH R3 -N
Rl_NH Rl-NH
C-S03H + R2NH2 > ~C~NH-R2 -~ H2S03
R3 -N ~ R3 -N
It will be noted that dependen-t upon the choice of` the
substituents Rl, R2, and R3, the process will yield mono-,
di- or -trisubs-tituted guanidines.
As illustrated by the schemes of reaction, hydrogen
peroxide is the preferred oxidizing agent, because it forms
water by the reaction, but other peroxides may be used.
I'he following examples are illustrative of the present
process.
Example 1
A. N-Benzyl-N'-methylformamidine sulphonic acid
To a mixture of 100 g of 34.6% hydrogen peroxide (1 mole)
" ~8~3
and 200 ml of water were added 45 g (0.25 mole) of N-benzyl-
N'-me-thylthiourea in small portions during two hours. The re-
action being exothermic, the temperature of the reaction mix-
ture was kept below 18C by cooling the reaction vessel in a
mix-ture of ice and water.
After the addition of the thiourea derivative, the re-
action mixture was left for two hours wi-thout cooling, thus
slowly reaching room temperature.
Then, it was again cooled in ice-water, whereby the title
compound precipitated as white crystals. The crystals were
filtered off and washed with a small volume of cold water and
finally with ether. The yield was 44 g (0.19 mole), correspond-
ing to 76% of the theoretical yield. The compound mel-ted at
120-125C under decomposition.
B. N-Benzy]-N',N'-dimethyl~uanidinium iodide
4.56 g (0.020 mole) of N-benzyl-N'-methylformamidine
sulphonic acid, a 24% solution of 15 ml methylamine in water,
and 50 ml of water were mixed, and the mixture was refluxed
for 6 hours. Excess of methylamine was removed by suction in
vacuum, after which -the volume of the reaction mixture was 50
ml. The mix-ture was acidified with concentrated hydrochloric
acid -to a pH between 1 and 2, after which 10 ml of a saturated
aqueous solution of NaI and 5 g of solid NaCl were added. The
mixture was then left overnight with stirring to yield a
cream-coloured precipitate of the title compound. The preci-
pitate was filtered off and recrystallized from ethanol to
yield 3.5 g (0.01148 mole), corresponding to 57.4% of the
theoretical yield. The melting point was 192-194C.
1~836~3
Example 2
N-Benz~1-N',N'-dimethyl~uanidinium iodide
A mixture of 3.0 g (0.0197 mole) of N,N'-dime-thylform-
amidine sulphonic acid (produced from N,N'-dimethylthiourea
in similar manner as described in step A of Example 1), 10 ml
(0.092 mole) of benzylamine and 60 ml of water were mixed and
refluxed for 3 1/2 hours. Concentrated hydrochloric acid was
added to a pH between 1 and 2, and then 10 ml of a saturated
aqueous solution of NaI were added. After s-tanding for a
short time, an almost white precipitate was formed.
The reaction mixture was cooled for about 2 hours in a
mixture of ice and water, when -the precipitate, consisting of
the title compound, was fil-tered off and recrystallized from
ethanol in a yield of 4.7 g (0.0154 mole) (7~%) with melting
point 192-194C.
.
Example 3
N-Benz~1-N'-N"-dimeth~lguanidinium iodide
A mixture of 12 g of N,N'-dimethylformamidine sulphonic
acid, 20 ml of benzylamine and 120 ml of waterwas stirred
overnight at room temperature. The mixturew~s then acidi-
fied to pH 1 with hydrochloric acid, and a saturated aqueous
solution of sodium iodidewas added. Af-ter stirring and cool-
ing for about one hour, the precipitate, consisting of the
title compound, was filtered off, washed first with water
and then with ether, and finally dried at 30C. The melting
point was 195C, and the yield was 19 g (79~).
8~6~313
Example l~
N,N',N"--trimethylguanidinium iodide
15.2 g (0.10 mole) of N,N'-dime-thylformamidine sulphon-
ic acid and 75 ml of a 24% aqueous solution of methylamine
were dissolved in 250 ml of water. The mixture was refluxed
for 3 hours. The surplus of methylamine was sucked off in
vacuum, after which concentrated hydrochloric acid was added
to give a pH between 1 and 2. Then, a saturated aqueous so-
lution of sodium iodide was added, resulting in a white pre-
cipitate of the -ti-tle compound. The precipitate was removed
by filtration and recrystallized from watèr as shining
white needles. The yield was 18.0 g (0.0786 mole, 78.6%)
with melting point above 320C.
Example 5
N,N'-dimethyl-N"-(3,4-meth~lenediox~benz~ nidinium
iodide
4.56 g (0.030 mole) of N,N'-dimethylformamidine sulphon-
ic acid and 18.1 g (0.12 mole) of 3,4-methylenedioxybenzyl-
amine were dissolved in 60 ml of water, and the solution
was refluxed for 4 1/2 hours. The reaction mixture was
then concentrated to a volume of 40 ml, af-ter which concen-
trated hydrochloric acid was added to give a pH between 1
and 3, and then 25 ml of a saturated aqueous solution of
sodium iodide were added. A white crystalline precipitate
of the title compound was formed, filtered off and washed
wi-th water. The yield was 8.4 g (0.0241 mole) corresponding
to 80.3% of the -theoretical yield, and -the melting point
was 211.0-212.0C.
10836~3
Example 6
N-(2-Chlorobenzyl)_N',N"-dime-thyl~uanidinium iodide
4.56 g (0.030 mole) of N,N'-dlrnethylformamidine sulphon-
ic acid and 17.0 g (0.12 mole) of 2--chlorobenzylamine were
dissolved in 60 ml of water, and the solution was refluxed
for 5 1/2 hours. The solution was acidified with concen-
trated hydrochloric acid to pH 1-3 and then 25 ml oi~ a sa-
turated aqueous solution of sodium iodide were added, where-
by a yellow oily substance separated. The reaction mixture
was stirred overnight, whereby the separated oil became semi-
crystalline. The paren-t lye was decan-ted off, and -the resi-
due was washed repea-tedly with ether, whereby all became
crystalline. The substance was recrystallized from water,
the solution being purified with active carbon 9 the title
compound again separating as an oil which, however, rapidly
became crystalline by scraping. The yield of the cream-
coloured compound was 6.7 g (0.0197 mole, 65.7%) with melt-
ing point 157.5-158.5C.
Example 7
N,N'-dimethyl-N"-(4-methoxybenz~ -guanidinium iodide
The procedure of Example 5 was repeated using 16.44 g
(0.12 mole) of 4-methoxybenzylamine instead of 2-chloro-
benzylamine. The title compound, also first separating as
an oil, was finally recovered as a white substance in a
yield of 5.8 g (0.0173 mole, 57.7%) with melting point
162.0 162.5 C D
336~3
Example 8
N-C~clohexyl-N',N"-dimethyl~uanidin:ium iodide
4.56 g (0,030 mole) of N,N'-dime-thylformamidine sulphon-
ic acid and 12.0 g (0.12 mole) of cyclohexylamine were dis-
solved in 60 ml of water. The mixture was stirred overnight
and then concentrated by evaporation to a volume of about
30 ml. The reaction mixture was then acidified with hydro-
chloric acid to pH 2, after which 10 ml of a saturated
aqueous solution of sodium iodide were added. An oily sub-
stance separated, which rapidly crystallized when scraping.
The solid subs-tance was filtered off and recrys-tallized
from water. The white solid, consis-ting of the ti-tle compound,
was recovered in a yield of 3.70 g (0.0125 mole, 41.7%) with
melting point 195.5-196.0C.
In the present specification the terms "alkyl group",
including "cycloalkyl group", and "phenyl-alkyl group" are
understood to mean the corresponding substituted or unsub-
stituted groups.
