Note: Descriptions are shown in the official language in which they were submitted.
1323032
PROCESS FOR PREPARING 2-GUANIDINOTHIAZOLE DERIVATIVES
This invention relates to a new process for
preparing 2-guanidinothiazole derivatives of the
general formula (I)
~12N ~ N '~S--Y ( I)
wherein
Y stands for the group of the formula (II)
~NH2
~ NH (II)
or the group of the formula (III)
-CH2-CH2-CN (III)
and their salts.
These compounds are important intermediates
for the preparation of famotidine /chemically N-sulfamyl-
-3-(2-guanidinothiazol-4-ylmethylthio)propionamidineJ
which has been proved to be an outstanding drug in the
therapy of gastric and duodenal ulcers.
The compounds prepared according to the inven-
tion are known in the literature. Chronologically, the
nitrile of the formula (I) wherein Y stands for the group
A4157-67 SZ6/sM
.
,'
1323032
-- 2
of the formula (III) had first been prepared from the
aminonitrile of the formula (VIII)
N~S ~CN
\~
H?N S (VIII)
by a 4-step lengthy route in a moderate yield according
to the United States patent specification No. 4,283,408.
According to the authors of the European patent
specification No. ~7,274, the isothiourea of the formula :
(I), wherein Y means a group of the formula (II), was
obtained in a yield above 90 % by reacting a compound
of the formula (V)
H 2~ N ~--X
H2N ~S~ HX ( )
wherein X is halogen, with thiourea in alcohol.
A drawback of this process, however, consists
therein that the starting chloromethyl compound is an
allergenic agent which irritates the skin and the mucous
membranes.
The isothiourea obtained in the above manner
was reacted with 3-chloropropionitrile in the presence of
, ~ : . - .. . ~:
- .,, ~ ~ ,
~, ~ ,: .:
:: :- : ~
~: . ,, : :~ , ~. . . .
1 323032i
_ 3 _
sodium hydroxide in aqueous alcohol under cooling to
give the nitrile in 89.8 % yield. This process is
cumbrous, demanding much time and work as the product
has to be isolated by using extraction, azeotropic drying
and recrystallization from a solvent mixture.
The researchers of the Yamanouchi Co. tried to
eliminate the drawbacks of the above methods by
developing an other process disclosed in the European
patent ~ No. 128,736. Dichloroacetone was
condensed with amidinothiourea below O C for several
days to obtain the thiazoline of the formula (VI)
OH
~2N~N ~ HCI (VI)
in 96.4 % yield. The thus obtained thiazoline was heated
with thiourea in alcohol to give the compound of the
formula (I), wherein Ymezns the group of the formula (II),
in 75.0 % yield (B3.8 % as calculated for thiourea) which
in turn was transformed with 3-chloropropionitrile in
the presence of an aqueous alkali, in a mixture of iso-
propanol and water to give the nitrile of the formula (I)
wherein Y is a group of the formula (III) in 79.2 % yield.
Thus, the overall yiéld of the compound of the formula (I),
/~7~
- . ' .: , ',
: ` ' ''' ,. -' : .
- . . , :
l323a~2
wherein Y is the group of the formula (II) amounts to
72,3 % that of the compound of the formula (I), wherein
Y is the group of the formula (III), to 57.2 % as calculat-
ed for amidinothiourea.
The reaction of the thi~zoline of formula (VI)
with thiourea was carried out also in an aqueous medium.
The aqueous solution of the compound obtain~ in situ was
diluted with isopropanol and then transformed with 3-
-chloropropionitrile in the presence of sodium hydroxide
under cooling to obtain the nitrile compound of the formula
(I), wherein Y is the group of formula (III), in a yield
of 83.5 % as calculated for the thiazoline of the formula
(VI) and in a yield of 80.5 %, respectively, as calculated
for the starting dichloroacetone and amidinothiourea.
The most important disadvantage of the above method
appears therein that the technological procedure is
cumbrous and lengthy, the cyclization requires cooling
for the whole reaction period and the thus obtained
thiazoline compound of the formula (VI) is quite unstable.
According to our investigations, this thiazoline d~rivative
is very unstable at room temperature.
The intermediary skin-irritating chloromethyl
compound of the formula (V), wherein X means chlorine, was
for the first time described in the Belgian patent
specification No. B66,156 according to which dichloroacetone
was reacted with amidinothiourea by stirring in acetone
solution overnight at room temperature. However,
- 132~2
the yield of the pure chloromethyl compound obtained by
recrystallization from alcohol was not given. According
to our determinations, this yield is lower than ~O %.
Other methods of the preparation are not known in the
literature, or are equivalents to or variants of the
above process.
Thus, the aim of the present invention is to
provide a process wherein the intermediates of the general
formula (I) of famotidine can be prepared in a single
pot whereby the isolation of the other intermediary
products having inconvenient properties becomes unnecessary.
The invention is based on the recognition that the
S-alkylation carried out by reacting a dihaloacetone with
amidinothiourea of the formula (IV) - --
H2N NH2
H2 N J~ S (IV)
and the following cyclization can selectively be achieved
by using a iodide catalyst in a solvent medium to result
in the separation of the halomethyl compound of the
~eneral ~ormula (V) in a crystalline form from the
reaction mixture. After adding water and thiourea, this
compound can be transformed to one of the target products,
i.e. to the compound of the formula (I), wherein Y means
" . " " : " " ," " ~
-` 132333~
the group of the formula (II), which separates in a pure
crystalline state from the reaction mixture.
Further on, it has been recognized that the
isolation of all other intermediates can be eliminated
in the preparation of the compound of the formula (I),
wherein Y means a group of the formula (III). Thus after
diluting with water, removing the acetone and adding
alcohol, acrylonitrile and sodium hydroxide, the in
situ formed mercaptan compound of the formula (VII).
~ ~ S ~J ( V I I )
H2N N S
may be S-cyanoethylated easily in alkaline medium.
The thus-obtained nitrile product separates from the
reaction mixture in a crystalline form.
Novel and surprising elements are also involved
in the above recognition. Namely, it could not be expected -
that such a degree of selectivity would be achieved
both in the cyclization as well as in the S-alkylation
by using an iodide catalyst in an acetone medium. This
is well supported by the fact that without an iodide
catalyst in the reaction of dichloroacetone with amidino-
thiourea followed by the reaction with thiourea, the
yields obtained were by 25 to 35 % lower as compared
to the yield of the reaction based on our recognition
although the only difference consisted in the catalysis.
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:, ' ' ' ,' ' ~'.' ' ' ,' '.' .
'.' ' ~ ' . ' ' ' .~ ' ' ' ~ ' .
.
~323~2
-- 7
In addition, the selectivity-enhancing role of
the iodide catalysis was also verified in the case of
2-amino-4-chloromethylthiazole hydrochloride of the
formula (IX)
N - -.~CI (IX)
H N /~ 5 9 ~ HC I
a compound known from the literature. By reacting
thiourea with dichloroacetone in an 1:1 molar ratio,
the compound of the formula (IX) was obtained in 58.5 %
yield and the following reaction with thiourea resulted
in the compound of the formula (X)
~`~H2
~<~ ~ 2 HCI
H2~ S
in a yield of 22.2 % /J. Am. Chem. Soc. 68, 2156 (1946)/.
In contrast to these yields, the compound of the formula
(IX) was obtained in a yield of 86 % by using the
iodide catalysis recognized in our experiments.
It is also known that the cyclization of theco~xund of
formula (IV) involves at least three elemental steps.
As it can be expected that the first step~ i.e. the
S-alkylation is only accelerated by the iodide catalysis,
. ,,~
, ' '' . '
.
' ~ " ' ' , , . ' . ,
,
1323032
~- a-
it is also surprising that, in addition to the increase
in the selectivity, the whole thiazole formation is
accelerated.
Thus, the present invention relates to a new
process for preparing the 2-guanidinothiazole
derivatives of the general formula (I), wherein Y
stands for the group of the formula (II) or (III), as well
as their salts, which comprises
a) cyclizing amidinothiourea of the formula (IV)
with an l,3-dihaloacetone in a solvent preferably in
acetone and in the presence of an iodide
catalyst soluble in said solvent, preferably sodium iodide
and reacting, without isolation, the thus obtained
halogen derivative of the formula (V), wherein X represents
halogen, with thiourea in the presence of water, to give the
compound of the formula (I), wherein Y means the group
of the formula (II),
bl) cyclizing amidinothiourea of the formula
(IV) with an 1,3-dihaloacetone in a solvent, preferably
in acetone and in -~he presence OI an iodide ca-talyst
sol~ble in said solvent, preferably scdi.um iodide,
then reacting without isolation the thus obtained
halogen derivative of the formula (V), wherein X is
halogen, with thiourea in the presence of water and then
S-cyanoethylating with acrylonitrile in an alkaline aqueous-
-alkanolic medium to give the compound of the formula (I),
:, ~ , , ; . , , . : :
1323032
wherein Y stands for the group of the formula (III),
b2) S-cyanoethylating as starting substance
the compound of the formula (I), wherein Y means a group
of the formula (II), with acrylonitrile in an alkaline
aqueous-alkanolic medium to obtain the compound of the
formula (I), wherein Y means the group of the formula
(III).
Accordlng to a preferred embodiment of the
process of the invention, the iodide catalyst is used
in an amount of 1 to 10 mole%, preferably 4 to 6 mole~A
In the process of the invention, the compound of
the formula (I) wherein Y means a group of the formula
(II) is formed at a tempe~ture between 20 C and 60 C
and the thus obtained compound is S-cyanoethylated at
a pH value of 11 to 13, at a temperature between 20 C
In the process of the invention, amidinothiourea
of the formula (IV) is portionwise added to the appropriate
preferably of dichloroacetone/
dihaloaceton~/in a solvent, preferably in acetone also
containing sodium iodide. Water and thiourea are added
to the thus formed crystal suspension and after boiling
and cooling, the thus obtained compound of the formula (I),
wherein Y stands for the group of the formula (II), is
filtered, washed with aqueous acetone and dried.
When the aim is to obtain the nitrile, i.e. the
compound of the formula (I), wherein Y is the group of
the formula (III), then during the boiling with thiourea
- -, - -
1323~32
- 10 -
in water, acetone is continuously distilled out from
the reaction mixture simultneously with the portionwise
addition of water. The thus resulting aqueous solution is
cooled, diluted with alcohol and then, the desired amount
of acrylonitrile and aqueous sodium hydroxide solution
are added. The thus formed nitrile is filtered, washed
and dried.
The advantages of the process of the invention can
be summarized as follows.
a) Owing to the iodide catalysis, the carrying
out of a cyclization lasting for several days below O C
as well as the isolation of the unstable intermediates
become unnecessary.
b) The obtained skin-irritating product of the
formula (V) can further be transformed without isolation
in the same pot.
c) The solvent system used provides the separa-
tion of the compounds of the formula (I) and their salts
in a pure state whilst the contaminations remain in the
mother liquor.
d) For preparing the nitrile, the much more
simply available and cheaper acrylonitrile can be used
instead of 3-chloropropionitrile described in the
literature.
e) By using the process of the invention, the
compound of the formula (I), wherein Y is a group of
the formula (III), can ~also be prepared from the iso-
- , , ~; , , :.,, :,~i
: ~
,. . . . ... .
~32~
thiourea derivative of the formula (I), wherein Y is a
group of the formula (II) formed in situ.
f) Due to the low worktime input and the excellent
yields, the process of the invention is extremely
useful for the industri~ realization The volume utiliza-
tion is also very advantageous: 240 kg of the compound
of the formula (I), wherein Y is a group of the formula
(II), or 100 to 160 kg of that, wherein Y is a group of
the formula (III), can be prepared in a working volume
of 1 m3.
The process of the invention is illustrated in
detail by the following non-limiting Examples~
Example 1
Preparation of 5-(2-guanidinothiazol-4-yl-
methyl)isothiourea dihydrochloride monohydrate /compound
of the formula (I), wherein Y is the group of the formula
(II)/
Example 1.1
11.8 9 (0.1 mole) of amidinothiourea are added to a
stirred solution containing 12.7 9 (0.1 mole) of 1,3-di-
chloroacetone and 0.75 9 (0.005 mole) of sodium iodide in 92
ml of acetone during 2 hours. After stirring for additional
2 hours, 9.2 9 of water are added and a solution is
formed after boiling for a short time. To this solution,
7.6 9 (0.1 mole) of thiourea are added whereupon the mixture
is boiled for one hour. The reaction mixture containing
.: . . . .
, : . - . ~
.: , .. '
1323~32
- 12 -
the oily reaction product is allowed to cool while
stirring. The thus formed crystal suspension is cooled
at 0 C, then filtered, washed twice with acetone and
dried to give the title product, m.p.: 209-213 C (with
decomp.), in a yield of 27.86 9 (85 %) with an active
ingredient content of 98 % as determined by potentio-
metric titration.
Example 1.2
35,4 9 (0.3 mole) of amidinothiourea are
portionwise added to a stirred solution containing 36.1
9 (0.3 mole) of 1,3-dichloroacetone and 2.25 9 (0.015
mole) of sodium iodide in 240 ml of acetone at 30 to 36 C
during one hour. The thus obtained crystal suspension is
stirred at the same temperature for one additional hour
and, after adding 30 ml of water and 24 9 (0.315 mole)
of thiourea, the mixture is refluxed while stirring for
one hour. The mixture is allowed to cool to room temperature,
the crystalline product is filtered and washed twice
with 40 ml of 90 % acetone each to give the title product,
m.p.: 210-214 C (with decom.), in a yield of 88.02 9
(89.7 %) with an active ingredient content of 98.2 %
as determined by potentiometric titration.
Example 1.3
127.0 kg (500 moles) of 1,3-dichloroacetone in
a 50 weight% acetonic solution are pumped into a reactor
of 1000 litres. After adding 257 kg of acetone and 3.75 kg
(25 moles) of sodium iodide, 60.5 kg of amidinothiourea
.. ~
-
:
: : , : ,: -
: - ~- : : :.
-
: -
~:. . - ~. . ~ ,.
1323~
- 13 -
of 97.6 % purity (500 moles) are portionwise added to
the reaction mixture during 1.0 to 1.5 hours under
stirring. The desired inner temperature of 30 to 40 C
is maintained by flowing cold industrial water in the
jacket. After stirring the reaction mixture for one
additional hour, 50 litres of water and 41.2 kg of thio-
urea of 97 % purity (525 moles) are added and the mixture
is boiled under stirring for one hour. Then, the
temperature of the reaction mixture is smoothly cooled
to room temperature within 2 to 3 hours, the suspension is
centrifuged, the product is washed in the centrifuge with
an 8:1 mixture of acetone and water and dried to give the
title product, m.p.: 209-214 C (with decom.) in a yield
of 148.3 kg (90.0%) with an active ingredient content
of 97.5 %.
Example 2
Preparation of 3-(2-guanidinothiazol-4-ylmethyl-
thio)propionitrile /compound of the formula (I), wherein
Y is the group of the formula (III)/
Example 2.1
20 ml of 10 N sodium hydroxide solution (of
40 ~) are portionwise added to a solution containing
32.7B g (0.1 mole of 98%) of S-(2-guanidinothiazol-4-
-ylmethyl)isothiourea dihydrochloride monohydrate (as
prepared in Examples 1.1, 1.2 or 1.3) and B.0 9 (0.15 mole)
of acrylonitrile in 100 ml of water and 40 ml of isopropanol.
After stirring for 2 hours, 30 ml of water are added and
after cooling by ice the precipitated product is filtered,
,, ,, . "
" ' :: . ' ~ ' . ' . "' .
'' ~ '
-` 132303~
- 14 -
washed with water, then with isopropanol and dried to
give the title product, m.p.: 127-129 C in a yield
of 22 9 (91 %) with an active ingredient content of
99.0 % as determined by potentiometric titration with
hydrochloric acid.
Example 2.2
65.8 9 (0.20 mole) of the product prepared
according to Example 1.1 are mixed with 16 9 (0.30 mole)
of acrylonitrile, 80 ml of water and 60 ml of alcohol.
After adding 43 ml (0.43 mole) of 10 N sodium hydroxide
solution, the mixture is stirred for 2 hours, filtered at
15 to 20 C, washed with water and then withalcohol and
dried to give the title product in a yield of 45.4 9
(94 %), m.p.: 127-128.5 C, with an active ingredient
content of 99.1 % as determined by titration. -
Example 2.3
A solution of 3~.1 9 of 1,3-dichloroacetone and
2.25 9 of sodium iodide in 240 ml of acetone is
treated with 35,4 9 of amidinothiourea under stirring
as described in Example 1.2. After adding 120 ml of water
and 24 9 of thiourea, 220 ml of acetone are distilled
from the reaction mixture. To the residue cooled down 90
ml of ethanol, 24 9 of acrylonitrile and 63 ml of 10 N
sodium hydroxide solution are poured. After stirring
for additional 2 hours and cooling below 20 C, the mixture
is filtered, the precipitate is washed with water, then
1323~32
with alcohol and dried to give the title product, m.p.:
127-128 C, in a yield of 62.1 9 (~4.~ %) with an active
ingredient content of 98.9 %.
: ^ ''
