CA1323032C

CA1323032C - Process for preparing 2-guanidinothiazole derivatives

Info

Publication number: CA1323032C
Application number: CA000549936A
Authority: CA
Inventors: Erik Bogsch; Ferenc Trischler; Peter Bod; Kalman Harsanyi; Eva Againe Csongor
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1986-11-12
Filing date: 1987-10-21
Publication date: 1993-10-12
Anticipated expiration: 2010-10-12
Also published as: PT86113B; FI84912B; NO874698D0; FI875003A0; CS268693B2; NO167387B; NO874698L; AT389510B; PT86113A; ES2005441A6; CS810187A2; SU1678205A3; DK587287D0; YU204987A; DK169966B1; KR900006556B1; DK587287A; HU195959B; FI84912C; AR243874A1

Abstract

Abstract The invention relates to a process for preparing 2-guanidinothiazole derivatives of the general formula (I) (I) wherein Y stands for the group of the formula (II) (II) or (III) -CH2-CH2CN (III) as well as their salts, which comprises a) cyclizing amidinothiourea of the formula (IV) (IV) with an 1,3-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) (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), b1) cyclizing amidinothiourea of the formula (IV) with an 1,3-dihaloacetone in a solvent, preferably in acetone and in the presence of an iodide catalyst soluble in said solvent, preferably sodium 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), 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).
The compounds of the invention are valuable intermediates in the preparation of pharmaceutics of antiulcer effectiveness.

Description

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

.
,' 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) - --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 ) 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.

., , ., ' ! ' ' ' ' ' J '~

:, ' ' ' ,' ' ~'.' ' ' ,' '.' .
'.' ' ~ ' . ' ' ' .~ ' ' ' ~ ' .
.

~323~2 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, . ,,~

, ' '' . ' .
' ~ " ' ' , , . ' . , , ~- 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), :, ~ , , ; . , , . : :

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 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 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~

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~

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 %.

: ^ ''

Claims

1. A process for the production of 2-guanidinothiazole derivatives of the general formula (I) (I) wherein Y stands for the group of the formula (II) (II) or (III) -CH2-CH2-CN (III) as well as their salts, which comprises cyclizing amidinothiourea of the formula (IV) (IV) with a 1,3-dihaloacetone in a solvent and in the presence of an iodide catalyst soluble in said solvent and reacting, without isolation, the thus obtained halogen derivative of the formula (V) (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); or cyclizing amidinothiourea of the formula (IV) with an 1,3-dihaloacetone in a solvent and in the presence of an iodide catalyst, soluble in said solvent, then reacting without isolation with 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), wherein Y stands for the group of the formula (III); or 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).

2. A process as claimed in claim 1, which comprises using the iodide catalyst in an amount of 1 to 10 mole %.