Note: Descriptions are shown in the official language in which they were submitted.
5~8
This inVention relates to a process of obtaining
R,S-2,3,5,6-tetrahydro~6-phenyl-imidazo(2,1-b)-thiazole, of
formula I
C6}I5 / N ~ / Sl
~4 J 3
also known as Tetramisole~ and to its pharmaceutically-
acceptable salts with inorganic or organic acids.
As communicated by D.C.I. Thienpont et al., Nature
209, 1084-6 (1966) and A.H.M. Raeymaekers et al., J. Med. Chem.
9 (4), 545-555 (1966) and disclosed in British patents
1,043,489 and 1,076,109, Tetramisole has valuable pharmacological
properties that make it useful as a potent broad-spectrum anthel-
mintic. Recently, the interest in this product has considerably
increased, because of the discovery of new immunoregulating
properties and their application in the therapy of neoplastic
diseases (see German published application DOS 2,340,632).
The antidepressive (see German DOS 2,340,634) and
antianergic (see German DOS 2,340,633) action of R,S-2,3,5,6-
tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole and of its pharma-
cologically active salts, ha~ also been reported.
A plurality of methods for the syntehsis of Tetramisole
have been reported, in which, in most cases, the formation of a
tetrahydro-imidazothiazole ring system takes place by forming
a bond between the carbon atom (in the 6th position) and the
nitrogen atom (in the 7th position) (see formula I3, that is
by forming a C(6)-N(7) bond, this formation being achieved by
elimination of a xY molecule in a compound of the general formula
II
~ ' .
110~)5~8
6 5 ~ H / X ~ ~ II
N
; wherein X represents -OH ~see British patentsl,043,489 and
1,109,149); -Cl, -Br (see Brîtish patents 1,076,109 and
1,109,149), -NHSO2C6H4CH3p (see French patent 1,544,972);
-NH2, -NHCOR (see German DOS 2,236,970), while Y represents
most often hydrogen (see British patent 1,109,149), RCO-
(see British patent 1,043,489), or an alkyl radical (see
German DOS 2,236,970).
The method of synthesis of the initial compound of
the general formula II, is rather differentiated than different
in various patents. In short, one might say that usually this
compound is obtained by five-step syntheses, wherein reagents
such as styrene, styrene oxide, phenacyl bromide, ethanolamine,
aziridine, sodium borohydride, inorganic acid halides, thiou-
rea, thiocyanic acid derivatives, and others are used.
Another method ~described in German DOS 2,n34,081,
and French patent 2,224,472) is used to form the above mentioned
two-ring heterocyclic system, by formation of a N(4)-C(5)
bond (formula Il.
These methods have no advantages over those already
discussed, since the very complicated multi-step synthesis
of the final product, makes it difficult to obtain the desired
compound. Considering the said complications, and the fact
that opening of the-aziridine ring in a compound of the formula
III (see French patent 2,224,472):
C6H5
~ 1 III
y ~ 2
4 3
~ 2
., " .
~.. . .
llU~5(~8
can be carried out not only by clea.ving of the N(7)-C(5) bond
of formula III, but also by scisson o~ the N(7~-C(6) bond of
fonrula III, it clearly appears that this approach of a
- synthetic method has a reduced value.
A variant of the two methods already examined, has
been reported in French patent 2,237,900, wherein the tetra-
hydro-6-phenyl-imidazothiazole ring system is devised by
simultaneous formation of N(4)-C~5) and C(6)-N(7) bonds
(formula I), by interaction of l-phenyl-1,2-dibromoethane with
2-aminothiazoline-2. This method has no advantages over those
already discussed as it allo~s for a ~lossible ad~litional forma-
tion of 5-phenyl derivative of the said two-ring heterocyclic
system, giving low yields in final product.
A third method of forming a tetrahydro-imidazothiazo-
le system, superstructural to an already existing imidazole
ring-system, has been described in British patent 1,043,489.
The second heterocycle i.e. the thiazolidine part of the
molecule, is obtained by simultaneous formation of S(l)-C(2)
and C(3)-N(4) bonds (see formula I).
Essential shortcomings o~ this synthetic scheme, are
as follows:
- difficulty of obtaining the initial, essential 4-phenyl-
imidazolidine-2-thione product;
- high cost of the lithium amide which is hazardous to work
with, as condensing agent; and
- low yields in final product, especially when sodium carbonate
is llsed, as a condensing agent.
Modifit ations of the above method, also having no
advantages, have been disclosed in French patents 2,258,379
and 2,258,380. Thev are concerned with the formation of a
tetrahydroimidazothiazole ring system by C(3)-N(4) cyclization
(see formula I~.
-- 3 --
. :~ .
5~8
U.S, patent 3~726~894~ wherein the heterocycle is
obtained by ~orming a S(l)~C(2) bond (formula I) also belongs to
the third synthetic method of forming a tetrahydroimidazothia-
zole system. The only purpose of this U.S. patent is utilizing
R-(t)-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole, a-by
product, obtained by resolving the Tetramisole racemic mixture.
The authors effect this resolution by converting the physiolo-
gically inactive R~t)-2,3,5,6-tetrahydro-6-phenyl-imidazo
(2,1-b)-thiazole into racemic R,S-1-2(2-hydroxyethyl)-4-phenyl-
imidazolidine-2-thione by means of a multistep synthesis, com-
plex and technologically difficult to manage. Under the
thionyl chloride effect, R,S-1-(2-hydroxyethyl)-4-phenyl-
imidazolidine -2-thione is cyclizased again to form a Tetrami-
sole racemic mixture. This process gives low yields - about
40% of the theoretical.
According to U.S. patent 3,726,894 already mentioned
hereinabove, R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-
2-thione (VII), is a key intermediate product for obtaining
R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole (I).
The only method of obtaining this key product (VII) has been
described in the patent. This method, however, is almost
inapplicable industrially, due to reasons already described.
It is worth emphasizing the impossibility of obtaining
R,S-1-(2-hydroxyethyl)-4 phenyl-imidazolidine-2-thione (VII),
as disclosed in U.S. patent 3,726,894 without synthesizing
Tetramisole in advance, following some of the known schemes.
The above patent, therefore, describes a method of utilizing
R-(+)-2,3,5,6-tetrahydro-6-phenyl~imidazo(2,1-b)-thiazole,
giving no rational solution to the problem of forming a tetra-
3~ hydro-imidazothiazole structure.
Other methods of obtaining Tetramisole, which more or
less contain elements of the above methods, are described in
the following French patents Nos. 2,183,313; 2,258,379;
B - 4 -
11UC~SQ~
2,258,380; 2,259,092; 2,259,823i 2,264,017; 2,264,018; 2,271,211;
2,271,212; 2,271,213; and the German published application
DOS 2,264,911 and 2,326,308.
The aim of this invention is a new process of
obtaining Tetramisole, easy to manage tecnnologically and
suitable for industrial production, utilizing more accessible
raw materials, mainly R,S- a-(2-hydroxyethylaminomethyl)-benzyl-
amine, obtained from basic products of the organic synthesis.
The process of obtaining R,S-2,3,5,6-tetrahydro-6-
phenyl-imidazo-(2,1-b)-thiazole tI), according to this invention,
comprises the steps of reacting the R,S-~-(2-hydroxyethylaminome-
thyl)-benzylamine* of Formula IV:
C6H5-CH-CH2-NH-CH2-CH2-OH
IH2 IV
with a compound of Formula V:
\ / V
li
wherein Rl and R2 are identical and represent chlorine, or
differ from one another, in which case Rl represents a lower-
alkoxy radical having from 1 to 4 carbon atoms, and R2 is -SM,
M representing sodium or potassium, to form the R,S-1-(2-hydroxy-
ethyl)-4-phenyl-imidazolidine-2-thione of Formula VI:
~ VI
N-CH CH -OH
* The name of compound IV is formed according to the nomenclature
rules, as adopted by the Chemical A~stracts. This compound can
also be named R,S-2-(2-hydroxyethylamino)-1-phenyl-ethylamine.
~ ' .
llO~SQ~
and subjecting the so formed thione to cyclodehydration to form
the thiazole of formula I.
When the compound of formula V is thiosphogene, the
reaction of R,S-~-(2-hydroxyethylaminomethyl)-benzylamine (IV)
with thiophosgene can be carried out in an anhydrous medium.
When the compound of formula IV is an alkaline alkylxanthate,
the reaction with this alkaline alkylxanthate may be performed
in an aqueous or aqueous-organic medium.
The cyclodehydration of the compound of formula VI
may be carried out with various dehydrating agents, such as
polyphosphoric acid or its esters, phosphorus pentoxide,
concentrated sulfuric, hydrochloric acid, or a mixture of the
said substances under increased temperature, to give the desired
R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo-(2,1-b)-thiazole of
Formula I:
6 5 ~ / ~ ~ I
According to a preferred embodiment of the present
invention, tetramisole can ~be obtained by reacting R,S-a-(2-
hydroxyethylaminomethyl)-benzylamine (IV) with an alkaline
alkylxanthate and subsequently heating of the formed R,S-l-
(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione (VI) in a
hydrochloric acid medium. This process provides for a new and
much more simple method of obtaining directly the pharmaceutically
acceptable hydrochloride salt of R,S-2,3,5,6-tetrahydro-6-
phenyl-imidazo(2,1-b)-thiazole (Tetramisole hydrochloride~.
The process according to the invention provides an
economically effective and easy approach to the synthesis of
the key, intermediate product R,S-1-(2-hydroxyethyl)-4-phenyl-
imidazolidine-2-thione (VI~, having incomparably better ~uality
indices, as compared with those obtained by the method described
,--. ,,
, .
llUC~S~
in U.S. Patent 3,726,894. For example, the melting temperature
of the compound according to the invention, is 10 C higher than
that recorded in the U.S. Pa~ent. This essential advantage
also explains Tetramisole high yields, and its very high
qualitative indices. In this way, it was found unnecessary
to apply special methods of purifying the final product.
In conclusion, the process according to this invention,
represents a new, paying method of converting R,S-1-(2-
hydroxyethyl)-4-phenyl-imidazolidine-2-thione (VI) into Tetra-
misole. This method suggests an integral, completed, and
economically profitable scheme of synthesizing R,S-2,3,5,6-
tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole (I).
The invention will be better understood with reference
to the following non restrictive-examples.
EX~LE 1. R,S-1-(2-hydroxyethyl)-4-~henyl-imidazolidine-2-
thione (VI). (Cyc~ization with potassium ethylxanthate).
9 g (0.02 moles) of R,S-~-(2-hydroxyethylaminomethyl)-
benzylamine were dissolved in 40 ml of water. To the solution
stirred at room temperature, 16 g (0.04 moles) of potassium,
ethylxanthate were added dropwise, dissolved in 40 ml of water.
The reaction mixture was first heated under reflux for three
hours, cooled to 20C, and extracted with three 100 ml portions
of methylene chloride.
Followinga complete methylene chloride distillation,
- 6a -
., ~ '
1100~8
4.1 g of R9S-1-(2-hydroxyethyl)~4-phenyl-imidazolidine-2-thione
were obtained; m.p.91-93C. Yield - 37 % of the the~retical.
The ~ame results were obtained on u~ing potas~ium methyl or n-butyl
xanthate~.
~XAMPIæ 2. R,S-1-(2-hydroxyethyl)-4-phenyl-imidaæolidIne-2-thione
(VI). (Cyclization with thiopho~gene~.
To 17.8g (0.02 moles) of imidazole solution stirred with
140 ml methylene chloride were added dropwise and stirred 50 ml
15 % benzene ~olution of thiophosgene. After one hour stirring at
room t~perature~ the imidazole hydrochloride separated, wac fil-
tered o~f. ~he filtrate was cooled to 0C and placed dropwi~e into
a ~olution of 9 g (0.02 moles) of R,S-~ -(2-hydroxyethylaminomethyl)-
benzylamine in 90 ml of methylene chloride. After ~tirring at 25C
for four hour~ the ~olvent was di~illed off. Carbon tetrachloride
was added to the dry residue and the imidazole remaining undissolved,
wa~ filtered off. ~he filtrate was washed with 20 ml 10% aqueous so-
lutio~ of h~drogen chloride, then washed with water to adju~t pH-6.
The carbon tetrachloride extract was dried over anhydrous sodium
sulfate, followed b~ a full distillation of the ~olvent~ 9.8 g of
crude R,S-1-(2-hydroxye~hyl)-4-phenyl-imidazolidine-2-thione were
obtained.
After the crude product was recristallized from methyle-
ne chloride, a purer R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-
2-thione was isolated; m.p. 91-93a. Yield - 88 % of the theore-
tical.
~XAMPLE 3. R~S-2,~,5,6-tetrahydro-6-phenyl-imidazo(2~1~b)-thiazole
hydrochloride (I). (Cyclodehydration with hydrochloric acid).
11.2 g (0.05 moles) of R,S-l (2-hydroxyethyl)-4-phenyl-
imidazolidine-2-thione were di~solved on stirring in 100 ml of
hydrochloric acid, and the reaction mixture heated under reflux for
three hour~. ~he ~olvent was fully distilled under reduced pres-
~ure, and the crude product obtained, was sucpended in 40 ml of
` llOOS(~8
i~opropanol and filtered. 11.6 g of R,S-2,3,5,6~tetrahydro-6-phenyl
-imidazo(2,1-b)-thiazole ~ydrochloride were obtained; m.p.
256-258C. Yield - quantitati~e.
EXAMPLE 4. R,S-2,3,5,6-tetrahydro-6-phengl-imidazo(2,1-b)-thiazole
(I). (Cy¢lodehydration with polyphosphoric acid).
8.9 g (0.04 mole~) of finely ground to powder R,S-l-
(2-hydrox~ethyl)-4-phenyl-imidazolidine-2-thione were added to 200
ml of polyphosphoric acid. The reaction mixture was heated at
150C for ~ix hour~ then poured into a m~xture of 600 g cru~hed ice
and 200 ~1 of water. The acid mixture wa~ alkalized with 45 ~
aqueou~ solution of sodium hydroxide to ad~u~t pH=11.5, then the
alkaline solution wa3 extracted with three 200 ml portions of me-
thylene chloride~ After distilling the solvent, 2 g of R,S-2,3,5,6-
tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole were obtained. The melt-
ing point of the product recrystali~ed from cyclohexane, wa~ 90-92 C~
Yield - 24 % of the theoretical.
EXAMPLE 5. R~S-2~3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole
(I), (Cyclodehydration with phoephoru~ pento~ide).
22 2 g (0.10 moles) of R,ST1-( 2-hydroxyethyl)-4-phenyl-
imidazolidine-2-thione were dis~olved in 250 ml of mesitylene~
then 28.5g (0.20 moles) of pho~phoru~ pentoxide were added. ~he
~u~pen~ion was stirred at 110C for one hour. After the reaction
mixture wa~ cooled to room temperature, 100 ml of 30 % aqueous solu-
tion of sodium hydroxide were added, and the organic layer ~eparated
from the aqueous alkaline solution. The organic 301ution wa~ wa~h-
ed with two laO ml portion~ of water to adju~t pH=5, and dried over
anhydrous sodium ~ulfate. ~he me~itylene was evaporatel under re-
duced pres~ure, producing 12 g of R,S-2,3,5,6-tetrahydro-6-phenyl-
imidazo(2,1-b)-thiazole. ~he melting point of the product recry~tal-
lized from cyclohexane wa~ 90-92C. Yield - 58.5 % o~ the theoreti-
cal.
EXAMPLE 6. R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)~thiazole
.. . .
--8--
~lO~S~8
hydrochloride tI). ~Cyclodehydration with sulfuric acid).
~ o 196 g (2 mole~) of cool~d to -5C sulfuric acid were
added portionwi~e 22.2 g (0.10 moles) of R,S-1-(2-hydroxyethyl)-4-
phenyl-imldazolidine-2-thione. ~he reaction mixture obtained was
stirred at room temperature for ten hours~ then alkalized with
30 ~ aqueous solution of sodium hydroxide to adjust pH--11.5. The
alkaline mixture waæ extracted with three 100 ml portions o~ methyl-
ene chloride. ~he methylene chloride extract~ were washed with
water, adjusting to pH-5~ then dried over anhydrous sodium sulfate.
~he solvent was distilled off at atmospheric pressure and the crude
product was disRo]~ed in acetone and preclpitated wiht 20% ~olution
of hydrogen chloride in isopropanol. ~he compound R,S-2,3,5,6-
tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole hydrochloride had m.p.
254~256C.
