Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
s~
This invention relates to a process o~ obtaining
R,S-2,3~5~6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole~ of
formula I
~' .
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 8ritish 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, has 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 I), 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
.i.-~l
7 .
~ 1 --
.,~ ,, ,, ,~
-
1~00507
6 5 - CH / X YN ~ S
-N
wherein X represents ~OH tsee British patentsl,043,489 and
1,109,149); -Cl, -Br (see British 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 2,034,081,
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 I).
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
5 ~ 1 III
~ 2
4 3
- 2 -
~..
11(1~507
- can be carried out not only by clea~ing of the N(7) C(5) bond r
of formula III~ but also by scisson o~ the N(7)-C(6) bond of
formula 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 allows for a possible additional 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 exlsting 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 of 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 used, as a condensing agent.
Modifications of the above method, also having no
advantages, have been disclosed in French patents 2,258,379
and 2,258,380. They are concerned with the formation of a
tetrahydroimidazothiazole ring system by C(3)-N(4) cyclization
(see formula I).
- 3 -
,~ j~,
S(~7
U.S. patent 3~726~894~ wherein the heterocycle is
obtained by forming 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 cyclizated 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 3j726,894 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,
gi~ing no rational solution to the problem of forming a tetra-
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;
110(~S~7
~,258,380; 2,259,092; 2,259~823; 2,264,017; 2,264,018;
2,271,211; 2,Z71,212; 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 o~
obtaning R,S-2,3,5,6-tetrahydro-6~phenylimidazo(2,1-b)-
thiazole (Tetramisole), easy to manage technologically, suitable
for industrial production, utilizing more accessible raw mate-
rials, mainly R,S ~-(2-hydroxyethyl-aminoethyl)-benzylamine (IV),
6 5 fH CH2-NH-cH2-cH2-oH IV
NH2
obtained from basic products in the organic synthesis.
The process of obtaining R,S-2,3,5,6-tetrahydro-6-
phenyl-imidazo (2,1-b)-thiazole, according to this invention,
comprises reacting R,S-d-(2-hydroxyethylaminomethyl)- benzyla-
mine (IV) with carbon disulfide in an aqueo~s or aqueous-organic
medium. This reaction leads to the formation of the
R,S-N-/ 2-hydroxyethylamino)-1-phenylethyl)-amide of dithio-
carbonic acid, of formula Va
C H -CH-CH -NH -CH -OH Va
] \ S~
which in turn is converted into R,S-1-(2-hydroxyethyl)-4-
phenyl-imidazolidine-2-thione of the formula VII
......
C H ~ ~ S VII
-C~2-CH2-OH
The name of a compound with formula IV is formed according
to the nomenclaturerules, as adopted by the Chemical Abstracts.
0
This compound can also be named R~S-2~(2-hydroxyethylamino)-1-
phenyl-ethylamine,
5(~7
according to one of the following me.thods:
a) by thermal cyclization of the compound of formula Va, by
heating in a medium of inert solvents;
b) by chemically induced cyclization of the compound of
formula Va, with reagents of the general formula RX,
wherein R represents a lower alkyl radical, and X is an
acid residue. Methyl iodide, dimethyl sulfate, diethyl
sulfate, n-butyl bromide, alkyl esters of the p-tolyenesul-
fonic, methanesulfonic and fluorosulfonic acids could be
used as such reagents;
c) by converting the compound of formula Va, into R,S-N-(2-
(2-hydroxyethylamino)-I-phenylethyl)-amide-S-alkyl esters of
the dithiocarbonic acid of formula Vb
C6H5-cH-cH2-NH-cH2-cH2-oH
Vb
~H-C ~
\ S-R'
wherein R' represents allyl, benzyl, cinnamyl group, and
subsequently melting the compound of formula Vb, to obtain
the compollnd of formula VII.
In this way, according to the above variant 'C', the
compound of formula VII, is synthesized from a compound of
formula IV, according to the following scheme:
C6H5-cH-cH2-NH-cH2-cH2-oH t CS2 _ >
1H2 IV
~ R'Br
~ C6H5-CH-CH2-NH2-CH2-CH2-OH _ ~ .
NH-C ~ _ Va
\ S
--) C6H5-cH-cH2-NH-cH2-cH2-oH _ ~
NH-C ~ Vb - RISH
`S-R'
B~
~lO~S~7
C H
) 6 ~ H ~
VII
I ~CH -CH2~OH
Allylbromide~ benzyl bromide, propargyl bromide and
cinnamyl bromide, are most suitable for alkylating agents R'Br.
It is preferable to carry out the above reaction in aqueous,
aqueous-alcohol or alcohol medium.
By cy~lodehydration of the compound (VII), obtained by
using various dehydrating agents, such as polyphosphoric acid or
its esters, phosphorus pentoxide, concentrated sulfuric acid,
hydrochloric acid or a mixture of the said substances, there
is obtained the desired R,S-2,3,~,6-tetrahydro-6-phenylimidazo
(2,1-b)-thiazole, of formula I
C6H5 y ~ \ ~S ~ I
2~ :
According to a preferred embodiment of this invention,
Tetramisole can be obtained by reacting the compound of
Formula IV, with carbon disulfide, melting the compound obtain-
ed, of formula Va, converting it into R,S-1-(2-hydroxyethyl)-
4-phenyl-imidazolidine-2-thione (VII), and cyclisiæing the
obtained product by using hydrochloric acid.
'rhe process accordipg to the invention, allows for
a direct production of the pharmaceutically hypochloride salt
of R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole
(Tetramisole hydrochloride) in a new and simpler method.
The process according to this invention, provides
an economically effective and simple approach of the synthesis
of the key, intermediate product ~,S-1-(2-hydroxyethyl~-4-
phenyl-imidaæolidine-2~thione (VII), having considerably
better quality indices, as compared with those descxibed in
Yf - 7
~ ..
~qlr J~
S ~ sa7
U.S. patent 3,726~894. For example~ the melting temperature of
the compound according to this invention, is 10C higher than
that recorded in the above~ment;oned U S. patent. This
essential advantage also explains the ~uantitative yields of
Tetramisole, as well as its very high qualitative indices.
It was found, therefore, unnecessary to apply methods of
purifying the final product.
The process, according to this invention, represents
a new, paying method of converting R,S-1-(2-hydroxyethyl)-4-
phenyl-imidazolidine-2-thione into Tetramisole. It suggests an
integral, completed and economically profitable scheme of
synthesizing R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-
thiazole.
The invention will be better understood with reference
to the following non-restrictive examples.
EXAMPLE 1. R,S-N-(2-(2-hydroxyethvlamino)-1-phenylethyl)-
amide of the dithiocarbonic acid.
18 g (0.10 moles) of R,S-~-(2-hydroxyethylaminomethyl)-
benzylamine were dissolved in 60 ml of 36% ethanol. After a
homogenous solution was obtained, 11,4 g (0.15 moles) of carbon
disulfide were added dropwise at 40C. After a period of 4
hour heating under reflux, the precipitate separated was
filtered and washed with 10 ml of ethanol. R,S-N-(2-(2-hydroxy-
ethylamino)-l-phenylethyl)-amide of the dithiocarbonic acid
yield was 18.1 g (70% of the theoretical); m.p. 136-138C
(decomp.).
Elemental analysis of CllH16H2OS2
(M-256.38)
8 ~
S(~7
Element Calculated 0/O
C 51.52 51.95
H 6.29 6.35
N 10.93 10.70
S 25.01 24.80
EXAMPLE 2. R,S-1-(2-hydroxyethyl~-4-phenyl-imidazolidine-2-
thione (VII). (Cyclization by melting of a compound, with
Formula Va).
97 g (0.38 moles) of R,S-N-(2-(2-hydroxyethylamino)-1-
phenylethyl)-amide of the dithiocarbonic acid were heated at
150C for 4 hours. 120 ml of methylene chloride were added
to the melt, cooled to 20C. The solution was filtered, the
filtrate extracted with 120 ml of 10% aqueous potassium hydroxide
solution, and washed with 120 ml hydrochloric acid (1:3). The
methylene chloride extract was washed with water to adjust to
pH=5, and dried over an anhydrous sodium sulfate. After
distilling the solvent off, 42 g of R,S-1-(2-hydroxyethyl)-4-
phenyl-imidazolidine-2-thione were obtained, m.p. 91-93C.
The yield was 50% of the theoretical.
EXAMPLE 3. R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-
thione (VII). (Cyclization with dimethyl sulfate).
To 100 ml of 5% aqueous sodium hydroxide solution
were added 25.6 g (0.10 moles) of R,S-N-(2-(2-hydroxyethylamino)-
l-phenylethyl)-amide of the dithiocarbonic acid, and the solu-
tion thus obtained filtered through an asbestos-cellulose
surface. The filtrate was cooled to -5C, adding, at the same
time, dropwise 13 g (0.10 moles) of dimethyl sulfate. A gummy
~ The melting point of R,S-1-(2-hydroxyethyl)-4-phenyl-imidazo-
lidine-2-thione, as reported in the U.S. Patent 3 726 894, is
81-83-C. ~ _ g
~,
, ~,.
` llO~S~7
mass and a upper aqueous layer were obtained~ After decanting
the liquid, the gummy mass was dissolved in methylene chloridet
The methylene chloride solution was dried over an anhydrous
sodium sulfate and then the solvent distilled. 10.4 g of
R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione were
obtained. After recrystallization of the crude product from
n-butyl acetate, R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-
2-thione was obtained; m.p. 91-93C. The yield was 47% of the
theoretical.
EX~MPLE 4. R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-
thione (VII). (Cyclization with n-butyl bromide).
25.6 g (0.10 moles~ of R,S-N-(2-(2-hydroxyethylamino)-
l-phenyl ethyl)-amide of the dithiocarbonic acid, were suspended
in 100 ml of water. The suspension was added to 150 ml 5%
aqueous solution of sodium hydroxide, and the resulting mixture
filtered through an asbestos-cellulose surface. 16.5 g (0.12
moles) of n-butyl bromide were added to the filtrate at 50C,
and after stirring for four hours - 100 ml of methylene chloride,
The methylene chloride layer was separated, dried over an
anhydrous sodium sulfate, and the solvent was fully distilled.
10.7 g of crude R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-
2-thione were obtained and recrystallized from butyl acetate,
m.p. 91-93C. The yield was 48.2% of the theoretical.
EXAMPLE 5O R,S-N-(2-(2-hydroxyethylamino)-1-phenylethyl)-
amide-S-allyl ester of the dithiocarbonic acid (Vb)~
25.6 g (0.10 moles) of R,S-N-(2-(2-hydroxyethylamino)-
l-phenylethyl)-amide of the dithiocarbonic acid were suspended
in 100 ml of water. The suspension was added to 100 ml 5%
aqueous solution of sodium hydroxide, and the resulting mixture
was filtered through an asbestos-cellulose surface~ 14.5 g
(0.12 moles) of allyl bromide were added to the filtrate,
and the mixture stirred for one hour at room temperature.
-- 10 --
S(~7
100 ml of methylene chloride were added to the mixture, sepa-
rating and filtering the crystals obtained. 8.7 g of R,S-N-
~2-(2-hydroxyethylamino)-1-phenylethyl)-amide-S-allyl ester
of the dithiocarbonic acid were obtained; m.p. 124-126C.
The yield was 32% of the theoretic&l.
Infrared spectrum: Nujol mul
~ /CH = CH2 ~ = 1625 cm 1
Elemental analysis of C13H18N20S2
(M=282.42)
Element Calculated Found
-
C 55.31 55.01
H 6.38 6.70
N 9.92 10.20
S 22.69 22.93
EXAMPLE 6. R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-
thione (VII). (Cyclization by melting of a compound, with
Formula Vb).
8.7 g (0.032 moles) of R,S-N-(2-(2-hydroxyethylamino)-
l-phenylethyl)-amide)-S-allyl ester of the dithiocarbonic acid
were heated for two hours at 150C. After cooling the mixture
to room temperature, 50 ml of methylene chloride were added
and the solution obtained, filtered through an asbestos-
cellulose surface. The filtrate was washed initially with
25 ml of 10% aqueous-sodium hydroxide solution, then with
25 ml aqueous solution of hydrochloric acid (1:3), and in
the end with 50 ml of water to adjust pH=6. The extract of
methylene chloride was dried over an anhydrous sodium sulfate.
2.47 g of crude R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-
thione were obtained, after distilling the methylene chloride.
R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione,
11C~ L?507
recrystallized from methylene chloride, had m.p. 91-93C. The
yield was 34% of the theoretical.
EXAMPLE 7. ~,S-2,3,5,6-tetrahydro-6-phenylimidazo(2,1-b)-
thiazole hydrochloride. (Cyclodehydration with hydrochloric
acid).
11.2 g (0.05 moles) of R,S-1-(2-hydroxyethyl)-4-
phenyl-imidazolidine-2-thione were dissolved on stirring in
100 ml of hydrochloric acid, the reaction mixture obtained
was heated under reflux for three hours, and the solvent
distilled under reduced pressure off. The crude material was
suspended in 40 ml of isopropanol and filtered. The yield
of R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b~-thiazole
hydrochloride was 11.6 g; m.p. 256-25~C. The yield was
quantitative.
EXAMPLE 8 R S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-
,
thiazole (I). (Cyclodehydration with polyphosphoric acid).
To 8.9 g (0.04 moles) of finely grounded to powderR,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione were added
200 ml of polyphosphoric acid, the reaction mixture obtained
heated at lS0C for six hours, and poured into a mixture of
600 g crushed ice and 200 ml of cold water. The acid mixture
was alkalized with 45% aqueous solution of sodium hydroxide to
adjust pH=11.5, and the alkaline solution extracted with three
200 ml portions of methylene chloride,2 g of R,S-2,3,5,6-tetra-
hydro-6-phenyl-imidazo(2,1-b)-thiazole were obtained, after
distilling the solvent. The melting point of the product,
recrystallized from cyclohexane, was 90-92C, and the yield
24% of the theoretical.
EXAMPLE 9. R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-
thiazole (I). (Cyclodehydration with phosphorus pentoxide).
22.2 g (0.10 moles) of R,S-1-(2~hydroxyethyl)-4-
phenyl-imidazolidine-2-thione were dissolved on stirring in
- I2 -
liV~S(~7
250 ml of mesitylene. After adding 28.4 g (0.20 moles) of
phosphorus pentoxide, the suspension was stirred at 110C
for one hour. The reaction mixture was cooled to room
temperature, and then added 100 ml of 30% aqueous sodium
hydroxide solution. The organic layer obtained was separated
from the alkaline solution, the organic phase washed twice
from water, adjusting a neutral reaction, and dried over
anhydrous sodium sulfate. 12 g of R,S~2,3,5,6-tetrahydro~6-
phenyl-imidazo(2,1~b)-thiazole were obtained, after evaporating
mesitylene at reduced pressure off. The product's melting
point, recrystallized from cyclohexane was 90-92C, and the
yield 58.5% of theoretical.
EXAMPLE 10. R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-
thiazole hydrochloride (I). (Cyclodehydration with sulfuric
acid).
To 196 g t2 moles) cooled to -5C sulfuric acid,
22.2 g (0.10 moles) of R,S-1-(2-hydroxyethyl)-4-phenyl-imidazo-
lidine-2-thione were added portion wise, and the reaction
mixture was stirred at room temperature for ten hours. The
acid mixture was alkalized with 30% aqueous solution of sodium
hydroxide to adjust p~I~11.5, and the alkaline solution extracted
with three 100 ml portions of methylene chloride. The extract
was washed with water, adjusting a neutral reaction, then dried
ovér anhydrous sodium sulfate. The crude R,S-2,3,5,6-tetra-
hydro-6-phenyl-imidazo(2,1-b)-thiazole was obtained, after
distilling the methylene chloride off. It was dissolved in
acetone and the desired product precipitated with 20% solution
of hydrogen chloride in isopropanol. The compound R,S-2,3,5,6-
tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole hydrochloride, thus
obtained had a melting point 254-256C.
- 13 -
. "' ~
