CA1100508A

CA1100508A - Process of obtaining r,s-2,3,5,6-tetrahydro-6-phenyl- imidazo (2,1-b)-thiazole

Info

Publication number: CA1100508A
Application number: CA306,851A
Authority: CA
Inventors: Kina V. Konstantinova; Ventzel G. Michaylov; Hristo P. Daskalov; Atanas G. Georgiev
Original assignee: Pharmachim DSO
Current assignee: Pharmachim DSO
Priority date: 1977-07-06
Filing date: 1978-07-05
Publication date: 1981-05-05
Also published as: IT7850170A0; YU162278A; DE2829822A1; JPS5414997A; ES471356A1; FR2396761B1; SU922107A1; FR2396761A1; GB2002350B; BE868744A; HU181927B; IT1174324B; GB2002350A; NL7807266A

Abstract

ABSTRACT OF THE DISCLOSURE:

R,S-2,3,5,6-Tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole (Tetramizole), of the formula:

is obtained by reacting R,S)-.alpha.-(2-hydroxyethylaminomethyl)-benzyl-amine of the formula:

with a compound of the formula:

wherein R1 and R2 are identical and represent chlorine, or differ from one another, in which case R1 represents a loweralkoxy radical with 1 to 4 carbon atoms and R2 is SM, M representing sodium or potassium, to form R,S-1(2-Hydroxyethyl)-4-phenyl-imidazolidine-2-thione of the formula:

Description

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):

~ 1 III

y ~ 2 ~ 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~.

. :~ .

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;

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:

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 .. . .

~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.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows-

1. A process for preparing R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo (2,1-b)-thiazole of formula I;

I

and its pharmaceutically acceptable salts with the non-toxic acids, comprising the steps of reacting the R,S-.alpha.-(2-hydroxye-thylaminomethyl)-benzylamine of formula IV:
IV
with a compound of formula V:

wherein R1 and R2 are identical and each represent chlorine, or differ from one another, in which case R1 represents a loweralkoxy radical having from 1 to 4 carbon atoms and R2 is -SM,M representing sodium or potassium, to form the R,S-1(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione of formula VI:

VI

and subjecting the so formed thione to cyclodehydration to form the R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole of Formula I which may be subsequently reacted with a non-toxic acid to form the corresponding pharmaceutically acceptable salt.

2. A process according to claim 1, wherein R, S-.alpha.-(2-hydroxyethylaminomethyl)-benzylamine is reacted with an alkaline ethylxanthate to form the thione of formula VI.

3. A process according to claim 1 wherein R,S-.alpha.-(2-hydroxyethylaminomethyl)-benzylamine is reacted with an alkaline methylxanthate to form the thione of formula VI.

4. A process, according to claim 1, wherein R,S-.alpha.-(2-hydroxyethylaminomethyl)-benzylamine is reacted with an alkaline butylxanthate to form the thione of formula VI.

5. A process according to claim 2, 3 or 4, wherein the reaction with the alkaline alkylxanthate is carried out in boiling water or in an aqueous-alcohol medium.

6. A process according to claim 1, wherein R,S-.alpha.-(2-hydroxyethylaminomethyl)-benzylamine is reacted with thio-phosgene and imidazole in a methylene chloride and benzene solution at a temperature from 25°C to 80°C.

7. A process according to claim 1, wherein R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclodehy-drated in a boiling hydrochloric acid medium to produce directly the hydrochloride salt of R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo (2,1-b)-thiazole.

8. A process according to claim 1, wherein R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclo-dehydrated by heating in a polyphosphoric acid ester medium.

9. A process according to claim 1, wherein R,S-1 (2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclo-dehydrated by heating in a medium of inert organic solvents in the presence of phosphorus pentoxide.

10. A process according to claim 1, wherein R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclo-dehydrated in a concentrated sulfuric acid medium.

11. A process according to claim 1, wherein R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclo-dehydrated by heating in a mixture of cyclodehydrating agents.

12. A process according to claim 11, wherein the mixture of cyclodehydrating agents is selected from the group consisting of the mixtures of polyphosphoric acid and phosphorus pentoxide, concentrated sulfuric and hydrochloric acids, and concentrated sulfuric acid and phosphorus pentoxide.