CA1100507A - Process of obtaining r,s-2,3,5,6-tetrahydro-6-phenyl- imidazo (2,1-b)-thiazole - Google Patents
Process of obtaining r,s-2,3,5,6-tetrahydro-6-phenyl- imidazo (2,1-b)-thiazoleInfo
- Publication number
- CA1100507A CA1100507A CA306,849A CA306849A CA1100507A CA 1100507 A CA1100507 A CA 1100507A CA 306849 A CA306849 A CA 306849A CA 1100507 A CA1100507 A CA 1100507A
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- hydroxyethyl
- thione
- acid
- imidazolidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/42—Sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
R,S-2,3,5,6-Tetrahydro-6-phenyl-imidazo (2,1-b)-thiazole (Tetramisole), of the formula:
is obtained by reacting R,S-.alpha.-(2-hydroxyethylaminomethyl)-benzylamine, of the formula:
with carbon disulfide, to form R,S-N-(2-(2-hydroxyethylamino)-1-phenylethyl)-amide of the dithiocarbonic acid, of the formula:
which is cyclisized to R,S-1-(2-hydroxyethyl)-4-phenyl-imidazo-lidine-2-thione, of the formula:
R,S-2,3,5,6-Tetrahydro-6-phenyl-imidazo (2,1-b)-thiazole (Tetramisole), of the formula:
is obtained by reacting R,S-.alpha.-(2-hydroxyethylaminomethyl)-benzylamine, of the formula:
with carbon disulfide, to form R,S-N-(2-(2-hydroxyethylamino)-1-phenylethyl)-amide of the dithiocarbonic acid, of the formula:
which is cyclisized to R,S-1-(2-hydroxyethyl)-4-phenyl-imidazo-lidine-2-thione, of the formula:
Description
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):
5 ~ 1 III
~ 2
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):
5 ~ 1 III
~ 2
- 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).
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
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.
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 _ >
~ 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)-
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
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.
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 _ >
~ 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.
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 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.
. "' ~
'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.
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 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.
. "' ~
Claims (13)
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 carbon disulfide to produce the R,S-N-(2-(hydroxyethyl-amino)-1-phenylethyl)-amide of dithiocarbonic acid of formula Va:
Va cyclisizing the so produced amide to produce the R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione of formula VII:
VII
and cyclodehydrating the compound of formula VII to produce R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole which may be subsequently reacted with a non-toxic acid to form the corresponding pharmaceutically acceptable addition salt.
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 carbon disulfide to produce the R,S-N-(2-(hydroxyethyl-amino)-1-phenylethyl)-amide of dithiocarbonic acid of formula Va:
Va cyclisizing the so produced amide to produce the R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione of formula VII:
VII
and cyclodehydrating the compound of formula VII to produce R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole which may be subsequently reacted with a non-toxic acid to form the corresponding pharmaceutically acceptable addition salt.
2. A process according to claim 1, wherein R,S-.alpha.-(2-hydroxyethylaminomethyl)-benzylamine is reacted with carbon disulfide in an aqueous-organic medium;
3. A process according to claim 2, wherein the aqueous organic medium is a boiling ethanol medium.
4. A process according to claim 1, wherein the R,S-N-(2-(2-hydroxyethylamino)-1-phenylethyl)- amide of dithiocarbonic acid is cyclizised into R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione by heating.
5. A process according to claim 4, wherein the R,S-N-(2-(2-hydroxyethylamino)-1-phenylethyl)-amide of dithiocarbonic acid is cyclizised into R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione by heating in an organic solvent medium.
6. A process according to claim 1, wherein the R,S-N-2-(2-hydroxyethylamino)-1-phenylethyl)-amide of dithiocarbonic acid is cyclizised into R,S-1-(2-hydroxyethyl) -4-phenyl-imidiazolidine-2-thione by means of a S-alkylation intermediate in an alkaline medium in the presence of an alkylating agent of formula RX, wherein R represents a lower alkyl radical having from 1 to 4 carbon atoms, and X is an acid residue.
7. A process according to claim 1, wherein the R,S-N-(2-(2-hydroxyethylamino)-1-phenylethyl)-amide of dithio-carbonic acid is cyclizised by reacting it with an alkylating agent of formula R'X', wherein R1 represents a hydrocarbon radi-cal of the allyl, propargyl or benzyl type, and X' is a halogen to produce a R,S-N-(2-(2-hydroxyethylamino)-1-phenylethyl)-amide-S-alkyl ester of dithiocarbonic acid, and heating the so produced ester to produce R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione,
8. A process according to claim 1, wherein the R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclodehydrated in a hydrochloric acid medium to produce directly the boiling hydrochloride salt of R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole.
9. A process according to claim 1, wherein the R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclodehydrated by heating in a polyphosphoric acid or ester medium.
10. A process according to claim 1, wherein the R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclodehydrated by heating in an inert organic solvent medium in the presence of phosphorus pentoxide.
11. A process according to claim 1, wherein the R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclodehydrated by heating in a concentrated sulfuric acid medium.
12. A process according to claim 1, wherein the R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione is cyclodehydrated by heating in a mixture of cyclodehydrating agents.
13. A process according to claim 12, wherein the mixture of cyclodehydrating agents is selected from the group consisting of the mixture of polyphosphoric acid and phosphorus pentoxide, the mixture of concentrated sulfuric acid and hydrochloric acid and the mixture of concentrated sulfuric acid and phosphorus pentoxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG7700036812A BG25138A1 (en) | 1977-07-06 | 1977-07-06 | A method of obtaining of rs-(+/-)-2,3,5,6-tetrahydro-6-phenylimidazo-(2,1-b)-thiazol(tetramizol) |
| BG36.812 | 1977-07-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1100507A true CA1100507A (en) | 1981-05-05 |
Family
ID=3903588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA306,849A Expired CA1100507A (en) | 1977-07-06 | 1978-07-05 | Process of obtaining r,s-2,3,5,6-tetrahydro-6-phenyl- imidazo (2,1-b)-thiazole |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5414996A (en) |
| BE (1) | BE868743A (en) |
| BG (1) | BG25138A1 (en) |
| CA (1) | CA1100507A (en) |
| CS (1) | CS199459B1 (en) |
| DE (1) | DE2829823A1 (en) |
| ES (1) | ES471355A1 (en) |
| FR (1) | FR2396760A1 (en) |
| GB (1) | GB2000778B (en) |
| IT (1) | IT1174323B (en) |
| NL (1) | NL7807267A (en) |
| SU (1) | SU920056A1 (en) |
| YU (1) | YU162178A (en) |
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| CN105130982B (en) * | 2015-08-24 | 2017-04-05 | 华南农业大学 | A kind of imidazoheterocycles dithiocarbamates and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3726894A (en) * | 1971-06-24 | 1973-04-10 | American Cyanamid Co | The compound 1-(2-hydroxyethyl)-4-phenyl-2-imidazolidinethione |
| US3865836A (en) * | 1972-12-08 | 1975-02-11 | Janssen Pharmaceutica Nv | Bicyclic imidazoles |
-
1977
- 1977-07-06 BG BG7700036812A patent/BG25138A1/en unknown
-
1978
- 1978-07-03 ES ES471355A patent/ES471355A1/en not_active Expired
- 1978-07-05 IT IT50169/78A patent/IT1174323B/en active
- 1978-07-05 CA CA306,849A patent/CA1100507A/en not_active Expired
- 1978-07-05 JP JP8247178A patent/JPS5414996A/en active Pending
- 1978-07-05 BE BE2057118A patent/BE868743A/en not_active IP Right Cessation
- 1978-07-05 NL NL7807267A patent/NL7807267A/en not_active Application Discontinuation
- 1978-07-05 SU SU787770242A patent/SU920056A1/en active
- 1978-07-06 DE DE19782829823 patent/DE2829823A1/en not_active Ceased
- 1978-07-06 YU YU01621/78A patent/YU162178A/en unknown
- 1978-07-06 GB GB7829072A patent/GB2000778B/en not_active Expired
- 1978-07-06 FR FR7820187A patent/FR2396760A1/en active Granted
- 1978-07-06 CS CS784514A patent/CS199459B1/en unknown
Also Published As
| Publication number | Publication date |
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| FR2396760A1 (en) | 1979-02-02 |
| FR2396760B1 (en) | 1981-12-18 |
| SU920056A1 (en) | 1982-04-15 |
| JPS5414996A (en) | 1979-02-03 |
| DE2829823A1 (en) | 1979-01-25 |
| IT1174323B (en) | 1987-07-01 |
| ES471355A1 (en) | 1979-10-01 |
| BE868743A (en) | 1978-11-03 |
| YU162178A (en) | 1982-08-31 |
| IT7850169A0 (en) | 1978-07-05 |
| GB2000778B (en) | 1982-04-07 |
| CS199459B1 (en) | 1980-07-31 |
| BG25138A1 (en) | 1978-08-10 |
| NL7807267A (en) | 1979-01-09 |
| GB2000778A (en) | 1979-01-17 |
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