Derivatives of R,S-[X2-(2-hydroxyethylamino)-1-phenyl]-ethylamine, and process

An R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine of the formula III ##STR1## wherein R represents hydrogen, allyl, propargyl or benzyl. These compounds provide valuable intermediates for the synthesis of Tetramisole.

This invention relates to 
R,S-[[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine derivatives which are 
valuable intermediates with production of 
R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole, of Formula I 
##STR2## 
also known as Tetramisole, and its pharmaceutically-acceptable salts with 
inorganic and organic acids. The invention also relates to a process for 
producing these compounds. 
As noted by D.C.I. Thienpont et al. Nature, 209, 1084-6, (1966), British 
Pat. No. 1,043,489, A.H.M. Raeymaekers et al., J. Med. Chem., 9, (4), 
545-555 (1966), and British Pat. No. 1,076,109, Tetramisole has valuable 
pharmacological properties, and is used as a potent broad-spectrum 
antihelminthic. Recently, the interest in this agent has considerably 
increased because of the discovery of its immunoregulating properties, and 
the use of the drug in the therapy of neoplastic diseases (the Ger. Offen, 
No. 2,340,632). 
Antidepressive (the Ger. Offen. No 2,340,634) and antianergic (the Ger. 
Offen. No. 2,340,633) activities of 
R,S-2,3,5,6-tetrahydro-6-phenylimidazo(2,1-b) thiazole and its 
pharmacologically active salts have also been described. 
The Ger. Offen. No. 2,236,970 describes the compound 
R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylanine.sup.+, having Formula II 
##STR3## 
wherein a five step synthesis, including the use of reagents such as 
hydrogen chloride, thionyl chloride, ammonium thiocyanate, and two thermal 
cyclizations, results in obtaining of Tetramisole, of Formula I. *L6 
.sup.+ Another possible name of the compound with Formula II is 
R,S-.alpha.-(2-hydroxyethylaminomethyl)-benzylamine. 
The object of the present invention is to provide 
R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine derivatives which enable 
a new and highly effective method of synthesis of 
R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole, of Formula I. 
According to this invention, the new R,S-[2-(2-hydroxyethylamino)-1-phenyl9 
-ethylamine derivatives are of Formula III 
##STR4## 
wherein R represents hydrogen, hydrocarbon radicals containing a double or 
triple bond, or arylaliphatic type groups. 
Those derivatives, of Formula III, wherein R represents hydrogen, allyl 
(prop-2-en-1-yl), propargyl (prop-2-in-1-yl), or benzyl are preferred. 
R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine derivatives are 
synthesized by interacting 
R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine (II) with carbon 
disulfide, and the compound obtained, of Formula III, wherein R is 
hydrogen is then reacted with alkyl halides having allyl, propargyl or 
benzyl groups in aqueous, aqueous-organic, or organic medium, producing 
ester-amides of the dithiocarbonic acid. 
The R,S-N-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamide of the 
dithiocarbonic acid, of Formula III, wherein R represents hydrogen, can 
also exist in the form of an internal dithiocarbamic salt of Formula IV 
##STR5## 
These R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine, derivatives, 
allow for a method, easily accomplished, for example: by heating, giving 
good yields of R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione (V), 
which is dehydrated quantitatively, giving 
R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(2,1-b)-thiazole (Tetramisole) (I), 
as described in the Bulgarian author's certificates; Nos. 24864 and 25138. 
According to this invention, the derivatives of 
R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine, and especially 
R,S-N[2-(2-hydroxyethylamino)-1-phenyl]-ethylamide of the dithiocarbonic 
acid (IV), have the advantage of easily forming the Tetramisole 
heterocyclic ring system, employing a three-step synthesis.

This invention is explained bythe following examples: 
EXAMPLE 1.R,S-N[2-(2-hydroxyethylamino)-1-phenyl]-ethylamide of the 
dithiocarbonic acid (IV). 
18 g (0.10 moles) of R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine were 
dissolved in 60 ml of 96% ethanol. After a homogeneous solution was 
obtained, 11,4 g (0.15 moles) of carbon disulfide were added dropwise at 
40.degree. C. After a period of four hour heating under reflux, the 
precipitate which separated was filtered and washed with 10 ml of ethanol. 
The R,S-N-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamide of the 
dithiocarbonic acid yield was 18.1 g (70% of the theoretical); m.p. 
136.degree.-138.degree. C. (decomp.). 
Elemental analysis of C.sub.11 H.sub.16 N.sub.2 OS.sub.2 (M=256.38) 
______________________________________ 
Calculated Found 
Element % % 
______________________________________ 
C 51.52 51.95 
H 6.29 6.35 
N 10.93 10.70 
S 25.01 24.80 
______________________________________ 
EXAMPLE 2. 
R,S-N-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamide-S-allyl ester of the 
dithiocarbonic acid. 
25.6 g (0.10 moles) of R,S-N-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamide 
of the dithiocarbonic acid (Example 1) 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 filter. 14.5 g (0.12 moles) of allyl bromide were added 
to the filtrate, and the mixture stirred for one hour at room temperature. 
100 ml of methylene chloride were added to the mixture, separating and 
filtrating the crystals obtained, 8.7 g of 
R,S-N-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamide-S-allyl ester of the 
dithiocarbonic acid were obtained; m.p. 124.degree.-126.degree. C. 
Yield--32% of the theoretical. 
Infrared spectrum: Nujol.RTM.mull (CH.dbd.CH.sub.2)=1625 cm.sup.-1. 
Elemental analysis of C.sub.13 H.sub.18 N.sub.2 OS.sub.2 (M=282.42). 
______________________________________ 
Calculated Found 
Element % % 
______________________________________ 
C 55.31 55.01 
H 6.38 6.70 
N 9.92 10.20 
S 22.69 22.93 
______________________________________ 
EXAMPLE 3. R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione (V). 
(Cyclization by melting of a compound, with Formula IV). 
97 g (0.38 moles) of R,S-N-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamide of 
the dithiocarbonic acid (Example 1) were heated at 150.degree. C. for four 
hours. 120 ml of methylene chloride were added to the melt, and cooled to 
20.degree. C. 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 pH=5, and dried over an anhydrous sodium sulfate. After 
distilling the solvent off, 42 g of 
R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidin-2-thione were obtained; m.p. 
91.degree.-93.degree. C. yield--50% of the theoretical. 
EXAMPLE 4. 
R,S-1-(2-hydroxyethyl)-4-phenyl-imidazolidine-2-thione (V). (Cyclization by 
melting R,S-N[2-(2-(2-hydroxyethylamino)-1-phenyl]-ethylamide-S-allyl 
ester of the dithiocarbonic acid). 
8.7 g (0.032 moles) of R,S-N-[2-(2-hydroxyethylamino)-1-phenyl]- 
ethylamide-S-allyl ester of the dithiocarbonic acid were heated for two 
hours at 150.degree. C. 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 initially washed 
with 25 ml 10% aqueous solution of sodium hydroxide, 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 
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, recrystallized 
from methylene chloride, had m.p. 91.degree.-93.degree. C. Yield--34% of 
the theoretical. 
EXAMPLE 5. R,S-2,3,5,6-tetrahydro-6-phenyl-imidazo(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.degree.-258.degree. C. Yield--quantitative.