CS199459B1 - Method of preparing r,s-2,3,5,6-tetrahydro-6-phenylimidazo-/2,1-b/thiazole - Google Patents

Abstract

<IMAGE> d,1-1-(2-Hydroxyethyl)-4-phenyl-imidazolidine-2-thione, is obtained by reacting d,1- alpha -(2-hydroxyethylaminomethyl)-benzylamine with carbon disulphide and subjecting the resulting d,1-N-[2-(2-hydroxyethylamino)1-phenylethyl]-amide of dithiocarbonic acid to a cyclization process.

Description

METHOD OF PREPARATION R, S-2 ', 3,5,6-TETRAHYDRO-6-PHENYLIMIDAZO- (2,1-THIAZOL)

The invention relates to a process for the preparation of R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1-b) thiazole of the formula I,

also referred to as tetramisole, and pharmaceutically acceptable salts thereof with inorganic and organic acids.

From the literature D. С. I. Thienpont et al. Nature 209, 10.84-6 (1966), brit. U.S. Pat. No. 1,043,489, A. Η. M. Raeymaekers et al., J. Med. Chem., 2, (4),

545-555 (1966), British patent δ. No. 1,076,109, tetramisole is known to have valuable pharmacological properties and is used as a potent anthelmintic with a broad spectrum of activity. Recently, interest in this substance has increased considerably when its immunoregulatory properties and applications have been discovered in the treatment of neoplastic diseases (published patent application NSR 2,340,632).

It has also been reported that R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1-b) thiazole and its pharmacologically active salts have antidepressant (DE-OS.

340 '634) and anti-allergic (DE-OS.2 340.633) effect.

It Is · ^p o ^p sucked series. In a way, s ^{y e} nt ^y of tetra-sol. · When nothing of vět.šině ^{h 'j} AVU ^rea e ^y dro tetrahydro ⁱ m ^{i i} dazoth azole ring s ^y st ^e m e ^f :, flow in ^yt a bond ^{of manufacture'} between carbon 'atom position 6 and nitrogen at the 7-position (Formula I), i.e. a C (6) -N (7) -binding is formed. by eliminating the compound of formula XY in the compounds

where

X represents OH (British patent 1,043,489, British patent 1,109,149), -Cl, -Br (British patent 1,076,109, British patent · 1,109,149), -N 'OgCgH3CH3 (French) Patent ^1,544,972), · NH _2, -NHCOR · (DE-OS 2236970). and

Y is most often hydrogen (British patent

109 149), but equ^Ethat can^exRCO (British patent 1 043 489) or an alkyl group (DE-OS 2 236 970).

Methods of synthesis of the starting compounds II listed in obecného.vzorve different Atentát ^P RP ^and are set otoobn ^e Yai and only in the 'jednotyvostech. ^J e mo ^from NO summarize, ^from the e · these acrylate ^alkyl usually ^conn ravuj ^{as PE} TIST ^p-tier syntozou, CMD which is · use of such reagents as · styrene, styrene oxide, female • cylbromid, ethanolamine, aziridine, sodium borohydride , inorganic acid halides, thiourea, thiocyanate acid derivatives, etc.

In the second method (popsaneho'v Offenlegungsschrift no. 2 034 · 081 · and in French Patent no. 2224472) 'from above' said double-circuit heterocyclic ^conn ight to ^F e, to create · N ⁽⁴⁾ -O (5) bond (in ^iz 'formula I). .

These methods have no advantage in comparison with the aforementioned methods poněvad ^{from K} ompl ^also ovan ^of Jai multistage ^Y ntoza ^to one ^no n ^e he ^p roducts zalamujerovněž 'determines ^whether t ^e compound ^No. ene ^and n ^y, which are difficult ^of ( iosaží availably ^ Vzhle ^d em kt ^to these complications, and due to the fact that when opening the aziridine · ring of compound III (French Pat. No. 2,224,472) not only to cleave ^{the N} (7) ^{"C (5)} VA ^zb y SLE • ^Also к Roza ^I cleavage of ^{N (7) -} C (6) · va ^{zb y} .MA tonto'z ^Pooh method syntozy lower value.

French patent δ ... 2237900 describes a variant of connecting the two aforementioned SKU ^pi n ^y methods. p? ^{and -} that this unit ^P ůsobením L-phe ^{ny l, 2-dibromo} methane ^{2-amino- 2} am ^and -TH azole ⁱ n ^y forms simultaneously N (4) -C (5) and C (6) -N ⁽⁷⁾ Till to give tetrahydro-6-fenylimidazothiazolového ring. This method has no ^dy The advantage Opro ^TI ME ^t o ^be m Shiori Uve eným ^{d p of} vaďž he may also occur 5-phen ^y l ^d e ^r Ivat the double circle of the heterocyclic system, which reduces the yields of final '- product.

Three ^and metho ^d and ^the creature ^{tetrahydrofuranyl} roim az.ot ^{hi id} azole ^Y STEM ^{'pop N} and British Patent δ. The second heterocycle, i.e. the thiazolidine portion of the molecule, is obtained by the simultaneous formation of S (1) -C (2) and C (3) -N (4) bonds (see formula · I). Main 'drawbacks of this procedure are difficult' availability klíčivého 4-phenyl-imidazolidin-2-thione, expensive condensing agent such as lithium amide, and n ^{a dangerous} work and -able and low howl ^{ěžky 'final} Joint ^p roducts, especially kd ee as ^{characterized o} 'condensation product' uses sodium carbonate.

. Nor do modifications of this method have any 'advantages (French patents ² ' ² 58 379 and 2 ² 58 '380)'. When těctoo mo ^dif polymorph ^I CH tetrahydroimidazothiazolový obtained by cyclizing the ring system at C (3) -N (4) (see formula I).

The ^three et ^d 'sjyntetická meto ^ga execution tetra ^hy droite dazot ^{hi and h} azole system ^runs nal TE, ^from the' method after the Sanyo ^{p p} aten ^t u δ USA. 3726 ^- 894. ^In this method ^- a heterocycle obtained such that ^- in a ^{RI yl} (l) -C ^{(2) -} linkage (see formula I). The only reason why this method was developed, is to make good use of R - (+) - 2,3,5,6-tetrahydro-6-phen ^yl limidazo (2-b) thiazole, který.je side · product of IA ^to AnyMem ^at Ste ^p en ^s. tetramethyluronium-naphthoic acid ^To a mixture racemi.c. ^A uto ^s Rovai ^{ga p} j ⁱ This sterling ^ep en ^d 'such that the ^straight Evad ^{of fy r} a z ⁱ olo ^gi ck ^y' neútonný ^R - ⁽⁺⁾ - ^2, 3,5,6-tetra-y ^d ro - ^6- phenylimidazo (2,1b) -thiazole. - to racemic R, SL (2-Hydroxy ^y eth ^y l) -4-phenyl-imidazolidine-2-thione ^p dip ^{i - y} multistep syntheses that is. s ^ Htéí and 'technologically difficult ^{e p} rove ^{di n} a telephone. . Pteoben thionyl ^d ^ u ^{R, S} T ^{(2-hy d} ro3y etlty 1) -4-phenyl-imidazolidine-2-thione again cyclized to give the racemic mixture ^{tetrámisolóvé-monthly. T} his ^p Ostu ^pp oskytuje tozk yield ^off-f alkyl, ASI 4 ^0% teorÍLe.

As already mentioned, according to -US patent 3,726 -894, - R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione VII is a key intermediate to obtain

R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1b) -thiazole I. The only method of obtaining a compound of formula VII is the method disclosed in the - quoted - patent. This of ^p Úsobí However, as already indicated b ^y lo, Prakt c ^ prílmyslov ^of unworkable.

It should also be noted that R, S1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione according to U.S. Pat. No. 3,726,894 cannot be used. other than by pre-synthesizing tetramisol in some other known manner. Cited Patent, using ^even the R - (+) - ^2, 3,5, ^{6-t.etrah yd} ro-6-yl-imidazo fer ^{N (2} lb) + t ^hi azole ^of the TE does not ^always constitute no e ^d solve the problem - tetrahydroimidazothiazole formation. 'structures.

Ji.n ^é Meto ^dy Z ^{and Ka i o} n - te.trrmisolu ^- ter ^{the Star.} more ^- not ^b om them contained ^{é í h} uj PRVT uvedenýchmetodách contained in the above are described Velim French Patent Nos. 2183313, 2-258 -379 - 2258 - 380, 2259 092,2 259 823, 2 264 017, 2 264 018, 2 271 211, 2 271 212, - 2 271 213, - wildlife - NSR 2 264 911. and 2,325,808.

The challenge in ^y n ^{u and} lies in the ^y coil ^-. New ^PU reindeer with ntéz ^{y y} tetramisole that ^{-. and} which would be suitable for industrial use, using more accessible raw materials, in particular R, S-cL- (2-hydroxyethylaminomethyl) benzylamine of formula IV, - which - can be obtained from basic organic products synthesis.

According to the invention, the R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1- ^b ) thiazole is prepared by the preparation of R, S-o (R, S) -thiomethylmethylaminomethylmethylene benzamide of the formula IV '

CGH ₅ - -.CH CH ₂ - NH -'CHg --CH₂ - OH, - ^NH 2 IV ^Pooh with ^bi- sulfur ^h l in ^CART em ^{- originally} NETIO m in ^d or not ^g ^ Annie ostředí. ^R ^^ ESPONDING gave N-phenyl-fP ^ hiytoox thylaminoJi feJWlethyl L-amino} ^d ^ t ^ oubli-Cite kyselica formula Va '. ·. * © ·. '' · '. \

CgHj - CH - CH2-NH2 - CH - CH ₂ -OH (Va)

X.® which is converted to -R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-rione of formula VII.

(VII)

- 5 by one of the following methods:

a) thermal cyclizing the compound of formula Va by heating the compound, optionally in an inert solvent environment;

b) cyclisation of a compound of formula Va chemically induced using reagents of formula RX wherein R is lower alkyl and X is an acid residue. Examples of such reagents include methyl iodide, dimethylsulfate, diethylsulfate, n-butyl bromide, and alkyl esters of p-toluenesulfonic, methanesulfonic and fluoroulfonic acids;

c) converting the compound of formula Va into the R, S-N- [2- (2-hydroxyethylamino) -1-phenylethylamine-amide-S-alkyl ester of dithiocarbonic acid of formula Vb,

(Vb) where

R 'is allyl, benzyl, or cinnamyl, followed by melting the compound of formula Vb to form the compound of formula VII.

The name of the compound of formula IV is formed according to the nomenclature principles applied in Chemical Abatracte. The same compound can also be referred to as R, S-2- (2-hydroxyethylamino) -1-phenylethylamine.

When proceeding according to variant c), the synthesis of the compound of formula VII proceeds according to the following reaction scheme;

(IV)

4.0

..... .C. ₆ ^H 5 - ' ^GH - θ ^Η 2 · №'' ^C H2 ~ ^CH 2' ° H (Vb) ''. · '/ ”Ř'SH -. ·. S '. ~ '.

, NH - C

- (VII)

As the alkylating agent of formula R * X. Most preferably, it uses allyl bromide, benzyl bromide, propargyl bromide and clnamyl bromide. Reactions ae preferentially ^{BC p} rovádí in vočlném, ^originally alkoholrókta or · a ^lk oholickém midst.

Cyclodehydration of compound (VII) by various. · dehydrating agents such as acid · polyfoaforečná or its esters, phosphorous .kysličník, 'with a concentrated acid amide ^s Rovai, chloro or íková ^d'. ' of the mixture to give R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1b) thiazole of formula IIa. _;

(AND)

Fo ^d le ^Pr A more preferred variant of the invention, ^y · tetra-AOL may 'ziíekat. reacting the compound of formula IV with carbon disulfide. The compound of formula obtained. Va. ^BC is melted and converted to ^{R, S} -l- (2-h ^yd rox ^y et ^{hydroxymethyl)} -4-phen ^yl lim ^{d id} azole-2-t ion of the formula ^{V H-P} and the dip cyklí.zuje ^s hydrochloric Tí.mto · ^PU with ^b e em directly · ^{ANNUAL running in} physiologically acceptable salt thereof, R, S-2,3,5,6-tetrahydro-6-ferjlimidazo (2-b) thiazole hydrochloride (tetramiso: Uhyů: rochloride), new. a. simpler. way.

^PU with ^b em ^p o e ^dl to the invention will be well as ^d and ^d USE 'economy preferably synthesized germinating interm R SL (2-hydroxyethyl) -4-phenyl-imidazolidine-2' - ^7th -.

The thion of formula VII, which is of incomparably higher quality than the product obtained by the process of the above-mentioned US patent δ. 3,726,894 Tak'například · The temperature Subtraction ^s -slou ^No .enin ^y formula VI ^{'ANNUAL b measured} to the ^d le ^{y zu} nal. is about 10 ° C, ^{characterized} in SSI than the melting point of the product 'according to said U.S. Pat .. This major advantage of ^Y St. ^{ETL also} U is O ^towards you ^and the ^{yields against} y' and tťt.ramisolu 'in the ^y Sokou kvalí.tu. . Of Eden ^{u c} h · reasons it is not necessary to use special. methods of cleaning the final product.

^{From the} mouth ^{of b} p le VYN ^s lezu However VUJE ^ · ^I N ^T egr ^and LN ^i, e ⁱ c Hereafter ^the above ^{alkyl, h} o ^d Nu ^PU synthesis method '· ^ Ε -2,3,5,6-ΐθίΓβΙχ7 <1Γθ-6- ββγγ1ΐιιιί (ϊβζο (2,14)). thiazole and effective methodology · ^{d s} for converting ^{R, S} -l- ^(2-hydroxy-t hy roxy ^d) -4- ^{phenyl and} mi.dazdidin-2-thione at tetrami-. sol.

^N and ^{a l i} Ci eduj ^comm ice ^Gd compound ^Y · ^kl e ^psi him ^but objasnění'vy ⁿ u.

Example 1 and d-l

^{R, S-N-} [2- (2- ^-h yíroxye ^{ethylamino) -} l- ^phenyl-Ewa amí.d dithio.uhHčité k ^{y y} Selin

18.g (0.10 mol). R, S 0 - (2-hydroxyethyl laminomethyl ^yl) benzylamine were dissolved in 60 ml of 96% ethanol. When a homogeneous solution was added dropwise 11.4 g (0.15 mol) of ⁱ rouhl ^Cart u'při 40 ° C. Po'4 ^H of N ^and CH, ^di boiled under ^PE sLex condenser, the precipitate is filtered off and washed · 10 ml of ethanol. Yield · R £ Sn 2- (2-h ^y dro :! yethylam ^{x and} NO) -l- ^{phenyl th} yl] anii dithioudiliČité ^d. acid 'in the howl ^of YC ⁱⁿ 18.1 ^g (70% ^of te RIE), TE ^p lota mp 136-138 ° C (decomp r ^{a and} d).

Elemental analysis for C-ujHggNgOSg · · 256.38

Element Calculated. % Found%

0. 51,52 51.95 H 6.29 ’ 6.35 N 10.93 10.70 WITH 25.01 24.80 Example. 2

R SL (2-hydroxyethyl) -4-phenylimide ^d azoles ^d ift-2-thione of formula VII (cyclization melting compound. Va) ^{g '(0,} 38 moles) ·. ^R, Sn [2- ⁽² -h ^yd roxyethylam ⁱ no) -1-amino fenyletiyŮ ^d .u dithi.uhli ^No ite sel k ^y n ^{y i.} For 4 hrs; ^HRI in ^g · 5 to ^{1 0} ° C. Avenin К ^{t E} P ^s can. ¹²⁰ ml ^with ethylene and ^m .sm ^E is the cooled ^says. on . ^{Deň: 18} ° C. The solution ^of p ^filt e r ^filt oestrus and ^ATs. extract with 120 ml. 10% aqueous sodium hydroxide solution and washed with 120 mL of 1: 3 hydrochloric acid. The methylene chloride extract was washed with 'water' to adjust the pH to. 5, and dried over anhydrous magnesium sodným.- After oddeatilování solvents' 42 g R, SL (2-hydroxyethyll-4-phen ^yl limidazolidin- ^2-thione with a melting .tán ^{s of} .91 and ^{93 -} ° C. Yield ^The yield is 5 ⁰ % of theory.

The melting point of R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione disclosed in U.S. Pat. No. 3,726,894 is 81-83 ° C.

Example 3

R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione of formula VII (cyclization with dimethyl sulfate)

To 100 ml of a 5% aqueous solution of sodium hydroxide, 25.6 g (0.10 mol) of dithiocarbonic acid R, SN-2- (2-hydroxyethylamino) -1-phenylethyl] amide are added and the solution thus obtained is filtered through a pad of asbestos and cellulose fibers. The filtrate was cooled to -5 ° C and 13 g (0.10 mol) of dimethyl sulfate was added dropwise at the same time. A resinous material and an upper aqueous layer are formed. Decant the liquid and dissolve the resin mass in methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and the solvent was distilled off. 10.4 g of R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione are obtained. Recrystallization of the crude product from n-butyl acetate gave R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione, m.p. 91-93 ° C. Yield: 47%.

P a 1 and d. 4

E, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione of formula VII (cyclization with n-butyl bromide)

25.6 g (0.10 mol) of Dithiocarbonic acid R, S-N- [2- (2-hydroxyethylamino) -1-phenylethyl] amide were suspended in 100 ml of water. 150 ml of 5% aqueous sodium hydroxide solution are added to the suspension, and the resulting mixture is filtered through a pad of Šebest and cellulose fibers. 16.5 g (0.12 mol) of n-butybromide are added to the filtrate at 50 DEG C. and after stirring for 4 hours 100 ml of methylene chloride. The methylene chloride layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off completely. 10.7 g of crude R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione are obtained. The product is recrystallized from butyl acetate and then has a melting point of 91-93 ° C. Yield: 48.2%.

Example 5

Dithiocarbonic acid R, S- [2- (2-hydroxyethylamino) -1-phenylethyl] amide-S-allyl ester of formula Vb

Dithiocarbonic acid R, S-N- [2- (2-hydroxyethylamino) -1-phenylethyl] amide (25.6 g, 0.10 mol) was suspended in 100 ml of water. The suspension is added to

100 ml of 5% aqueous sodium hydroxide solution and the resulting mixture was filtered through a pad of asbestos and cellulose fibers. 14.5 g (0.12 mol) of allyl bromide are added to the filtrate and the mixture is stirred at room temperature for 1 hour. 100 ml of methylene chloride are added to the mixture and the precipitated crystals are filtered off.

8.7 g of di-carbonic acid R, S-N- [2- (2-hydroxyethylamino) -1-phenylethyl] amide-S-allyl ester, m.p. 124 DEG-126 DEG C., are obtained. Yield: 32%.

Infrared spectrum ζin suspension - nujol} (CH = CH 2 = 1625 cm -1 ⁾

Elemental Analysis for ^ 13 ^ 13 ^ 2 ^ 2 (282.42)

Element Calculated% Found%

C 55.31 55.01 H 6.38 6.70 N 9.92 10.20 with 22.69 22.93 Example 6

R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione of Formula VII (Melt Cyclization of Compound of Formula Vb)

8.7 g '(0.032 mol) of R, S-N- [2- (2-hydroxyethylamino) -1-phenylethylamide] -S-allylcarbonic acid ester was heated at 150 ° C for 2 hours. The mixture is cooled to room temperature, 50 ml of methylene chloride are added and the solution obtained is filtered through a pad of asbestos and cellulose fibers. The filtrate was washed first with 25 ml of a 10% aqueous solution of thorn hydroxide, then with 25 ml of aqueous hydrochloric acid solution (1: 3) and finally with 50 ml of water until pH 6. The methylene chloride extract was dried over anhydrous sodium sulfate. After distillation of methylene chloride, 2.47 g of crude R, S-1- (2-hydroxyethyl) -4-phenylimidazolidine-2-thione is obtained. R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione recrystallized from methylene chloride has a melting point of 91-93 ° C. Yield: 34%.

Examples

R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1-l) thiazole hydrochloride (cyclodehydration with hydrochloric acid)

11.2 g (0.05 mol) of R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione are dissolved in 100 ml of hydrochloric acid with stirring and the reaction mixture is refluxed for three hours. The solvent was distilled off completely under reduced pressure, the crude product obtained was suspended in 40 ml of isopropyl alcohol and filtered off. 11.6 g of R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1-b) thiazole hydrochloride are obtained, m.p. 256 DEG-258 DEG. The yield is quantitative.

. . -10. -,.

Ex. La-d e

R, S-2,3,5, 6-tetrahydro-S-blacknylimidazo (2,1-b) thiazole of formula I '(polyphosphoric acid cyclodehydration)

9.9 g (0.04 mol) per powder of finely divided R, S1- (2-hydroxyethyl) -4-phenylimidazolidine-2-thione were added. to 200 ml of polyphosphoric acid. The reaction mixture ^of the 6 ^h of ^di n zaliřív ^{Å. 0} to 15 ° C. and ^p and ^k. spill .. into the siren. 60 ^{0 g} . drcentoo ice and 200 ml water. The acidic mixture was basified with 45% NaOH with vodným.roztokem <3ného at ^p H 11.5 and Al ^{to Alice} characterized mites ^for ex-tratoje three ² ° 0 ml-portions of methylene chloride. After. distilling - rozpouštědla-, 2 g of R, ^{S-2,3,5,6-tetrahydro-r} of 6-phenylimidazo (2,1 ^- b) thiazole. Te ^pl ota counting ^{d p to} the genus p ^ ^y krystílovanáto zc klohexanu je.9 ⁰ - ² to 9 ° C. Yield ^{of 2} žek.je 4% of theory.

When ^the Tuning

R, S-2,3,5,6-tetrahydro-6-phenylimidazo- (2,1-b) thiazole of formula I '(cyclodehydration with phosphorus pentoxide)

22.2 g (0.10 mol) R, SL (2-hydroyyetyyl) -4-fervlimidazolidin-2-thione ^p ust be extended ^even in ² 50 ml of mesitylene and ^p s ^d and ² eighth, 5 ' g (0. 0 ² mol) kysHčnftu ^f osfore ^no tenderness. ^{It is} transferred. 1 hoMnu ^- Mito ^at 110 ° C. ^R EAK ^{N NU} mixture was cooled to room temperature, added se.100 ml of 30% cold aqueous solution of sodium kyůroxidu 'and-the organic layer. separated from aqueous alkaline. solution. The organic solution was washed with two 100 ml. portions of water to - pH 5 nastavilo.na and dried with anhydrous magnesium ^d Nym. Mosque ^y len se. ^'Release for snížetoho evaporation. tíaku. Zíakéí- se. ^{12 g} R, ^S -2, 3,5-б tytrahydro-6-phenylimide ^d AZC ((2l1bb) thiazole. M.p překryatalovaného from cyclohexane 90.až 9 ² ° C. Are ^you ZY ^{to 58,} 5 .% theory.

. Example 10

R, S-2,3,5,6-tУtгahydro-6-phenylimidazo (2 lb) ^d thiazolhy hydrochloride of formula I (cyclodehydration sulfuric acid) '. .

K 196 ^g . (2 mol). ^to yaelin ^{y sulfuric} cooled to -5 ° ^é ^ after částoch p ^Rida

22.2 g (0.10 mol) of R-l - ^ - hydroxyethyl) -4-phenylimide ^d azolides 2 - thione. The latent on the reaction mixture ^of the the temperature used ^during míchá'10 Hotin. místnis ^- ia and then. basified with 30% aqueous sodium hy ^^^ at the stem to ^{pH 11} with 5 · Ai-kalickši mixture ^E is in three .extíatoje 100th mL portions mytt leichlori ^{y d} n. Met ^those iri Lenc ^{hl i} b ^s .extíakty the variable ^y j ^ ^í vtoo lieu ^RAL-i .a žnjí then bezvtoým extrusions. tentem stoným. . The solution is then idiya-ilnjy at atmospheric pressure. and the crude product is dissolved in acetone and precipitated with a 20% solution of hydrogen chloride in isopropyl alcohol. Získá.se R, S-2,3,5 »б - Уtrahydro ^{- 6-y} fУi limiiazo ^(2, l ^- b) ttiazi ^{L and} the rich ^l or ^even to ² · melting temperatures from 54 to 256 ° C.

- и -.

Object of the invention

Claims (12)

Object of the invention A process for the preparation of R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1b) thiazole of formula I (I) and pharmaceutically acceptable salts thereof with inorganic and organic acids, characterized in that R is S - (L - (2-hydroxyethylaminomethyl) benzylamine of formula IV (IV) is reacted with carbon disulfide to form R, SN- [2- (2-hydroxyethylthylamine) -1-phenylethyl] amide carboxylic acid amide of formula Va, Θ - CH - CH ₂ - NH ₂ - CH ₂ - CH ₂ - OH (Va) ^{С б И} 5 which is cyclized to R SL (2-hydroxyethyl) -4-phenyl-imidazolidin-2-thibn VII (HV), and finally, the compound is cyclodehydrated to R, S-2,3,5,6-tetrahydro-6-phenylimidazo (2,1b) thiazole. 2. The process of claim 1 wherein R, S- (- (2-hydroxyethylaminomethyl) benzylamine) is reacted with carbon disulfide in an aqueous organic medium. 3. The process of claim 2 wherein the reaction is carried out in ethanol at boiling. 4th ^bp caused by ^dl bo e ^d u ¹ .vyznačený TLM that the cyclization R with N- [2- (2-hydroxyethyl ^ylamino) -1-phenylethyl] amide dithiouhli-Cite kyselily Rovai ^{P D} I by heating to give R, S1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione. 5. Method - ^{d p} ccording bo u 1, characterized Move by c ^{R yk tion,} with N- [2- ⁽² -hydroxy -h ^{y y} eth ^y lami.no) -1-phen ^yl yljam ^th e u ^id - dit ^h ibuh ichi ^{l t} s ^p rov tyseliny ^Adi heated ^and ním- in an organic solvent za- give the R, SL (2-hydroxyethyl) -4-phenyl-imidazolidine-2-thione. 6. Úsobí ^{p - p} o <3LE bo <3u 1, characterized in that c ^YKL ISATIO ^{R, S-N} - ^[2 - ⁽² -hy- ^d rox ^y eth ^ylamino) -l- ^{f y} enyleth l] ^and m ⁱ d dithíouhličitá acid to the ^{R, S-l-} (2-hydroxyethyl) -4-phenyl-imidazolidine-2-thione is carried out - through an intermediary -alk ^y Lacey alkalictam ^p rost ^{of hereditary} assistance ⁱ al ^alkyl la ^No whom you makes ^dL formula ^R X; wherein R - represents a lower alk ^y lsku ^P inu 1 ^and 4, ^the atom ^Y u, X Uhl ^Cart -represents acid residue. . ^ 7. The method of claim 1, ^{characterized} in that ^considerable Eny. The ^S -a to ^l-yl U is ^{R, S} - ^N - ^[2 - (2-hydroxyethy-lami.no) -lf-phenyl ethyl] amino. d ^ thi.ouhHčíté - k ^y n ^{y where} alk ^y la ^N N ^U m agent of the formula X R ^Z wherein R ^z e ^{d BC} constitutes the angularly ^says metals and residue ^l l ^{s s} hunting him ^p ro ^p ar ^{Gy Star} catching him or ^b enz ^y hunting ^{eh O.tYP} ua X represents ^from about ^{l g} ha ^ene, as ^{well as} for ^{R MMN,} Sn [2-hydroxy-ethylamino-l feitylethyijam ^ -S-alkyl ester ^dit hiouhl ^IR iT ^Star acid. and the latter is C ^y KL ^i, we consider the per-IV ^and heated to the ^{R, S} -l- (2-h ^y droxyeth ^yl) -4-phenyl-imidazolidine-2-thione. 8. The method of claim 1, wherein the cyclodehydration SE-R SL (2- Hydroxy -h ^{y y} eth ^y l) -4-phen ^yl limidazolidin- ^2-thione at rave tetrsmisol performed in plain-acid ^y o hydrochloric ^{thanks halogenated} and ^BC directly isolated, ^and tetramethylthiuram Solh rochlóri ^{d d.} 9. The method according to claim 1, characterized in - that -cyklodehydratace R, 3-1- (2-h ^yd róxyeth ^yl) -4- ^{f i} enylim dazolidin-2-th one ^{and p} rov ^{ADI - p} rost ^R e ^{diacid yp} axis ols ^{f f s} orečn ° or esters under heating ^'R iv ^ck, as ^{well as} in -tataamisolu MMN. 10. The method of claim 1, wherein the cyclodehydration SE-R SL (2-h ^yd roxyeth ^{yl) -4-phenyl-di n-2-thione p} rov ^{ADI p} rost ^{of hereditary} an inert or ^g CK ⁱ ^ s maiden ^p ou ^N Tadel ^- the heated ^{Ri ck} in ^Preparation presence of acid-axis protrude ^{f f s} orečn him. to form tetramisole. 11. The method according to claim 1, characterized in that - the cyclodehydration R, S -l- (2-hydroxy róxyethyl ^d) -4- ^{phenyl and} azole I ^{d d 2} in- ^and -TH one emb ^ I ^- V ros e ^{p class saith} concentrated sulfuric acid to form - tetramisole. 12.'Způsob point by -1, wherein the cyclodehydration R SL (2-hydroxyethyl) ^{-4-phenyl imidazol d} in- -TH ^{2 and} one carried ^{Di -} prostaeS - mixtures of the above c ^h uvedenýc ^ lodehycirataStah ^{- C} n ⁱ del ^- such as directional ^E - KYSE ^ ny pol ^ osforeč ^ if ^y aličníku phosphoric ^ him mixture ^of a concentrated ^acetic acid with ^d Eq ^é and ctoorovodítav ^{s -} and mixtures ^- Concentrate ^E k ^{If y} n ^{y s} and ^y sfrov with ^LiC n ^e to ^f os ^F ore ^{eh N} N o. Printed -Nitrianske tiskarne, Narodni podnik, Nitra. -Price .Kčs 2,40