FI58122B - PROCEDURE FOR FRAMSTATING WITH VIDEO FRAME FOR TETRAMISOL ANVAENDBAR MELLANPRODUKT 2-IMINO-3- (2-HYDROXI-2-PHENYL-THYL) THIAZOLIDINE - Google Patents

Description

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Patent tneddelat (51) »« .w1 c ° 7 D 277/18 // C 07 D 513/0 * FINLAND —FINLAND (21) FW «lh» k «mti * —Pit« i ** n.eknln | 762751 (22) Htkemhpilvi —Amttknlnftdif 27.09.76 (23) Alkupllvi — Glhljh * t »d» j 03.07.72 (41) Tulhit Julkltaksl— Bllvlt offtntllg 2γ 09 76

National Board of Patents and Construction / 44) Date of issue and date of publication

Patent- och ragifterstyralsan Anadkan utlafd oeh utUkriftan publfcarad 29.o6.8o - (32) (33) (31) Requested «TuoMc · ** - Bagirt prtorltat 09.07.71 06.04.72 English-England (GB) 32330/71 15849 / 72 (71) Imperial Chemical Industries Limited, Imperial Chemical House,

Millbank, London SW1, England-England (GB) (72) Thomas Paterson Roy, Macclesfield, Cheshire, England-England (GB) (74) Oy Kolster Ab (54) Method for the preparation of an intermediate used in the preparation of tetramisole, 2-imino-3- For the preparation of (2-hydroxy-2-phenylethyl) thiazolidine - Preparation for the preparation of 2-imino-3- (2-hydroxy-2-phenylethyl) thiazolidine (62) Separated from application 1881/72 (Patent 55490) This invention relates to a new process for the preparation of 2-imino-3- (2-hydroxy-2-phenylethyl) thiazolidine and its acid addition salts which can be used as intermediates in the preparation of an anthelmintic, tetramisole.

Tetramisole, i.e. dl-2,3,5,6-tetrahydro-6-phenylimidazo (2,1-b) -thiazole and its pharmaceutically acceptable acid addition salts and the corresponding 1-enantiomers are well known as anthelmintic agents. A process for the preparation of tetramisole and its pharmaceutically acceptable acid addition salts is known, which comprises ring closure in the acid addition salt of 2-imino-3- (2-hydroxy-2-phenylethyl) thiazolidine (said base is hereinafter referred to as "IHPT") and its formula X is presented later). It is also known to prepare IHPT and its 58122 acid addition salt by reacting thiourea or thiocyanic acid of the formula: ^ ^ -ch-ch2-hh-ch2-ch2w'hw 1

OH

wherein W represents a halogen atom, for example a chlorine or bromine atom, or a group of the formula -O-.SO 2 R in which R represents a phenyl or tolyl group.

The present invention therefore relates to a novel multi-step process for the preparation of IHPT and tetramisole and its acid addition salt. For ease of understanding, the following reaction scheme is shown: / "Λ / 0χ

V y-CH - CH2 + H2NCH2CH2OH

II ^ III

(larger part) (smaller part) jhch2ch2oe

chohch2NHCH2CH2OH ^ ^ CHCHgOH

IV VI

NHCH CH Y

^ _ | ^

/ V CHYCHnNHCH CH Y U 'V- CHCH Y

2 2 2 \ = y

V VII

CIi2 \ **

\ NCH CH Y

V> Ch /

\ VIII

\ i

and CHOHCH? NHCH2CH2Y

j: x Ψ 3 58122 Y3 - (y— chohch2 n "1 x \ _ / I tetramisole

OF

XI

The process according to the invention is characterized in that the formulas (/ \\ - CH-CH -NH-CH -CH OH (IV) W / '

OH

and

NH-CH -CH OH

/Winter)

{'y-CH-CH OH

a mixture of the compounds of formula I or their acid addition salts with a compound of formula SO 2, SO 2 Cl 2, POY 2 or PY 4, wherein Y represents a halogen atom, and then the product is reacted with water, if desired in the presence of an acid, and then

^ ^ -chohch2nhch2ch2y IX

wherein Y is as defined above, or an acid addition salt thereof, to react with a thiourea or thiocyanic acid in a manner known per se to give the desired end product.

The advantage of the method according to the invention is e.g. the fact that the intermediates formed do not have to be separated but the reaction mixture obtained can be used directly.

58122

As can be seen from the above reaction scheme, a mixture of compounds of formulas IV and VI is obtained by reacting styrene oxide (II) with ethanolamine (lii) at a temperature of about 60 ° C for about 3 hours. The mixture of isomeric compounds formed in this reaction can be converted into a compound of formula IX in two steps. This is because the same compound (IX) is finally obtained from both isomers.

A suitable meaning for Y is, for example, a chlorine or bromine atom. A suitable acid addition salt of a compound of formula IV or VI is, for example, a hydrohalide, for example the hydrochloride or hydrobromide or a hydrosulphate, phosphate, perchlorate or p-toluenesulphonate, or a -C 1-4 alkanoate, for example -acetate. _

A suitable reactant in the first step of the process is, for example, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride or phosphorus pentachloride. The reaction may, if desired, be carried out in an organic medium, for example an unsubstituted or substituted aromatic hydrocarbon, for example toluene, xylene or chlorobenzene, or a halogenated C 1-4 alkane, for example ethylene dichloride. The reaction may be carried out at room temperature or at a moderately elevated temperature, for example at 20-60 ° C.

In a second step of the process, a mixture of compounds of formulas V and VII, or a mixture of acid addition salts of these compounds, reacts with water, preferably in the presence of an acid. Suitable acids are: a relatively strong acid such as hydrohalic acid, for example hydrochloric acid or hydrobromic acid, or sulfuric, phosphoric, perchloric or p-toluenesulphonic acid or a C 1-6 alkanoic acid, for example acetic acid. It is expected that this step will proceed primarily through the aziridine intermediate of formula VITI. However, when strongly acidic conditions are used, it is likely that the compound of formula V will be hydrolyzed both directly (i.e., V-IX) and indirectly (i.e., V-VIII-IX) and that if the acidity increases, this direct chain will progressively become more important. compared to the indirect chain.

The reaction of the base of formula VII (or its acid addition salt) should be carried out at pH 1-5 and preferably at pH 2-2.5. The pH of the reaction mixture is maintained in this range by the occasional addition of an inorganic base, for example sodium hydroxide. This second step may, if desired, be carried out in the presence of an organic solvent, such as a C 1-4 alkanol, for example ethanol, or isopropanol. The reaction may be carried out in the range of room temperature to a reasonably elevated temperature, for example at reflux temperature.

As mentioned above, the last step of the process according to the invention, namely the use of thiourea or thiocyanic acid, is known per se.

5 58122

In a preferred embodiment of this invention, Y represents a chlorine atom, the halogenating agent in the first step is thionyl chloride and the final product of formula X is obtained as p-toluenesulfonate.

The invention is further illustrated by the following example.

Example

Styrene oxide (50 g) was added to ethanolamine (1 + 60 g) stirred at 60 ° C over 2 hours and the solution was stirred at 60 ° C for a further 1 hour. Excess ethanolamine was distilled off by heating the solution to + 0 ° C under vacuum (20 mm Hg). The residue contained N - (- 2-hydroxyethyl) -N- (2-hydroxy-2-phenylethyl) amine (80% by weight) and N- (2-hydroxyethyl) -N- (2-hydroxy-1-phenylethyl) amine. nia (20% by weight). Toluene (1 + 00 ml) was then added and the solution was stirred and cooled to 1 + 0 ° C and then saturated with hydrogen chloride gas. Thionyl chloride (69 ml) was added in one portion and the solution was stirred at 1 + 5 ° C for 1 + 1 hour. The resulting solution contained N- (2-chloroethyl) -N- (2-chloro-2-phenylethyl) ammonium chloride and N- (2-chloroethyl) -N- (2-chloro-1-phenylethyl) ammonium chloride Water (380 ml) was added to the solution and the stirred mixture was heated to 0 ° C. The mixture was separated and the aqueous phase was adjusted to pH 2 by adding 18- sodium hydroxide, and heated to reflux for 2 hours, during which time the pH of the reaction mixture was maintained at 2.0-2.5 by the occasional addition (every other minute) of 18 N sodium hydroxide, the solution was then cooled to 60 ° C, the pH was adjusted to 1.0 12 thiourea (bj g) was added and the solution was heated to reflux for 10 hours, then p-toluenesulfonic acid (79 g) was added to the hot stirred solution, the resulting solution was cooled and the precipitate formed was filtered off. dried si m.p. in vacuo at 70 ° C to give 2-imino-3- (2-hydroxy-2-phenylethyl) thiazolidinium p-toluenesulfonate, m.p. 2-2l + 2i + l + ° C.

The same product was obtained when the pH was adjusted to 1 or 5 instead of 2 with 18 N sodium hydroxide.

The same product was also obtained when a mixture of water and methanol (9: 1, same volume) was used instead of water (380 ml), this mixture of water and ethanol (9: 1, same volume) was used.

Claims (7)

6 58122 A process for the preparation of 2-imino-3- (2-hydroxy-2-phenylethyl) thiazolidine and its acid addition salts as intermediates in the preparation of an anthelmintic, tetramisole, characterized in that the compounds of the formulas O CH-CH2-NH-CH2 A mixture of compounds of the formula -CH 2 OH IV OH and NH-CH 2 -CH 2 OH v y-ch-ch 2 oh vi or their acid addition salts reacts with a compound of the formula SOY 2, SO 2 Cl 2, PY 2, ^ 5, wherein Y represents a halogen atom, and then the product is reacted with water at pH 1-5, and then the product of formula ^ CHOHCH 2 NHCH 2 CH 2 Y IX, wherein Y is as defined above, or an acid addition salt thereof, is reacted with thiourea or thiocyanic acid in a manner known per se to give the desired end product. Process according to Claim 1, characterized in that Y is a chlorine or bromine atom. Process according to claim 1, characterized in that said reactant is thionyl chloride. Process according to Claim 1, 2 or 3, characterized in that the reaction with water is carried out by refluxing. Process according to one of Claims 1 to U, characterized in that the reaction with water is carried out in the presence of a C 1-4 alkanol. 1-5 Process according to any one of claims 1 to 5, characterized in that Y is a chlorine atom, said reactant is thionyl chloride and the final product is isolated as p-toluenesulfonate.