DE2034081C3 - Process for the preparation of 23A 6-tetrahydroimidazo [2,1 -b] thiazoles - Google Patents

Description

CH ₂ -OH

R-CH

NH ₂

(H)

in the

R has the meaning given above,

with a halogen ethyl mustard oil of the general formula III It is known that several representatives of the 2,3,5,6-tetrahydroimidazo [2, l-b] thiazoles have valuable pharmaceutical properties. For example, dl-6-phenyl-23,5,6-tetrahydroimidazo [2, l-b] thiazole hydrochloride a very valuable anthelmintic with a broad spectrum of activity.

The previously known manufacturing processes for this group of compounds run via a Thiazolidine of the general formula X:

(X)

in the

A is a hydrogen atom or an acyl group,

B is an aromatic group, e.g. B. the phenyl or a

Heteroaryl group, and
E is a hydroxyl or acyloxy group or, with the omission of the methine hydrogen atom, also an oxo group,

then the cyclization to 2,3,5,6-tetrahydro-imidazo [2, l-b] thiazole of the general formula Y:

(Y)

N-

CH ₂

CH,

Shark

is subjected. During this cyclization, the C-N 'bond is formed

To prepare a thiazolidine of the type of general formula X, J. Chem. Soc (C) 1966, P. 1226 or HU-PS 1 53 178 2-Immo-thiazoline initially

in which Hai means a halogen atom,

converts the 2-imino-thiazolodine of 40 obtained in this way with phenacyl bromide according to the following scheme:

general formula IV

CH ₂ -OH HN-R-CH

(IV)

by treatment with a halogenating agent into the corresponding 2 - [(2-haloethyl) -imino] -thiazolodine, which is converted as such or in salt form by treatment with a basic agent to the 2 ₁ 3,5,6-tetrahydroimidazo [2, Ib] thiazole of the general formula I cyclized, which, if desired, can be converted into a salt or released from a salt.

2. The method according to claim 1, characterized in that the halogenating agent used is hydrogen bromide, Phosphorus tribromide, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride used

3. The method according to claim 1 or 2, characterized in that the basic cyclizing agent is used Ammonium hydroxide, alkali hydroxide, alkali carbonate or alkali carbonate are used.

CH, -Br

HN

45 C ₆ H ₅ -CO + ΖΗΝ S

C ₆ H

, —Co

-N

HN

condensed and the condensation product obtained after acylation of the imino group by reduction with

Sodium borohydride reduced to the corresponding thiazolidine. This requires the use of the very corrosive acting and the mucous membrane irritating phenacyl bromide when used on an industrial scale complicated safety precautions. In addition,

the reduction with the expensive sodium borohydride rides difficulties.

According to GB-PS 10 76 109 a connection according to Forme! X by reacting the from 1,2-epoxy-2-phenylethane and ethylene imine obtained aziridine etha-

nols obtained with thiocyanic acid. The one used here Ethylenimine not only attacks the skin and mucous membrane, but also the material of the reaction containers and is also flammable and easily explodes.

The ring closure of a compound of the general formula X to give a compound of the general formula Y with formation of the C ⁶ -N ⁷ bond is carried out by the method of J. Chem. Soc. 1966, p. 1226 and HU-PS 1 53 178 carried out in the presence of acidic agents, especially in the presence of organic acid chlorides (J. Med. Chem. 9,545, 1966)

According to the HU-PS 1 55 OM it is known that with aromatic sulfonic acids formed salts of the compounds of the formula X in which A is a hydrogen atom, B denotes a phenyl group and E denotes a hydroxyl group, by means of sulfuric acid, and according to GB-PS 11 31 800 and 10 76 109 it is known to use compounds of the formula X in which A is a hydrogen atom or an acyl group, B denotes a phenyl radical and E denotes a halogen atom or an acyloxy radical, to the corresponding compounds of the formula Y to cyclize.

A method deviating from these processes consists in forming the S'-C ^{2 and C 3} -N ⁴ bonds simultaneously or one after the other (HU-PS 1 53 178).

It has been found that the difficulties associated with the previously known processes can be circumvented in a simple manner by choosing a completely new synthetic route in which starting materials which are difficult to handle and / or have an etching effect are avoided and which is in The final stage differs from the previously known synthetic routes in that the cyclization takes place with the formation of the N ⁴ -C ⁵ bond and not - as in the previously known processes - with the formation of the ON 'bond

The invention relates to a process for the preparation of 2,3,5,6-tetrahydro-imidazo [2, l-b] thiazoles in general Formula I.

converts the 2-imino-lhiazolidine obtained in this way general tautomeric formulas IVa and IVb

(IVa)

IO

> 5

CH ₂ -HO HN

R-CH

NH

(IVb)

in the

R denotes a hydrogen atom or a phenyl radical which is replaced by one or more halogen atoms, alkyl, Alkoxy or trihalomethyl groups can be substituted, or their salts,

which is characterized in that a 2-aminoethanol of the general formula II

(Π)

CH ₂ -OH
R-CH

NH ₂

in the

R has the meaning given above

with a halogen ethyl mustard oil of the general formula

N-

CH ₂
CH ₂

S shark

in which Hai means a halogen atom

by treatment with a halogenating agent into the corresponding 2 - [(2-halo-ethyl) -imino] -thiazolidine transferred as such or in salt form, z. B. as Hydrochloric Hydrobromide or Hydroiodide Treating with a basic agent to the 2,3,5,6-tetrahydroimidazo [2, l-b] thiazole of the general Formula I converts this into a salt if desired can be transferred or released from a salt.

The reaction of a 2-aminoethanol of the general formula II with a halogenated mustard oil general formula III is useful in one

inert solvent such as ethanol performed

Suitable halogenating agents for converting the hydroxy compounds of the general formula IVa and IVb into the corresponding halogen compounds are, for. B. hydrogen bromide, phosphorus tribromide, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride. The bromination is expediently carried out with hydrogen bromide in an aqueous medium; the chlorination is expediently carried out by treatment with thionyl chloride or phosphorus oxychloride. The chlorination with thionyl chloride is preferably performed at low temperature, about 5 to 10 ° C, which is carried out with phosphorus oxychloride, however, advantageously at elevated temperature, up to 100 ⁰ C, made about 80th The cyclization to a 2,3,5,6-tetrahydro-imidazo [2, lb] thiazole of the general formula I is carried out in the presence of basic agents. such as sodium or potassium carbonate, or alkali bicarbonates, such as sodium or potassium bicarbonate. The reaction is advantageously carried out in an aqueous medium. The ring closure usually takes place at room temperature.

According to a particularly advantageous embodiment of the method of the invention, the need 2-Halogenäthylderivate, by the halogenation of the hydroxyethyl compounds of the general formulas IVa and IVb are obtained, not to be isolated before the cyclization. Rather, it can in that obtained in the manufacturing process

(III) reaction mixture directly to the basic ring closure

be subjected. This procedure has been found to be particularly useful in the application

6s 2 - [(2-halo-l-phenyl-ethyl) -imino] -thiazolidines proved.

The 23A6, -Tetrahydro-imidazo [2, Ibjhiazole of the general formula I can be

are optionally converted into their salts, expediently by reacting the base with the equivalent amount the corresponding acid. Both inorganic acids, such as hydrochloric, hydrogen bromide, Sulfuric acid, etc., as well as organic acids such as amber, tartaric, citric, lactic and malic acids etc. can be used.

Further details of the process of the invention can be found in the examples.

example 1

14.4 g of 2-bromoethyl mustard oil are added to 60 ml of anhydrous Dissolved ethanol, then a solution of 12.03 g of 2-phenyl-2-aminoethanol in 100 ml of anhydrous ethanol was added dropwise at 25 ° C. over the course of 2 hours, and the reaction mixture obtained was 1 hour at room temperature stirred and then heated to boiling for 2 hours. The reaction mixture obtained is evaporated, the The residue suspended in water with a 2N sodium hydroxide solution made alkaline, the precipitate formed is filtered off and washed with gasoline, 13 g of 2 - [(2-hydroxy-l-phenyl-ethyl) -imino] -thiazolidine are obtained, which is recrystallized from ethanol can be. M.p. 154 ° C.

Analysis:

Calculated (%): C 59.42, H 6.35, N 12.60, S 14.42;
Found (%): C 59.37, H 6.56, N 12.65, S 13.96.

6.3 g of 2 - [(2-hydroxy-l-phenyl-ethyl) -imino] -thiazolidine are converted into 23 ml of thionyl chloride with ice-cooling given and the reaction mixture obtained after dissolution at room temperature for 2 hours touched. 105 ml of acetic anhydride are added dropwise to this solution and then the acetyl chloride according to 1 Stirring for 5 hours. After removal of the acetyl chloride, the solution is boiled for 2 hours heated and then evaporated to dryness. The residue obtained in this way is in 100 ml of a 10: 1 absorbed dilute hydrochloric acid, clarified with

ίο Ammonium hydroxide made alkaline and made with toluene extracted. The oil obtained after drying and evaporation of the toluene solution is dissolved in acetone and mixed with isopropanolic hydrochloric acid, the hydrochloride salt is precipitated. 1.33 g of 6-phenyl-2,3,5,6-tetrahydroimidazo [2, l -bJthiazole hydrochloride obtained.

Melting point: 245 to 25 ° C., after recrystallization anhydrous ethanol: m.p. 261-263 ° C.

Example 2

1.5 g of 2 - [(2-hydroxy-l-phenyl-ethyl) imino] -thiazolidine are heated for 2 hours at 100 ⁰ C with 20 ml of phosphorus oxychloride, the reaction mixture poured onto ice after 2 hours, basified with ammonium hydroxide and extracted with toluene. After removing the solvent, the residue is dissolved in acetone and the hydrochloride salt is precipitated with isopropanolic hydrochloric acid. 0.2 g of the 6-phenyl-2,3,5,6-tetrahydro-imidazo [2,1-thiazole hydrochloride is obtained.

Mp. 253 to 254 ⁰ C, after recrystallization from anhydrous ethanol: Mp. 261 to 263 ° C.

Claims (1)

Patent claims: 1. Process for the preparation of 23,5,6-tetrahydroimidazo [2, l-b] thiazoles the general formula (D in the R denotes a hydrogen atom or a phenyl radical which can be substituted by one or more halogen atoms, alkyl, alkoxy or trihalomethyl groups,
or their salts, characterized in that a 2-aminoethanol of the general formula II