DE2718059A1 - SUBSTITUTED IMIDAZOLINE COMPOUNDS, METHOD FOR THEIR MANUFACTURING AND USE - Google Patents

Description

PFENNING-

_E! ; -n-UiMKE-εροττ

HLSSSHEI ^ FlSTn. 299 6000 MUNICH 40

26 170

American Cyanamid Company, Wayne, New Jersey , V. St. A.

Substituted imidazoline compounds , process for their preparation and their use

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The invention relates to new ones which are disubstituted in the 1- and 4-positions Imidazoün- and imidazolidin-2-ones and -thiones the formula

" * jjr

respectively.

*1

where mean:

Hydrogen, an alkyl or haloalkyl group with 1 to 6 carbon atoms, a phenyl group or a phenyl group with up to 3 substituents, alkyl radicals with 1 to 6 carbon atoms, halogen, Alkoxy radicals having 1 to 6 carbon atoms or radicals of the formula

COR ₃

in which R _{3 is} hydrogen, an alkyl or haloalkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, a phenyl group or a phenyl or phenoxy group with up to 4 substituents, the alkyl groups with 1 to 6 Carbon atoms, halogen, tri fluorine thy l groups or alkoxy groups with 1 to 6 carbon atoms,

Hydrogen or a group of the formula

COR ₄ ,

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in which R _{4 is} an alkyl or alkoxy group with 1 to 6 carbon atoms, a phenoxy group, a cycloalkyl group with 5 to 10 carbon atoms, a phenyl group or a phenyl or phenoxy group with up to 4 substituents, the alkyl or alkoxy groups with 1 to 6 carbon atoms, halogen or trifluoromethyl groups,

R _{2 is} a phenyl group or a phenyl group with up to 2 substituents, which can be alkyl groups or alkoxy groups with 1 to 6 carbon atoms, halogen or trifluoromethyl groups, and

Z oxygen or sulfur.

The invention also relates to those acylated in the 3-position Derivatives of these imidazoline derivatives and their subsequent conversion in tetramisole or substituted tetramisols.

There are several methods of manufacture described in the literature of the anthelmintic tetramisole (Raemaekers et al., J. Med. Chem. 9, 545 (1966), Bakelien et al., Aust. J. Chem. 1557 (1968), U.S. Patent 3,855,234, U.S. Patent 3,845,070). The Raemaekers process requires sodium borohydride, an expensive reducing agent, for a reduction. The process of US Pat. No. 3,855,234 has the disadvantage that it is not regioselective and presents difficulties in isolating intermediates.

A process for the preparation of tetramisole from 1- (2-hydroxyethyl) -4-phenyl-4-imidazoline-2-thione and thionyl chloride is disclosed in U.S. Patent 3,726,894. This connection is made through the hydroboration reaction applied to 1-vinyl-4-phenyl-4-imidazoline-2-thione.

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■ '*

The invention consists first of all in the production of catalytically reducible, correspondingly substituted imidazolinones (IV) or derivatives thereof as illustrated in the following reaction scheme:

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R ₀ -C-CH -X + H N-CH -CH -OR-2 2 2 2

(D

(ID

Solvent 0 ° -50 * C

ΟΙΓ

-N solvent

0 ° -100 ° C cyanic acid

H ⁺

R ₂ -C-CH ₂ -NH-CH-CH-OR

(III)

catalyst

0 ° -100 ° C

■ β

= 0
(V)

70 ° -100 ° C 0R 0H ~

H ₂ O or alcohol

₂ 1 \ XO

catalyst

ir

(ivb)

Solvent SuIf Surfactant 80 ° -200 ° C.

OR

-N

HY

Solvent I (VI) o ° -2OO ° C

7098A5 / 0911 - JX) ■

(VII)

(R, R ₁ , R ₂ , R ₃ , X and Y have the meanings given above}.

An alpha-substituted ketone of the formula I, which can also be replaced by a nucleophilic reagent, is reacted with an amine of the formula II or its acid addition salt to give the compound of the formula III. The reaction can be carried out using an excess of the compound of the formula II or in the presence of a tertiary amine, such as triethylamine, or in the presence of a substance which yields a hydroxide, such as sodium carbonate, at a temperature of about 0 to 50 ^° C. in a solvent, for example an alcohol or halocarbon, in about 30 minutes to about 3 hours.

Compound III is dissolved in an arbitrary organic solvent such as methanol, chloroform or methylene chloride and is formed in the presence of cyanic acid and a hydronium ion supplying material from about 0 ° to 100 ⁰ C imidazolinone of formula IV.

delivering substance heated from about 0 ° to 100 ⁰ C, whereby the

There are two different routes available for the preparation of the imidazolidone of the formula V. The first of these two Ways is the imidazolinone of formula IV with a hydrogen

2
pressure of about 1 to 70 kg / cm in a solvent, for example alcohol, hydrocarbon, alcohol-hydrocarbon mixture or acetic acid, in the presence of a catalyst, for example palladium-on-carbon, at a temperature of about 0 to 100 ° C Hydrogenated for minutes or longer or reduced with a suitable reducing agent, whereby the imidazolidone of formula V is obtained. The compound IV can, however, also with an acid halide or anhydride of the formula

R ₄ COY or (R ₄ CO) ₂ O,

wherein y can be any nucleophilic reagent displaceable group, for example halogen, in the presence of a Substance yielding hydroxyl ions on refluxing in the presence or absence of a hydrocarbon solvent converted to the imidazolinone of the formula IVa

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will. The latter is hydrogenated under the same conditions as in the case of IV to V to give the imidazolidone of the formula IVb. During the hydrogenation of IV or IVa, _{halogen atoms contained in the radicals R, R 1} or R_ are removed and replaced by hydrogen, unless mild hydrogenation or other reduction conditions are used. The imidazolidone of the formula IVb is hydrolyzed in the presence of a substance which provides hydroxyl ions in water or alcohol at a temperature of about 70 to 100 ^° C., as a result of which the imidazolidone of the formula V is obtained. If R in the formula IVb R is COR ₃ , it should generally be stated that the group COR _{3 is} also hydrolyzed at this stage, whereby a compound is obtained in whose formula VR is hydrogen.

The imidazolidone of the formula V is heated in an inert solvent such as toluene, xylene or cyclohexane to a temperature of about 80 to 200 ^° C. in the presence of a reagent which, like phosphorus pentasulfide, is able to replace the oxygen with sulfur, whereby the imidazolidinethione of the formula VI and smaller amounts of the compound of formula VII (as free base) are formed. In the case of the compounds in whose formula V R is hydrogen, the reaction with phosphorus pentasulfide also affects the free hydroxyl group, which is converted into a sulfur-containing group which can be phosphorus-free or contain phosphorus. This altered group is nonetheless capable of cyclization in the final stage to form compounds of Formula VII. In the case of the compounds in whose formula VR stands for the COR ₃ group, it is often found that the COR ₃ group reacts with the sulfur-introducing reagent, for example phosphorus pentasulphide, to form the CSR _{3 group.} However, this does not impair the ability of the compounds of the formula VI which have undergone this change to form the compounds of the formula VII.

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The imidazolidinthione of the formula VI is with HY, wherein Y is a pharmaceutically acceptable anion such as chloride, fluoride, iodide, bisulfate, p-toluenesulfonate, warmed in a solvent to a temperature of about 0 to 200 ° C. , whereby the compound of the formula VII is formed. The compound of the formula III, in which R stands for an acyl group , can also be prepared as follows:

R ₂ COCH X (D

(ID

25 ° -65 ^e C

Solvents (e.g. chloroform)

(Ha)

ο ο

R ₂ C-CH ₂ NHCH CH ₂ OCR ₃

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(III)

The new intermediates according to the invention have the general principles formula

R ₀ -C-CH ₀ -NH-CH ₂ -CH ₂ -OR, O

wherein R and R ~ have the meanings given above.

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The invention is further illustrated by the following examples.

Example 1 1- (2-methoxyethyl) -4-phenyl-4-imidazolin-2-one

60 g of phenacyl bromide in 200 ml of methylene chloride are added to 52 g of 2-methoxyethylamine in 100 ml of methylene chloride in one hour and the mixture is cooled with an ice bath. The mixture is ^{stirred at 0 °} C. for 2 hours. 400 ml of water are added and the organic layer is separated off, dried over anhydrous sodium sulfate and concentrated in vacuo at room temperature. This gives 260 g of a viscous oil which was dissolved in 2OO ml of methanol, cooled to 0 ⁰ C and is treated with 80 ml acetic acid and 30 g of potassium cyanate. The mixture is refluxed for 90 minutes and the residue obtained after removal of the solvent under reduced pressure is taken up in 600 ml of chloroform and washed with saturated sodium bicarbonate solution. After washing, drying over sodium sulfate and concentrating the chloroform layer, a semi-solid substance is obtained which is triturated with ether and filtered off. As a result, the compound mentioned in the heading is obtained in the form of yellow crystals with a temperature of from ^{152 to 153 ° C.}

Example 1- (2-methoxyethyl) ^ -

199 g of phenacyl bromide in 400 ml of chloroform are added to a mixture of 82 g of 2-methoxyethylamine and 152 g of triethylamine in 200 ml of chloroform at 0 ° C. in half an hour. The mixture is stirred at 0 to 10 ° C. for 2 hours. 400 ml of water are added and the organic layer is separated off and washed once more with 400 ml of water. ^{The chloroform layer is cooled to 0 °} C. with an ice bath and treated with 72 g of glacial acetic acid,

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89 g of potassium cyanate and 100 ml of methanol are added. The mixture is refluxed for 90 minutes, cooled and washed with saturated sodium bicarbonate solution. After drying the organic layer over anhydrous sodium sulfate, it is concentrated until a semisolid substance remains. By triturating with 300 ml of ether and filtering, the compound named in the title is obtained in the form of yellow crystals with a F. = 152 to 154 ^° C.

Example 3 1- (2-methoxyethyl) -4-phenyl-2-imidazolidone

10.9 g of 1- (2-methoxyethyl) -4-phenyl-4-imidazolin-2-one and 1 g of palladium carbon with 10% Pd in 100 ml of ethanol are in a Parr shaker 45 minutes at hydrogen pressure

2
hydrogenated by 2.1 kg / cm. The catalyst is filtered off and washed with ethanol, and the filtrate is concentrated, whereby the compound named in the title is obtained as a waxy white solid with a melting point of 82 to 83 ° C.

The reduction described above can also be carried out with acetic acid as the solvent and also with both solvents at atmospheric pressure be performed.

Example 4 1- (2-Methoxyethyl) -4-phenylimidazolidine-2-thione

1 g of 1- (2-methoxyethyl) -4-phenyl-2-imidazolidone and 0.4 g of phosphorus pentasulfide are refluxed in toluene overnight (16 hours). The toluene is reduced under Pressure is distilled off and the remaining semi-solid substance is in a solution of 50 ml of chloroform and 30 ml of 20 percent Sodium hydroxide solution dissolved. The organic layer is separated, washed and dried and yielded after removal of the solvent 1 g of an oil. In the solution of this oil in 3 ml of acetone

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anhydrous hydrogen chloride is passed in for 2 minutes. The precipitated tetramisole hydrochloride is filtered off and the filtrate is evaporated to dryness. Recrystallization from benzene / cyclohexane gives the compound mentioned in the title as a white solid with a melting point of 76 to 78 ^° C.

Example 5

Production of tetramisole hydrochloride from 1- (2-methoxyethyl) -4-phenylimidazolidine-2-thione

236 mg 1- (2-methoxyethyl) ^ -phenylimidazolidine - ^ - thione, 5 ml concentrated hydrochloric acid and 5 ml of acetone are refluxed for one hour. The solution is reduced under The pressure is evaporated to dryness and the residue is triturated with 2 ml of ethanol. Obtained by filtering off the white solid one the connection named in the heading.

example

Production of tetramisole hydrochloride from 1- (2-methoxyethyl) '4-phenyl-2-imidazolidone

4.4 g of 1- (2-methoxyethyl) -4-phenyl-2-imidazolidone and 2 g of phosphorus pentasulfide are refluxed for 20 hours in 200 ml of toluene. After the toluene has been distilled off under reduced pressure, the residue is taken up in 100 ml of chloroform and washed with 50 ml of a 20 percent strength sodium hydroxide solution. The organic layer is washed with water, dried and the solvent evaporated to give a yellow oil. This oil is refluxed for one hour in a solution of 10 ml of concentrated hydrochloric acid in 10 ml of ethanol. After evaporation of the solution to dryness, the remaining semi-solid substance is triturated with 20 ml of ethanol, filtered off and dried, whereby the compound mentioned in the title of F. = 26Ο to 262 ⁰ C is obtained.

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Example 7 1- (2-Hydroxyethyl) -4-phenyl-4-imidazolin-2-one

60 g of phenacyl bromide in 100 ml of methylene chloride are added to 41 g of monoethanolamine in 100 ml of methylene chloride in 30 minutes. ^{The solution is cooled to 0 °} C. with an ice bath, stirred for a further 90 minutes at 0 ° to 5 ° C. and then treated with 400 ml of water. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure at about room temperature. The oil that remains is dissolved in 150 ml of methanol, cooled and a solution of 24 g of sodium cyanate in 30 ml of acetic acid is added. The mixture is refluxed for one hour and cooled. The white solid precipitate is filtered off, washed with water and methanol and dried, as a result of which the compound mentioned in the title with a melting point of 203 to 205 ^° C. is obtained.

Example 8 1- (2-Hydroethyl) ^ -phenyl ^ -imidazolidone

A slurry of 10.2 g of 1- (2-hydroxyethyl) -4-phenyl-4-imidazolin-2-one g) and 1 g of palladium carbon with 10% Pd in 2OO ml of ethanol is placed in a Parr shaker at et-

wa 2.1 kg / cm hydrogen hydrogenated for three hours. The catalyst is filtered off and washed with ethanol, and the combined filtrates are concentrated to a colorless oil, which solidifies ^{on standing to give the compound mentioned in the title, having a melting point of 60 to 63 ° C.}

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Production of tetramisole hydrochloride from 1- (2-hydroxyethyl) -4 -phenyl-2-imidazolidone

A mixture of 4.1 g of 1- (2-hydroxyethyl) ^ -phenyl - ^ - imidazolidone and 1.8 g of phosphorus pentasulfide in 25 ml of toluene is refluxed for 20 hours. After the toluene has been distilled off under reduced pressure, the residue is dissolved in a solution of 50 ml of chloroform and 50 ml of 20 percent strength sodium hydroxide solution. The organic layer is separated, washed, dried over sodium sulfate and concentrated to an oil. The oil is refluxed for one hour in a solution of 10 ml of ethanol and 20 ml of concentrated hydrochloric acid. After the solution has been evaporated to dryness, the residue is triturated with 20 ml of ethanol and filtered off. The compound mentioned in the title is thus obtained as a white solid with a F. = 260 ^° C.

Example 10 1- (2-Acetoxyethyl) -4-phenyl-2-imidazolidone

9.2 g of 1- (2-hydroxyethyl) -4-phenyl-2-imidazolidone are mixed with 25 ml of acetic anhydride and 2OO mg of p-toluenesulfonic acid for 4 hours touched. During this time, the imidazolidone goes completely into solution. This solution obtained is in 1OO ml a saturated sodium bicarbonate solution poured, causing a white solid precipitates, which is extracted three times with 100 ml of methylene chloride each time. The organic layer is separated, dried and the solvent removed to give a pale yellow solid. After recrystallization the compound named in the title is obtained from ether in the form of white crystals of F. = 88

up to 90 ⁰ C.

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Example 11

Production of tetramisole hydrochloride from 1- (2-acetoxyethyl) -4 -phenyl-2-imidazolidone

5 g of 1- (2-acetoxyethyl) -4-phenyl-2-imidazolidone and 1.8 g of phosphorus pentasulfide in 20 ml of toluene are refluxed for 20 hours. After the solvent has been distilled off under reduced pressure, the residue is dissolved in a solution of 100 ml of chloroform and 100 ml of 20 percent sodium hydroxide solution. The organic layer is separated, washed, dried over sodium sulfate, treated with charcoal, filtered and concentrated to an oil. The oil is refluxed for one hour in a solution of 20 ml of concentrated hydrochloric acid and 10 ml of ethanol. After the solution has been evaporated to dryness, the residue is triturated with 20 ml of ethanol and filtered off, whereby the compound named in the title is obtained with a brownish color, mp = 258 to 260 ^° C.

Example 12 1- (2-Acetoxyethyl) -4-phenyl-4-imidazolin-2-one

9 g of 2-methyloxazoline and 20 g of phenacyl bromide in 100 ml of chloroform are refluxed for one hour. After concentrating the solution under reduced pressure, 10 ml of acetic acid, 9 g of potassium cyanate and 100 ml of methanol to the remaining added oil, and the mixture is refluxed for one hour. After removing the methanol under reduced The residue is taken up under pressure in 200 ml of methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer is dried and concentrated to a semi-solid consisting of benzene / cyclohexane is recrystallized, as a result of which the compound of F. = 120 to 122 C mentioned in the title is obtained.

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ac

Example 13 Reduction of 1- (2-acetoxyethyl) - ^ phenyl-'i-iinidazolin - ^ - one

1 g of 1- (2-acetoxyethyl) -4-phenyl-4-imidazolin-2-one and 250 mg of palladium carbon with 10% Pd in 10 ml of ethanol are stirred in a hydrogen atmosphere. After about 3/4 hours the catalyst is filtered off and washed with 20 ml of ethanol. The combined filtrates are evaporated and yield the reduced compound as a white solid substance with a F. = 86 to 88 ^° C.

Example 14 1- (2-Methoxyethyl) -3-acetyl-4-phenyl-4-imida2olin-2-one

21.8 g of 1- (2-methoxyethyl) -4-phenyl-4-imidazolin-2-one and 120 ml of acetic anhydride are refluxed for four hours. After the acetic anhydride has been distilled off under reduced pressure, the semi-solid substance that remains is recrystallized from ether. As a result, the compound mentioned in the title is obtained as a white solid with a melting point of 73 to 75 ^° C.

Example 15 Racemic 1- (2-methoxyethyl) -3-acetyl-4-phenyl-2-imidazolidone

3.9 g of 1- (2-methoxyethyl) -3-acetyl-4-phenyl-4-imidazolin-2-one and 400 mg of 10 percent palladium carbon in 300 ml of ethanol are placed in a Parr shaker with a hydrogen

pressure of 2.1 kg / cm hydrogenated. After an hour the catalyst will filtered off and washed with 50 ml of ethanol. That with

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the combined filtrate of the washing liquid is concentrated, whereby the compound named in the title is obtained as a colorless oil.

Example 16

Hydrolysis of 1- (2-methoxyethyl) -B-acetyl- ^ phenyl- ^ - imidazolidone to 1- (2-methoxyethyl) -4-phenyl-2-imidazolidone

2.6 g of the 3-acetyl derivative are refluxed for one hour in 20 ml of 10 percent sodium hydroxide solution. After cooling, the solution is extracted twice with 20 ml of chloroform each time. The combined chloroform extracts are washed and concentrated dried over sodium sulfate, thereby obtaining the the title compound as a solid, mp = 81 to 83 ⁰ C.

Example 17 1- (2-Methoxyethyl) -3-benzoyl-4-phenyl-4-imidazolin-2-one

4.36 g of 1- (2-methoxyethyl) -4-phenyl-4-imidazolin-2-one, 3 g of triethylamine and 3 g of benzoyl chloride are refluxed in chloroform for 3 hours. The solution is cooled, washed with water, dried and freed from the solvent, whereby the O-benzoyl ester is obtained as an oil. This ester is refluxed for 3 hours in 20 ml of xylene. After removing the xylene under reduced pressure and recrystallizing the residue from ether, the compound named in the title is obtained as a pale yellow solid substance with a melting point of 112 to 117 ^° C.

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JLf

1- (2-Methoxyethyl) -S-benzoyl-'l-phenyl - ^ - imidazolin ^ -one

21.8 g of 1- (2-methoxyethyl) ^ -phenyl ^ -imidazolin ^ -one, 14.5 g of benzoyl chloride and 20 g of tri-n-butylamine are refluxed in 60 ml of xylene for 16 hours. The solvent is distilled off under reduced pressure and the remaining viscous oil is dissolved in 300 ml of benzene. The Bezol solution is washed twice with 100 ml of water each time, dried over sodium sulfate and freed from the solvent, whereby a semi-solid substance is obtained. The compound named in the title is obtained as a pale yellow solid with a melting point of 114 to 117 ^° C. by recrystallization from ether.

Example 19

Production of other 1- (2-methoxyethyl) -3-acyl-4-phenyl-4-imida zolin-2-ones

The following acyl derivatives are prepared according to the procedure described in Example 18 for the N-benzoyl derivative:

a) 1 - (2-Methoxyethyl) -S-cyclohexanecarbonyl ^ -phenyl ^ -imidazolin-2-one,

b) 1- (2-methoxyethyl) -3-p-trifluoromethylbenzoyl-4-phenyl-4-imidazolin-2-one,

c) 1- (2-methoxyethyl) -3- (1-adamantancarbony1) -4-phenyl-4-imidazolin-2-one,

d) 1- (2-methoxyethyl) -S-o-anisoyl ^ -phenyl ^ -imidazolin ^ -one,

e) 1- (2-methoxyethyl) -3- (2-chlorobenzoyl) ^ -phenyl - ^ - iinidazolin-2-one,

f) 1- (2-methoxyethyl) -3- (2,4-dichlorobenzoyl) ^ -phenyl ^ -imidazolin-2-one and

g) 1- (2-Methoxyethyl) -3- (2-methylbenzoyl) -4-phenyl-4-imidazoline-

² " ^{in #} ^ 09845/0911

* 9

Example 20 _ _Λ

Hydrogenation of 3-acyl derivatives of 1- (2-methoxyethyl) -4-phenyl- 4-imidazolin-2-one

The 3-acyl-1- (2-methoxyethyl) -4-phenyl-4-imidazolin-2-one and
10 percent palladium carbon as a catalyst is taken up in ethanol and placed in a Parr shaker at a
Hydrogen pressures of 2.1-3.5 kg / cm (30-50 psig) hydrogenated in about 30 minutes to 6 hours. After filtering off the catalyst, the filtrate is concentrated, whereby a 1- (2-methoxyethyl) -3-acyl-2-imidazolidone is obtained. In this way
the following connections are established:

a) 1- (2-methoxyethyl) -3-benzoyl-4-phenyl-2-imidazolidone,

b) 1- (2-methoxyethyl) -S-cyclohexanecarbonyl ^ -phenyl ^ -imidazolidone,

c) 1- (2-methoxyethyl) -3-p-trifluoromethylbenzoyl-4-phenyl-2-imidazolidone,

d) 1- (2-methoxyethyl) -S-o-anisoyl ^ -phenyl ^ -imidazolidone,

e) 1- (2-methoxyethyl) -3- (1-adamantanecarbonyl) -4-phenyl-2-imidazolidone,

f) 1- (2-methoxyethyl) -3- (2-chlorobenzoyl) -4-phenyl-2-imidazolidone,

g) 1 - (2-Methoxyethyl) -3- (2,4-dichlorobenzoy 1) ^ -phenyl ^ -imidazolidone and

h) 1- (2-methoxyethyl) -3- (2-methylbenzoy1) -4-phenyl-2-imidazolidone.

Example 21
1- (2-butoxyethyl) -4-phenyl-4-imidazolin-2-one

10 g of phenacyl bromide in 50 ml of chloroform are within
20 minutes to a mixture of 6 g of 2-butoxyethylamine and
7 g of triethylamine in 50 ml of chloroform at 0 ° C. the
The mixture is stirred for 2 hours. After adding 100 ml of water

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vr

the organic layer is separated, cooled to OC and 5 ml of glacial acetic acid, 5 g of potassium cyanate and 2O ml of methanol are added. The mixture is refluxed for 90 minutes heated, cooled, washed with saturated sodium bicarbonate solution, dried and freed from the solvent, whereby the substance named in the heading is obtained.

Example 22 1- (2-Butoxyethyl) -4-phenyl-2-imidazolidone

A solution of 1- (2-butoxyethyl) -4-phenyl-4-imidazolin-2-one in ethanol is reduced in the presence of 10 percent palladium carbon as a catalyst in a hydrogen atmosphere. To The catalyst is absorbed by the theoretical amount of hydrogen filtered off and the filtrate concentrated to the compound named in the title.

Example 23 1- (2-Methoxyethyl) -4- (2-chlorophenyl) -4-imidazolin-2-one

To 23.4 g of o-chlorophenacyl bromide in 100 ml of chloroform, 20 g of methoxyethylamine in 100 ml of chloroform are added within 30 minutes, cooling with an ice bath. The mixture is stirred at 0 ° C. for a further hour. After adding 200 ml of water, the organic layer is separated off, ^{cooled to 0 °} C. with an ice bath and then treated with 8 ml of glacial acetic acid, 10 g of potassium cyanate and methanol. The mixture is refluxed for 90 minutes, cooled, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent removed to give the title compound.

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1- (2-methoxyethyl) -4- (substituted-phenyl) -4-imidazolin-2-one

The following 1- (2-methoxyethyl) -4- (substituted-phenyl) -4-imidazolin-2-ones are prepared according to the procedure described in Example 23:

a) 1- (2-Methoxyethyl) -4- (2,4-dichlorophenyl) -4-imidazolin-2-one and

b) 1- (2-methoxyethyl) -4- (p-trifluoromethylphenyl) -4-imidazolin-2-one.

Example 25

Production of 1- (2-methoxyethyl) -4- (substituted-phenyl) -2- imidazolidone

A solution of 1- (2-methoxyethyl) -4- (substituted-phenyl) -4-imidazolin-2-one in ethanol is at a hydrogen pressure of

1 to 70 kg / cm in the presence of 10 percent palladium carbon reduced as a catalyst. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off, and the filtrate is concentrated to give the above imidazolidones. In this way the following connections listed:

a) 1- (2-methoxyethyl) -4- (m-trifluoromethylphenyl) -2-imidazolidone,

b) 1- (2-methoxyethyl) -4- (m-methylphenyl) -2-imidazolidone,

c) 1- (2-methoxyethyl) -4- (p-trifluoromethylphenyl) -2-imidazolidone and

d) 1- (2-methoxyethyl) -4- (m-methoxyphenyl) -2-imidazolidone.

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Example 26 1- (2-Benzoyloxyethyl) - ^ phenyl- ^ l-imidazolin - ^ - one

15 g of 2-phenyloxazoline and 20 g of phenacyl bromide are in 1OO ml Chloroform heated to reflux for one hour. The solvent is distilled off under reduced pressure and after 10 ml of acetic acid, 9 g of potassium cyanate and 100 ml of methanol have been added, the mixture is refluxed for one hour warmed up. The methanol is removed under reduced pressure and the residue is taken up in 200 ml of methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer is dried and concentrated, eliminating the one in the heading called connection is obtained.

Example 27

Production of other 1- (2-acyloxyethyl) -4-phenyl-4-imidazoline-

2-one

The following 1- (2-acyloxyethyl) -4-phenyl-4-imidazolin-2-ones are used according to the example 26 for the preparation of the benzoyloxy derivatives described method of operation:

a) 1- / 2- (propionyloxy) -äthy_l / -4-phenyl-4-imidazolin-2-one,

b) 1- / 2- (p-methylbenzoyloxy) ethyl _: / -4-phenyl-4-imidazolin-2-one and

c) 1- / 2- (p-Trifluoromethylbenzoyloxy) -ethyl / ^ - phenyl ^ -imidazolin-2-one.

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-yf-

Example 28 Preparation of 1- (2-acyloxyethyl) - ^ - phenyl - ^ - imidazolidones

The following 1- (2-acyloxyethyl) -4-phenyl-2-imidazolidones are produced by catalytic reduction of 1- (2-acyloxyethyl) ^ -phenyl- ^ - imidazolin-2-ones according to that in Example 13 in connection with the 1- (2-acetoxyethyl) derivatives described method of operation:

a) 1 - / ^ - BenzoyloxyäthyJL / ^ - phenyl ^ -imidazolidone,

b) 1- ^ 2-propionyloxy) ethy_l / -4-phenyl-2-imidazolidone,

c) 1- / 2- (p-methylbenzoyloxy) -ethyl / -4-phenyl-2-imidazolidone and

d) 1 - / 2- (p-trifluoromethylbenzoyloxy) ethy] L / -4-phenyl-2-imidazolidone.

Example 29

The following amino ketones of the formula A are made by reacting the corresponding ethanolamines with the corresponding phenacyl bromides produced according to the procedure described in Example 2:

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^R 2

R ₂ CCH ₂ NHCh ₂ CH ₂ OR (A)

C ₆ H ₅ C ₂ H ₅

C ₆ H ₅ C ₃ H ₇ -Xs

C ₆ H ₅ CH ₂ CH ₂ Cl

C ₆ H ₅ C ₆ H ₅ ^C 6 ^H s
C ₆ H ₅

CgH ₅ CgH ₄ - (E-OCH ₃ )

CgH ₅ CgH ₄ - (In-OCH ₃ )

CgH ₅ C (O) C ₂ H ₅

CgH ₅ C (O) C ₄ H ₉

CgH ₅ C (O) OCH ₃

C ₆ H ₅ C (O) OC ₆ H ₅

.H-OCH ₃ -CgH ₄ CH ₃

In-CL-C ₆ H ₄ H

709845/0911

R ₂ 2718059 H m-Br-C ₆ H ₄ C (O) CH ₃ m-Cl-C ^ H,
- 6 4 C (O) OCgH ₄ (E-CH ₃ ) C ₆ H ₅ C (O) OCgH ₄ (O-CH ₃ ) C ₆ H ₅ C (O) OC ₆ H ₄ (P-OCH ₃ ) ^C 6 ^H 5 C (O) C ₆ H ₅ C ₆ H ₅ C (O) C ₃ H ₅ C ₆ H ₅ C (O) C ₄ H ₉ ^C 6 ^H 5 C (O) OCH ^C 6 ^H 5. C (O) OC ₆ H ₅ ^C 6 ^H 5 CH ₃ In-OCH ₃ -C ₆ H ₄ H In-CL-C ₆ H ₄ H In-Br-C ₆ H ₄ C (O) CH ₃ In-Cl-C ₆ H ₄ C (O) OC ₆ H ₄ (E-CH ₃ ) ^C 6 ^H 5 C (O) OC ₆ H ₄ (O-CH ₃ ) C ₆ H ₅ C (O) OC ₆ H ₄ (P-OCH ₃ ) C ₆ H ₅ C (O) C ₆ H ₅ ^C 6 ^H 5 C (O) C ₆ H ₄ (E-CH ₃ ) C ₆ H ₅ C (O) C ₆ H ₄ (E-OCH ₃ ) » ^C 6 ^H 5 C (O) C ₆ H ₄ (In-CF ₃ ) C ₆ H ₅ C (O) C-H
0 5 51-Br-C ₆ H ₄ CH ₃ In-CF ₃ -C ₆ H ₄ CH ₃ 51-CH ₃ -C ₆ H ₄ C ₆ H ₅ In-Cl-C ₆ H ₄ C (O) OCH ₃ Tn ₇ -CF ₃ -CgH ₄ CH ₃ ^P - ^C1 - ^C 6 ^H 4 709845/0911 C ₃₁ H ₅ m-Br-c ₆ H ₄

The substituted ethanolamines and their acid addition salts
and the phenacyl bromides used as starting materials
are produced according to methods known from the literature.

Example 30

The following imidazolinones of the formula B are prepared from aminoketones prepared as described in Example 28 by reaction with potassium cyanate according to the procedure described in Examples 1 and 2 :

9099 * 5 / 0911-

, OR

^^
II
(B) R. Λ C ₂ H ₅ ^C 6 ^H 5 C ₃ H ₇ -ISO ^C 6 ^H 5 CH ₂ CH ₂ Cl ^C 6 ^dd 5 ^C 6 ^H 5 ^C 6 ^H 5 C ₆ H ₄ (E-CH ₃ ) ^C 6 ^H 5 CgH ₄ (E-Cl) ^C 6 ^H 5 C ₆ H ₄ (E-OCH ₃ ) ^C 6 ^H 5 CgH ₄ (In-OCH ₃ ) ^C 6 ^H 5 C (O) C ₂ H ₅ C ₆ H ₅ C (O) C ₄ H ₉ ^C 6 ^H 5 C (O) OCH ₃ ^C 6 ^H 5 C (O) OC ₆ H ₅ ^C 6 ^H 5 C (O) OC ₆ H ₄ (E-CH ₃ ) ^C 6 ^H 5 C (O) OCgH ₄ (O-CH ₃ ) ^C 6 ^H 5 C (O) OC ₆ H ₄ (E-OCH ₃ ) C ₆ H ₅ C (O) C ₆ H ₅ C ₆ H ₅ C (O) C ₆ H ₅ (E-CH ₃ ) ^C 6 ^H 5

709845/0911

^R 2

^C 6 ^H 5

^C 6 ^H 5 51-Br-C ₆ H ₄ 5.-CF ₃ -C ₆ H ₄ 5.-CH ₃ -C ₆ H ₄ 5.-OCH ₃ -CgH ₄ 5.-Cl-CgH ₄

5.-Cl-C ₆ H ₄ 5.-Cl-C ₆ H ₄ 5.-CF ₃ -C ₆ H ₄ E-Cl-C ₆ H ₄ 51-Br-C ₆ H ₄

C (O) C-H
D. ₄ (E-OCH ₃ ) 3 C (O) C ₆ H ₄ (m-CF ₃ ) 3 C (O) C ₆ H ₅ 3 CH CH CH (O) CH ₃ H C ₆ H ₅ H (O) OCH ₃ C. CH ₃ C ₂ II ₅ C.

709845/0911

example

The following imidazolinones substituted in the 3-position Formula C are as described in Example 18 using the corresponding acyl halides or anhydrides and the corresponding 3-H-imidazolinones produced:

^C 2 ^H 5

54 CH.

709845/0911

"*O

- i CgH ₅ C ₃ H ₇ -I «2718059 ^c e ^H s CH ₂ CH ₂ Cl C ₆ H ₅ ^c e ^H 5 C ₆ H ₅ CH ₃ O C ₆ H ₅ C ₆ H ₄ (P-CH ₃ ) C ₆ H ₅ O ^c e ^H ₅ C ₆ H ₄ (E-Cl) CH ₃ C ₆ H ₅ CgH ₄ (P-OCH ₃ ) C ₆ H ₅ C ₆ H ₄ (In-OCH ₃ ) > c ₆ ^H s C (O) C ₂ H ₅ ^c e ^H s C ₆ H ₅ C (O) C ₄ H ₉ C ₂ H ₅ C ₆ H ₅ C (O) OCH ₃ CH ₃ C ₆ H ₅ C (O) OC ₆ H ₅ C ₆ H ₄ (E-CH ₃ ) C ₆ H ₅ C (O) OC ₆ H ₄ (E-CH ₃ ) CH ₃ ^C ₆ ^H 5 C (O) OC ₆ H ₄ (O-OCH ₃ ) C ₂ H ₅ C ₆ H ₅ C (O) OC ₆ H ₄ (E-OCH ₃ ) C ₆ H ₃ (2 _f 4-di-CH ₃ ) C ₆ H ₅ C (O) C ₆ H ₅ CH ₃ C ₆ H ₅ . C (O) C ₆ H ₄ (E-CH ₃ ) C ₃ H ₇ C ₆ H ₅ C (O) C ₆ H ₄ (E-OCH ₃ ) C ₂ H ₅ O ^c e ^H 5 C (O) C ₆ H ₄ (In-CF ₃ ) O In-Br-C ₆ H ₄ C (O) C ₆ H ₅ C ₆ H ₄ (E-CF ₃ ) 5-CF ₃ -C ₆ H ₄ CH ₃ C ₆ H ₄ O (E-CH ₃ ) 51-CH ₃ -C ₆ H ₄ CH ₃ C ₄ H ₉ O 2-CH ₃ OC ₆ H ₄ ^CH 3 C ₆ H ₄ (E-OCH ₃ ) «• I
O
in In-Cl = C ₆ H ₄ H CH ₃ CD
* » m-Br-CfiH. H iso-c ₃ H ₇ 51-Cl-C ₆ H ₄ C (O) CH ₃ ^C e ^H 5 O
CD In-Cl-C ₆ H ₄ C ₆ ^H 5 C ₆ H ₄ (In-Cl) - In-CF ₃ -C ₆ H ₄ C (O) (KJH ₃ C ₆ H ₄ (E-CH ₃ O) E-Cl-C ₆ H ₄ CH ₃ C ₆ H ₄ (E-CH ₃₎ O In-Br-CgH ₄ C ₂ H CH ₃ C ₄ H ₉ OC (O) C ₆ H ₅

HA

example

32

The following imidazolidones substituted in the 3-position Formula D are obtained by catalytic hydrogenation of the corresponding imidazolinones substituted in the 3-position according to the example in 13 produced procedure described.

.OR

O (O CD

B.2

^C 6 ^H 5 C ₂ H ₅ CH ₃ ^C 6 ^H 5 C ₃ H ₇ -IsO C ₆ H ₅ C ₆ H ₅ C ₂ H ₅ ^{C! I} 3 ° ^C 6 ^H 5 ^C 6 ^H 5 C ₆ H ₅ O C ₆ H C ₆ H ₄ (E-CH ₃ ) CH ₃ C ₆ H ₅ C ₆ H ₅ D. C ₆ H ₅ C ₆ H ₄ (E-OCH ₃ ) C ₆ H ₅ C ₆ H ₅ C ₆ H ₄ (m-OCH ₃ ) C ₂ H ₅ C ₆ H ₅ C (O) C ₂ H ₅ CH ₃ ^C 6 ^H 5 C (O) C ₄ H ₉ C ₆ H ₄ (E-CH ₃ ) C ₆ H ₅ C (O) OCH ₃ CH ₃ C ₆ H ₅ C (O) C ₆ H ₅ C ₂ H ₅ ^C 6 ^H S C (O) OC ₆ H ₄ (E-CH ₃ ) C ₆ H ₃ (2,4-di-CH C ₆ H ₅ C (O) OC ₆ H ₄ (O-CH ₃ ) CH ₃ C ₆ H ₅ C (O) OC ₆ H ₄ (E-OCH ₃ ) C ₃ H ₇ C ₆ H ₅ C (O) C ₆ H ₅ C ₂ H ₅ O C ₆ H ₅ C (O) C ₆ H ₄ (E-CH ₃ ) O C ₆ H ₅ C (O) C ₆ H ₄ (E-OCH ₃ ) C ₆ H ₄ (E-CF ₃ ) C ₆ H ₅ C (O) C ₆ H ₄ (In-CP ₃ ) C ₆ H ₄ O (E-CH ₃ )

In-CF ₃ C ₆ H ₄ CH ₃ C ₆ H ₄ (P _- -OCH ₃ ) m-CH ₃ C ₆ H4 CH ₃ CH ₃ In-CH ₃ O-CgH ₄ CH ₃ iC ₃ H ₇ In-CF ₃ -C ₆ H ₄ C (O) OCH ₃ CH.

By hydrogenating the corresponding compounds of formula C in the presence of a homogeneous hydrogenation catalyst, such as tris (triphenylphosphino) chloro-rhodium, are the following compounds of the formula D:

m-Br-C ₆ H ₄ In-Cl-C ₆ H ₄ m-Br-C ₆ H ₄ m-Cl-C ₆ H ₄ m-Cl-C ₆ H ₄ E-Cl-C ₆ H ₄ m- Br-C ₆ H ₄

C (O) C ₆ H ₅ HHC (O) CH ₃

^C 6 ^H 5 CH ₃

C ₂ H ₄

«4
C ₄ H ₉ O

C ₆ H ₄ (m-Cl) C ₆ H ₄ (£ -CH ₃ O) C ₆ H ₄ (Pj-CH ₃ ) O C ₄ H ₉ OC (O)

^C 6 ^H 5

example

The following imidazolidones of the formula E are obtained by hydrogenating the corresponding imidazolinones which are unsubstituted in the 3-position produced according to the procedure described in Example 3:

709845/0911

H «2 R. (E) C ₆ H ₅ C ₂ H ₅ C ₆ ^H 5 C ₃ H ₇ iso C ₆ H ₅ C ₆ H ₅ C ₆ H ₅ C ₆ H ₄ (E-CH ₃ ) C ₆ H ₅ C ₆ H ₄ (E-OCH ₃ ) C ₆ HS C ₆ H ₄ (m-OCH ₃ ) C ₆ H ₅ C (O) C ₂ H ₅ C ₆ H ₅ C (O) C ₄ H ₉ C ₆ H ₅ C (O) OCH ₃ C ₆ H ₅ C (O) OCgH ₅ C ₆ H ₅ C (O) OCgH ₄ (E-CH ₃ ) C ₆ H ₅ C (O) OC ₆ H ₄ (O-CH ₃ ) C ₆ H ₅ C (O) C ₆ H ₅ C ₆ H ₅ C (O) C ₆ H ₄ (E-CH ₃ ) C ₆ H ₅ C (O) C ₆ H ₄ (E-OCH ₃ ) C ₆ H ₅ C (O) CgH ₄ (In-CF ₃ ) In-CF ₃ -C ₆ H ₄ CH ₃ E-CH ₃ -C ₆ H ₄ CH ₃ , -OCH ₃ -C ₆ H ₄ CH ₃

In-CF ₃ -CgH ₄ C (O) OCH ₃

All of the above-mentioned compounds and the following compounds can be prepared by hydrolysis of the corresponding compounds of the formula D (Example 32).

Ϊ09845 / 0911

«2 _R 2718059 ^C 6 ^H 5 ^C 6 ^H 4 <E ~ ^C1 > ^C 6 ^H 5 CH ₂ CH ₂ Cl S-Br-CgH ₄ C (O) C ₆ H ₅ S-Cl-C ₆ H ₄ H S-Br-CgH ₄ H m-Cl-CgH ₄ C (O) CH ₃ 51-Cl-CgH ₄ ^C 6 ^H 5 B-Ci-C ₆ H ₄ CH ₃ 511-Br-C ₆ H ₄ C ₂ H ₅

example

The following imidazolidine-2-thiones of Formula F are derived from the corresponding imidazolidones unsubstituted in the 3-position prepared by the procedure described in Example 4.

OR -Nf

H R. (F) C ₂ H ₅ B ₂ C ₃ H ₇ -I ₈ O C ₆ H ₅ ^C 6 ^H 5 ^C 6 ^H 5 C ₆ H ₄ (B-CH ₃ ) ^C 6 ^H 5 C ₆ H ₄ (P-OCH ₃ ) ^C 6 ^H 5 ^C 6 ^H 4 ⁽ E- ^{C1) C} 6 ^H 5 CH ₂ CH ₂ Cl ^C 6 ^H 5 ^C 6 ^H 5

51-CF ₃ -CgH ₄

π, -cH CH * 09β45 / 09.11

5J-CH ₃ -CH ^ HI-OCH ₃ -CgH ₄

Claims (1)

Patent claims where mean: R is hydrogen, an alkyl group with 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a phenyl group, a substituted phenyl group with up to 3 alkyl groups with 1 to 6 Carbon atoms, halogen atoms, alkoxy groups with 1 to 6 carbon atoms or groups of the formula COR ₃ , wherein R, hydrogen, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, a phenoxy group, a haloalkyl group having 1 to 6 carbon atoms, a phenyl group or denotes a phenyl or phenoxy group which has up to 4 alkyl groups with 1 to 6 carbon atoms, Halogen, trifluoromethyl groups or alkoxy groups can be substituted with 1 to 6 carbon atoms, 709345/0311 ORIGINAL INSPECTiO R _{1 is} hydrogen or a group of the formula COR ₄ , where R. denotes an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, a phenoxy group, a cycloalkyl group with 5 to 10 carbon atoms, a phenyl group or a phenyl or phenoxy group which has up to 4 alkyl groups with 1 to 6 Carbon atoms, alkoxy groups with 1 to 6 carbon atoms, halogen atoms or trifluoromethyl groups can be substituted, R _{2 is} a phenyl group or a phenyl group substituted by up to two alkyl groups with 1 to 6 carbon atoms, alkoxy groups with 1 to 6 carbon atoms, halogen atoms or trifluoromethyl groups and Z oxygen or sulfur, with the proviso that when R in the second formula given above is hydrogen, Z is oxygen. 709845/0911 2. As compounds according to claim 1 1- (2-methoxyethyl) - ^ phenyl- ^ imidazolin - ^ - one, 1- (2-acetoxyethyl) -'l-phenyl- ^ imidazolin ^ -one, 1- (2-methoxyethyl) -4- (3-methoxyphenyl) -4-imidazolin-2-one, 1- (2-methoxyethyl) -4- (3-bromophenyl) -4-imidazolin-2-one, 1- (2-methoxyethyl) -S- 1- (2-methoxyethyl) -B- 1- (2-methoxyethyl) -3- (2-methoxybenzoyl) ^ - dazolin-2-one,
1- (2-methoxyethyl) -3- (4-trifluoromethylbenzoyl) -4-phenyl-3- imidazolin-2-one,
1- (2-methoxyethyl) -3- (1-adamantanecarbonyl) -4-phenyl-4-irai- dazolin-2-one,
1- (2-methoxyethyl) -3-cyclohexanecarbonyl-4-phenyl-4-imidazo- 1in-2-on,
1- (2-methoxyethyl) -4- (3-trifluoromethyl) -phenyl-4-imidazolin-2-one, 1- (2-butoxyethyl) -4-phenyl-4-iπιidazolin-2-one, 1- (2-methoxyethyl) -4- (3-methylphenyl) -4-imidazolin-2-one, 1- (2-methoxyethyl) -4- (4-trifluoromethylphenyl) -4-imidazo- 1in-2-on and
1- (2-Benzoyloxyethyl) -4-phenyl-4-imidazolin-2-one. 709845/0911 3. As compounds according to claim 1 27 ivvOv * 1- (2-methoxyethyl) - ^ - phenyl - ^ - imidazolidone, 1- (2-hydroxyethyl) ^ - phenyl ^ -imidazolidone, 1- (2-acetoxyethyl) - ^ - phenyl ^ -imidazolidone, 1- (2-methoxyethyl) -4- (3-methoxyphenyl) -2-imidazolidone, 1- (2-methoxyethyl) -4- (3-bromophenyl) -2-imidazolidone, 1- (2-methoxyethyl) -S-acetyl ^ -phenyl ^ -imidazolidone, 1- (2-methoxyethyl) -S-benzoyl ^ -phenyl ^ -imidazolidone, 1- (2-methoxyethyl) -3- (2-methoxybenzoyl) ^ -phenyl ^ -imidazolidone, 1- (2-methoxyethyl) -3- (4-trifluoromethylbenzoyl) ^ -phenyl ^ -imidazolidone, 1- (2-methoxyethyl) -3- (1-adaman ^ ancarbonyl) ~ 4-phenyl-2-imidazolidone, 1- (2-methoxyethyl) -3-cyclohexanecarbonyl-4-ρhenyl-2-imidazolidone _/ 1- (2 -Butoxyethyl) -4-phenyl-2-iπιidazolidon, 1- (2-methoxyethyl) -4- (3-trifluoromethyl) -phenyl-2-imidazolidone, 1- (2-methoxyethyl) -A- (3-methylphenyl) - 2-imidazolidone, 1- (2-methoxyethyl) -4- (4-trifluoromethylphenyl) -2-imidazolidone, 1- (2-benzoyloxyethyl) -4-phenyl-2-imidazolidone and 1- (2-butoxyethyl) -3- acetyl-4-phenyl-2-imidazolidone. 4. As compounds according to claim 1, 1- (2-methoxyethyl) -4-phenylimidazolidine-2-thione, 1- (2-butoxyethyl) -4-phenylimidazolidine-2-thione and 1- (2-phenoxyethyl) ^ -phenylimidazolidine ^ -thione, Compounds of the formula 0
R ₂ -C-CH ₂ -NH-CH ₂ -CH ₂ -OR 709845/0911 wherein R and R _{2 have} the meanings given in claim 1. 6. Process for the preparation of compounds of the formula wherein R, R ₁ and R »have the meanings given in claim 1, characterized in that a substituted alpha-aminoketone of the formula Il R ₂ -C-CH ₂ -NH-CH ₂ -CH ₂ -OR in which R and R ″ have the meanings given above, as a solution in an organic solvent in the presence of cyanic acid and hydronium ion donating substances ^{heated to about 0 to 100 °} C. and the imidazolinone of the formula that is formed 709845/0911 wherein R and R- have the meanings given above, in Presence or absence of a hydrocarbon solvent and in the presence of a base at reflux temperature with an acyl halide or anhydride of the formula R ₄ COY or (R ₄ CO) ₂ O wherein R. has the meaning given in claim 1 and Y has a represents any group which can be replaced by a nucleophilic reagent. 7. Process for the preparation of compounds of the general formula wherein R, R ₁ and R- have the meanings given in claim 1, characterized in that an imidazolinone of the formula 709845/0911 • Λ- wherein R, R .. and R "have the meanings given above, by hydrogenation in the presence of a catalyst in an organic solvent at a temperature of about 25 to 80 ⁰ C is reduced. 8. The method according to claim 7, characterized in that the catalyst is palladium, Platinum, nickel, rhodium, iridium, ruthenium or cobalt is used. 9. The method according to claim 7, characterized in that the catalyst is palladium-carbon with a Pd content of 10% is used. 10. The method according to claim 7, characterized in that, in addition, the imidazolidone ^{obtained is heated to reflux in a solvent at a temperature of about 80 to 200 0} C with a reagent capable of replacing the oxygen with sulfur. 11. The method according to claim 10, characterized in, that phosphorus pentasulfide or hydrogen sulfide is used as a reagent. 12. The method according to claim 10, characterized that phosphorus pentasulfide is used as the reagent. 709845/0911 13. Process for the preparation of compounds of the formula R ₂ -C-CH ₂ -NH-CH ₂ -CH ₂ -OR wherein R and R _{2 have} the meanings given in claim 1, characterized in that an alpha-substituted ketone of the formula wherein R- has the meaning given above and X has a through represents a nucleophilic reagent displaceable group with an amine of the formula H ₂ N-CH ₂ -CH ₂ -OR y wherein R has the meaning given above, or an acid addition salt this amine in the presence of an excess of the amine or a tert - amine or a HydroxyHonen delivering substance, is reacted at a temperature of about 0 to 50 C, 30 minutes or longer. 14. Process for the preparation of a compound of the formula HY 709845/0911 wherein R _{2 has} the meaning given in claim 1 and Y is a pharmaceutically acceptable anion, characterized in that a substituted imidazolidinthione of the formula wherein R and R "have the meanings given in claim 1, with HY, in which Y has the meaning given above, in a solvent at a temperature of from about 0 to 200.degree heated and the acid addition salt of the free substituted 2,3,5,6-tetrahydroimidazo / 2,1-b / -thiazole base is obtained. 15. The method according to claim 13, characterized that the acid addition salt is neutralized with formation of the free base. 16. Process for the preparation of compounds of the general formula i-C-R 709845/0911 wherein R ₂ and R _{3 have} the meanings given in claim 1, characterized in that a compound of the formula R ₂ COCH ₂ X, wherein R _{3 has} the meaning given above and X represents a group which can be displaced by a nucleophilic reagent, with a compound of the formula in- wherein R- has the meaning given above, reacted in a solvent at a temperature of about 25 to 65 ⁰ C and then the solution is treated with potassium cyanate and acetic acid. 17. The method according to claim 16, characterized in that - indicates that an alpha-substituted ketone is used, in whose formula X stands for chlorine, fluorine, bromine, iodine or p-toluenesulfonate. 18. The method according to claim 16, characterized in that a chlorinated hydrocarbon, an alcohol having 1 to 6 carbon atoms, diethyl ether or tetrahydrofuran is used as the solvent . 709845/0911