NO130826B - - Google Patents

Description

.. Procedure for the manufacture of

5H-imidazo/"2,1-a/isoindoles.

The present invention relates to a method for production

of 5H-imidazo/2,1-a/isoindoles of the general formula I

in which R, R1 and B.^ in the individual case stand for hydrogen, chlorine, fluorine, trifluoromethyl, alkyl■ or alkoxy with each l-h carbon atoms, although a) two neighboring substituents R, and R2 do not simultaneously mean trifluoromethyl and b) if R or R2 stands for trifluoromethyl, R1 means hydrogen, chlorine or fluorine,

R^ means hydrogen, chlorine or fluorine, R^ and R^ stand in the individual case for hydrogen, chlorine, fluorine, trifluoromethyl, alkyl or alkoxy each with 1-<*>+ carbon atoms, however, if one of the substituents R^ or R^ means trifluoromethyl, the other of the substituents R^ or R^ stands for hydrogen, chlorine or fluorine, or R^_ and R^ together mean the -O-CH^-O- group, Rg stands for hydrogen

or fluorine, since in the individual case at most two of the substituents R^, R^, R^ and Rg and in the individual case -ti-lf or at most three of

the substituents R, R^ , R 2 , R^ ? R? ^^°§ ^5 has a different meaning than hydrogen, and the acid addition salts of the compounds.

The general formula I describes the compounds that can be produced by the process in their covalent form. However, the compounds can also appear in ionic form, illustrated by the general formula Ia

Likewise, the compounds with the general formula I can appear in tautomeric forms, which are in equilibrium with each other and are illustrated by the general formulas Ib and Ic? wherein, as in the general formula Ia, R-Rg has the above meaning.

The present invention therefore relates to the preparation of compounds of the general formula Ia-Ic as well as the preparation of the compounds of the general formula I. In the present preparation, they are therefore

manufacturable compounds for convenience denoted as

-compounds with the general-formula I...

The peculiarity of the method according to the invention is that 9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo/S,1-a/isoindol-5-one with the general formula II

wherein R-Rg has the above meaning, in a straight chain or cyclic ether, preferably diethyl ether or tetrahydrofuran,

and in an inert gas atmosphere at temperatures of at least <h>^ °C treated with, lithium aluminum hydride, the reaction products obtained are subjected to the influence of a mild oxidizing agent, preferably air,

and the thus obtained compounds of formula I are optionally transferred into their acid addition salts.

A preferred embodiment of the method according to the invention shall be described in the following: Compounds with the general formula II are dissolved in a straight-chain or cyclic ether such as diethyl ether or tetrahydrofuran, and the resulting ethereal solution is added in an inert gas atmosphere, preferably a nitrogen atmosphere, by temperatures between 15 and 35°C lithium aluminum hydride. The reaction mixture thus obtained is preferably stirred at room temperature (20 to 25°C) for 6 hours ----- to 8 days-and then treated with aqueous sodium hydroxide solution and water and/or ethyl acetate to remove unreacted lithium aluminum hydride. The reaction product that remains in the ethereal solution is then brought into contact with oxygen or air for 2 to 10 days.

The after the cleavage of it for the reduction of the compounds with

the general formula II necessary lithium aluminum hydride obtained reaction product-containing reaction mixture, to remove the cleavage products contained therein, must be filtered after,

but appropriate already for the impact of oxygen or air. If the compounds obtained according to the invention

with the general formula I exhibits such a low solubility

v'- that certain quantities crystallize out already before the filtration,

in order to avoid contamination and losses, it is more favorable to remove the cleavage products by filtration already before the impact of air or oxygen.

In the treatment of compounds of the general formula II

with lithium aluminum hydride in accordance with the invention, the temperature used is critical in so far as, when exceeding

the upper temperature limit ( k^ °C), i.e. already at 50°C and more, the desired turnover products are no longer obtained. These reaction products are compounds of the general formula III in which R-Rg has the above meaning. These can also appear in their tautomeric form, which is represented by formula Illa

wherein R-Rg has the above meaning. For simplicity, the compounds with fornier III and Illa are summarized under formula

III.

The subsequent formation of compounds of the general formula I from the above-mentioned reaction products with the aid of air or oxygen can be accelerated by passing air or oxygen through a solution of the reaction products in a lower alcohol, e.g. methanol or ethanol. In this way, already after •+ hours, formed amounts of the compounds with the general formula I can be detected.

The obtained compounds of the general formula I are isolated

from the reaction mixture in a known manner, e.g. by evaporation of the solvent, and then cleaned in a known manner, e.g. by' recrystallization. The thus obtained compounds of the general formula I can then optionally be converted into their acid addition salts by reaction with suitable organic or inorganic acids.

The compounds of the general formula II used as starting compounds are either previously known (e.g. from published Dutch patent application no. 6,501,677 from 12 August 1965) or can be prepared from known starting products using known methods. The preparation of some not previously known starting compounds is described in the examples. Further not previously known starting compounds can be prepared using the methods described therein.

The obtained compounds of the internal formula I are, at room temperature, well-crystallizing or amorphous bases, which can be converted into their acid addition salts by reaction with suitable organic or inorganic acids. As organic acids, benzoic acid, acetic acid, maleic acid, p-toluenesulfonic acid and benzenesulfonic acid have proven suitable and as inorganic acids hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid have proven suitable.

The compounds of the general formula I and their salts have favorable pharmacodynamic properties which manifest themselves in particular in an appetite-suppressing effect as well as in a stimulating effect on the central nervous system. The compounds with the general formula I and their salts can therefore be used as appetite suppressants and

as a psychological tonic. To achieve the desired therapeutic effect, 1-15 mg of a compound of the general formula I is administered daily, optionally in several small doses of 0.25-8 mg, 2-k times daily or in delayed form.

The compounds of the general formula I, wherein R, R^, R^, R^

and Rg in the individual case stands for hydrogen and one or both substituents R 1 and R 2 stand for chlorine are generally preferred.

The compounds with the general formula I which can be prepared by the method according to the invention can be used as pharmaceuticals either alone or in corresponding pharmaceutical forms for oral administration, e.g. in the form of tablets, extracts, suspensions or solutions, or for parenteral administration, preferably in the form of injection solutions.

In the following examples, which will illustrate the implementation of the method, all temperature indications are in °C which have not been corrected.

Example 1; 5_hydroxy-5-phenyl-2,3-dihydro-5H-imidazo/2,1 - aj~

isoindole.

Into a nitrogen-flushed flask fitted with a stirrer, reflux skirts and a gas supply stirrer, introduce 500 ml of diethyl ether,

2.5 g (0.07 mol) of lithium aluminum hydride and 15 g (0.06 mol) of 9b-phenyl-1,2,3-9b-tetrahydro-5H-imidazo/2,1-4/isoindol-5-one. The mixture is stirred for 8 days at room temperature (20-25°C), then cooled in an ice bath, 5 ml of an aqueous 2 N sodium hydroxide solution and 7.5 ml of water are added and then brought into contact with air for 6 days. It is then filtered and the solid components are washed twice with 75 ml of ethyl acetate each time. The filtrate is combined with the ethyl acetate washing solution, the resulting mixture is dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated in vacuo in a rotary evaporator. The ester is first recrystallized from diethyl ether/pentane (2:1) and then from tetrahydrofuran/diethyl ether (2:1), obtaining 5-hydroxy-5_phenyl-2,3-dihydro-5H-imidazo/2,1-α7isoindole with melting point 197"199°C.

Calculated analysis C 76.3 H 6.3 N 11.1 0 6.3

(<C>l6<H>llf<N>2<0>)

Found C 76.3 H 6.1 N 1 1.3 0 6.1.

IR.-spectrum: KBr press pieces

Tape at 3.28; 3.38; 3A8; 3.62; 6.03; 6.16;

6.72; 6.78 and 7.86 yx.

Mass spectrum: Doublet peak at 250. Additional distinct peaks at 232, 221, 20^, 178, 173, 165, 155, 151, 1^0, 116, 102, 89 and 77.

Example 2: 5-(p-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2.1-α7isoindole.

Into a nitrogen-flushed flask, equipped with stirrers, thermometer, dropping funnel, reflux skirts and a gas supply tube, 1000 ml of dry tetrahydrofuran and 10 g (0.263 mol) of lithium aluminum hydride are added. The resulting mixture is stirred and then a solution of 30 g ( 0.105 mol) 9b-(p-chlorophenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-aJ<;;>,isoindol-5-one in 1 50 ml of anhydrous tetrahydrofuran, with it is ensured that the reaction temperature does not exceed 30° C. The mixture is then stirred for 6 hours at room temperature, cooled in an ice bath and 100 ml of ethyl acetate is added,

20 ml of an aqueous 2N sodium hydroxide solution and 30 ml of water,

and then the mixture for 6 days in contact with air. It is then filtered, the filtrate is dried by adding anhydrous sodium sulphate, filtered again and evaporated in vacuum in a rotary evaporator. The residue is recrystallized from tetrahydrofuran/diethyl ether (2:1), then dissolved in chloroform and the chloroform solution is chromatographed on a silica gel column (250 g). After developing with chloroform, the following eluates are obtained:

Fractions 2 and 3 are combined and recrystallized from methanol/methylene chloride. The 5-(p-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/"2,1-a/isoindole thus obtained melts at 202-203°C.

Calculated analysis C 67.0 H 5.3 Cl 12.^- N 9.8 0 5.6'

(Cl6H1lfClN2O)

Found C 67.5 H 5,"+ Cl 12, k N 9.8 0 5.8

IR.-spectrum: KBr press pieces

Tape at 3.31; 3.39; 3,^<8>; 3.62; 3.82-, 6.06;

6.17; 6.72; 9.15; 9.38 p.

UV spectrum: (95% ethanol)

Mass spectrum: Doublet peak M at 28k. The ratio M : M + 1 : M + 2

is like 100 : 35.7 : 3^.3. Additional distinct peaks at 268, 256, 238, 231, 220, 190, 177,

176, 165, 155, 1^9, 139, 137, 130, 123, 111, 102, 83 and 81.

The preparation of 5-(p-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-a/isoindole hydrochloride is described in example 11.

Example 3: 5-(p-fluoroenyl)-5-hydroxy-2^-dihydro^H-imidazo/^,1-α7isoindole.

Into a nitrogen-purged flask fitted with a stirrer, reflux condenser and a gas supply stirrer is charged 1000 ml of diethyl ether, 2.0 g (0.063 mol) of lithium aluminum hydride and 15 g (0.06 mol) of 9b-(p-fluoro-phenyl)-1 ,2,3,9b-tetrahydro-5H-imidazo/2,1-a7isoindol-5-one. The mixture is stirred for 8 days at room temperature (20-25°C, then cooled in an ice bath, ^.8 ml of an aqueous 2 N sodium hydroxide solution and 7.2 ml of water are added and then kept for 6

even in contact with air. It is then filtered and the solids

parts are washed twice with each time 75 ml of ethyl acetate. The filtrate is combined with the ethyl acetate washing solutions, the mixture obtained is dried over anhydrous sodium sulphate, dried and the filtrate is evaporated in vacuo in a rotary evaporator. After recrystallization of the residue from tetrahydrofuran/diethyl ether (2:1) 5-(p-fluorophenyl)-5-hydroxy-2,3-dihydro-5K-imidazo/2,1-α7isoindole with melting point 198-199°C is obtained

Hydrochloride.

The free base is dissolved in tetrahydrofuran and hydrogen chloride gas is passed through the resulting solution. The 5-(p-fluorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-α-isoindole hydrochloride thus obtained melts at 279-280°C.

Example h: 5-(p-methoxyphenyl)-5-hydroxy-2,3-dihydro-5H-imidazo[2,1-α7isoindole.

Into a nitrogen-flushed flask, fitted with tubes, reflux skirts and gas supply tubes, is introduced. 1000 ml diethyl ether,

2.3 g (0.061 mol) lithium aluminum hydride and 15 g (0.05^ mol) 9b-(p-methoxyphenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-q^isoindole-5 -on. The mixture is stirred for 8 days at room temperature, then cooled in an ice bath, 6 ml of an aqueous 2N sodium hydroxide solution and 6.9 ml of water are added and then the mixture is kept in contact with air for 6 days. It is then filtered and the solid components are washed twice with 75 ml of ethyl acetate each time. The filtrate is combined with the ethyl acetate washing solutions,

the mixture obtained is dried over anhydrous sodium sulphate, filtered and the filtrate is evaporated in a rotary evaporator in vacuum. After recrystallization of the residue from methanol, 5-(p-methoxyphenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-α-isoindole with melting point 188-190°C is obtained.

Example 5: 5-(3'^'-dichlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-α7isoindole.

In a nitrogen-purged flask, equipped with stirrups, thermometer, dropping funnel, reflux skirts and gas supply stirrup, add 250 ml of dry tetrahydrofuran and 2.6 g (0.068 mol) of lithium aluminum hydride. The resulting mixture is stirred and then one solution of 20 g (0.063 mol) 9b-(3'^'-dichlorophenyl>1,2,3,9b-tetrahydro-5H-imidazo[^,1-a]isoindole is added dropwise -5-one in 500 ml

anhydrous tetrahydrofuran, whereby it must be ensured that the reaction temperature does not exceed 30°C. The mixture is then stirred

for 6 hours at room temperature, cooled in an ice bath and then 5.2 ml of an aqueous 2N sodium hydroxide solution and 7.8 ml of water are added. It is then filtered, the filtrate is dried by adding anhydrous sodium sulphate, it is filtered again and evaporated in a rotary evaporator in vacuum. The residue is dissolved in 200 ml of methanol and

air is passed through the solution for 12 hours at room temperature. The solvent is then evaporated and the residue obtained is recrystallized from methanol/tetrahydrofuran (1:1). The thus obtained 5-(3''-dichlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-α-isoindole melts at 200-201°cV

Example 6: 5-(m-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-α7isoindole.

Into a nitrogen-purged flask, fitted with stirrers, thermometer, dropping funnel, reflux skirts and a gas supply stirrer, are introduced 250 ml of dry tetrahydrofuran and 2.9 g (0.076 mol) of lithium aluminum hydride. The resulting mixture is stirred and then a solution of 20 g (0.07 mol) 9b-(m-chlorophenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-aJ7isoindol-5-one is added dropwise in 200 ml of dry tetrahydrofuran, whereby it must be ensured that the reaction temperature does not exceed 30°C. The mixture is then stirred for 6 hours at room temperature, cooled in an ice bath, 5.8 ml of an aqueous 2N sodium hydroxide solution and 8.7 ml of water are added and the mixture is then brought into contact with air for 6 days.

Then filtered, the filtrate is dried by adding water

free sodium sulfate, it is filtered again and in rotary

the evaporator evaporates in vacuum. The residue is chromatographed on a silica gel column. (360 g), the soil being developed with chloroform/methanol (99:1). After recrystallization from methanol, 5-(m-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-α7i indole with melting point 208-30°C is obtained.

Example 7: 5-(p-trifluoromethylphenyl)-5-hydroxy-2,3-dihydro-5H-imidazo. 1-α7isoindole.

Into a nitrogen-flushed flask, equipped with stirrups, thermometer, dropping funnel, reflux skirts and gas supply stirrups, introduce 250 ml of dry tetrahydrofuran and 2.6 g (0.068 mol) of lithium aluminum hydride. The resulting mixture is stirred and then a solution of 20 g (0.063) mol of 9b-(p-trifluoromethyl-phenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-α7isoindol-5-one is added dropwise in 200 ml of dry tetrahydrofuran, whereby it must be ensured that the reaction temperature does not exceed 30°C. Then the mixture is stirred for 6 hours at room temperature, it is cooled in an ice bath, ... 5.2 ml of an aqueous 2N sodium hydroxide solution and 7.8 ml of water are added and then the mixture is brought into contact with air for 6 days.

It is then filtered, the filtrate is dried by adding anhydrous sodium sulphate, it is filtered again and then evaporated in a rotary evaporator in vacuum. After recrystallization of the residue from benzene/diethyl ether (2:1), 5-(p-trifluoromethylphenyl)-5-hydroxy~2,3-dihydro-5H-imidazo/2,1-a/isoindole with melting point 210-212°C is obtained .

Example 8: 5-(p-tolyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-s-isoindole.

Into a nitrogen-flushed flask, equipped with stirrups, thermometer, dropping funnel, reflux skirts and gas supply stirrups, introduce 250 ml dry tetrahydrofuran and 2. g (0.063 mol) lithium aluminum hydride. The resulting mixture is stirred and then a solution of 15 g (0.057 mol) 9b-(p-tolyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-aJ<7>isoindol-5one is added dropwise in 120 ml of dry tetrahydrofuran, whereby it must be ensured that the reaction temperature does not exceed 30°C. The mixture is then stirred for 6 hours at room temperature, cooled in an ice bath, <>>+.8 ml of an aqueous 2N sodium hydroxide solution and 7.2 ml of water are added, and then the mixture is kept in contact with air for 6 days. It is then filtered, the filtrate is dried by adding anhydrous sodium sulphate, it is filtered again and finally evaporated in vacuum in a rotary

evaporates. After recrystallization of the residue from tetrahydrofuran/diethyl ether (1:2), 5-(p-tolyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-a/isoindole with melting point 203-206°C is obtained .

Example 9: 5-(p-ethylphenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2.1-α7isoindole.

Into a nitrogen-purged flask, fitted with stirrers, thermometer, dropping funnel, reflux skirts and a gas supply stirrer, introduce 500 ml of dry tetrahydrofuran and 2.6 g (0.068 mol) of lithium aluminum-

hydride. The mixture obtained is stirred and then a solution of 17.2 g of 9b-(p-e.tylphenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-yl'isoindole-5- is added dropwise on in 250-ml dry tetrahydrofuran,

whereby it must be ensured that the reaction temperature does not exceed 30°C. The mixture is then stirred for 6 hours at room temperature,

cooled in an ice bath, 5.2 ml of an aqueous 2N sodium hydroxide solution and 7.8 ml of water are added and then kept for 6 days in contact with air. It is then filtered, the filtrate is dried by adding anhydrous sodium sulphate, filtered again and finally evaporated in vacuum in a rotary evaporator. After recrystallization of the residue from tetrahydrofuran/methanol/diethyl-

ether (1:1:2) yields 5~ (p-ethylphenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-a/isoindole with melting point' 177-179°C.

Example 10: 6-chloro-5-hydroxy-5-phenyl-2,3-dihydro-5H-imidazo/2.1-α7isoindole.

Into a nitrogen-flushed flask equipped with stirrers, thermometer, dropping funnel, reflux skirts and a gas supply stirrer, add 100 ml of dry tetrahydrofuran and 1 g of lithium aluminum hydride. The resulting mixture is stirred and then a solution of 6.8 g of 9-chloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo/2,1-a/isoindol-5-one in 100 ml of dry tetrahydrofuran, whereby it must be ensured that the reaction temperature does not exceed

30°C. The mixture is then stirred for 6 hours at room temperature,

is cooled in an ice bath, 2 ml of an aqueous 2N sodium hydroxide solution and 3 ml of water are added and then brought into contact with air for 6 days. It is then filtered, the filtrate is dried by adding anhydrous sodium sulphate, it is filtered again and then evaporated under vacuum in a rotary evaporator. After recrystallization of the residue from tetrahydrofuran/diethyl ether (1:2), 6-chloro-5-hydroxy-5-phenyl-2,3-dihydro-^H-imidazo/"2,1-α7isoindole with melting point 22<1>+ is obtained -226<0>C.

Example 11: The hydrochloric acid salt of 5-(p-chlorophenyl)-5-hydroxy-2. 3-dihydro-5H-imidazo/2,1-α7isoindole.

5-(p-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-a^isoindole is dissolved in tetrahydrofuran/methanol (1:2) and the solution obtained is saturated with hydrogen chloride gas. The resulting hydrochloric acid

salt of 5-(p-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-aj7-

isoindole with melting point 175-177 C-f-raf Utreres....

Example 12:

By replacing the 9b~3^-dichlorophenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-a/isoindol-5-one used in Example 5 with the following described tetrahydro-511 -imidazo/2,1-ayisoindol-5-ones (starting compounds) using the method described in example 5 leads to the following described 5-hydroxy-2,3-dihydro-5H-imidazo/2,1 -a/isoindoles (end compounds).

Example 1 3: 5-(p-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2.1-α7isoindole.

Into a nitrogen-flushed flask, fitted with stirrers, thermometer, dropping funnel, reflux skirts and a gas supply stirrer, are introduced 1000 ml of dry tetrahydrofuran and 10 g (0.263 mol) of lithium aluminum hydride. The resulting mixture is stirred and then a solution of 30 g (0.105 mol) 9b-(p-chloro-phenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-a7isoindol-5-one is added dropwise in 150 ml of anhydrous tetrahydrofuran, as it must be ensured that the reaction temperature does not exceed 30°C. The mixture is then stirred for a further six hours at room temperature, cooled in an ice bath and 100 ml of ethyl acetate, 20 ml of an aqueous 2N sodium hydroxy solution, 30 ml of water and solid anhydrous sodium sulphate are added. The resulting mixture is filtered and the filtrate is kept for six days in contact with air at room temperature. The filtrate is then evaporated in a rotary evaporator in vacuum. The residue is recrystallized from tetrahydrofuran/diethyl ether (2:1). The product from the recrystallization is then dissolved in chloroform and the chloroform mixture is chromatographed on a silica gel column (250 g). After development with chloroform, the following eluates are obtained:

Fractions 2 and 3 are combined and recrystallized from methanol/methylene chloride. The 5-(p-chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo/2,1-a/isoindole thus obtained melts at 202-203°C.

In what follows, the preparation of various starting products is described: 9b-(3trifluoromethylphenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-a7-isoindol-5-one.

a) 2-^3^zili£luormet^lbenzo^l)-be

In 'a flask, provided with stirrups, drop funnel, retrograde joler and

500 ml of anhydrous tetrahydrofuran and 13.5 g (0.55 mol) of magnesium shavings are introduced into the gas supply pipe. The flask is flushed with nitrogen. A solution of 112.5 g (0.5 mol) of 3-bromo-trifluoromethylbenzene in 100 ml of anhydrous tetrahydrofuran is then added dropwise. After the turnover has begun, the addition is adjusted so that only a slight backflow takes place. After all the magnesium has been converted, the Grignard solution obtained is transferred in a nitrogen atmosphere into a dropping funnel which is attached to a flask above which is arranged a reflux condenser, a stirrer and a gas supply stirrer. In this flask there are 81.5 g (0.55 mol) of phthalic anhydride dissolved in 1000 ml of anhydrous toluene. This solution is added dropwise to the Grignard solution with stirring over a period of 1 hour. It is then heated for 15 hours while stirring until boiling. After cooling in an ice bath, 300 ml of 2N hydrochloric acid is added and the mixture is stirred for 1 hour. A 1N aqueous sodium bicarbonate solution is then added, the aqueous phase is separated and the remaining mixture is acidified with 2N hydrochloric acid. The acidic phase is extracted twice with 250 ml of dichloromethane each time, then dried over magnesium sulphate,

is filtered off and the solvent is evaporated in a vacuum. The residue is recrystallized from benzene/hexane whereby the pure 2-(3'-trifluoromethylbenzoyl)-benzoic acid with melting point 16°-166°C is obtained. b) 9b-(3'-trifluoromethylphenyl)-1,2,3,9b-tetrahydro-5H- imi d a z o/*2_j 1 - a/i s o indo 1-5-on. 10 g of 2-(3'-trifluoromethyl-benzoyl)-benzoic acid, 1 g of ethylenediamine, 1 50 ml of toluene and 0.5 g of p-tol are introduced into a flask equipped with a water separator (according to Dean-Stark) and a reflux decanter: --m- sulfonic acid. The reaction mixture thus obtained is heated with stirring until no water is separated. The solvent is then evaporated in vacuo and the residue is recrystallized from isopropanol. This gives 9b-(3'-trifluoromethylphenyl)-1,2,3,9b-tetrahydro-5H-imidazo/2,1-a^isoindol-5-one with melting point 135-137°C • During the use of this in the steps a) and b) described method, by using the benzene derivatives specified below for reaction with phthalic anhydride, the reaction products specified below are obtained:

7,8-dichloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one.

a) ^methyl-^j^i^ichlorobenzoph enone.

In a flask equipped with rudders, reflux skirts, drop funnel and et

91.5 g (0.69 mol) of anhydrous aluminum chloride and 250 ml of 3N-dichlorotoluene are introduced into the gas supply pipe. To this is added dropwise a stirred solution of 10 g (0.53 mol) benzoyl chloride in 250 ml of 3N-dichlorotoluene. The resulting reaction mixture is heated slowly until gaseous hydrogen chloride is evolved. After completion of hydrogen chloride gas excretion, the mixture is carefully poured into 500 ml of concentrated hydrochloric acid, in which there is also approximately 750 g of ice. The organic phase formed in this way is separated. The aqueous phase is washed with benzene. The organic phases are combined, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Then filtered off. After distillation of the solution in vacuum, 2-methyl-<1>+,5-dichlorobenzophenone is obtained as a fraction at 175-180°C/0.75 mm Hg.

b) ' 2=benzoyl-j+j5-dichlorobenzos^re_.

A mixture of 1500 ml of water, 18.5 g (0.075 mol) of 2-methyl-5,5-dichlorobenzophenone, 2 g of sodium hydroxide and 51 g of potassium permanganate is heated to reflux until the original coloration disappears. It is then filtered hot and the salts contained in the filtrate are extracted with 200 ml of acetone. The extract is freed of acetone in vacuum and the residue that remains is recrystallized from benzene/pentane. This gives the pure 2-benzoyl-i+,5-dichlorobenzoic acid with melting point 206-208°C, c) 7,8-dichloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo-</> ^jllskZisoindol-^-one.

In a flask equipped with a water separator (according to Dean-Stark) and a reflux condenser, introduce 10 g of 2-benzoyl-^,5-dichlorobenzoic acid,

k g of ethylene amine, 150 ml of toluene and 0.5 g of p-toluenesulfonic acid.

The reaction mixture thus obtained is heated while stirring until boiling until no more water is separated. The solvent is then evaporated in vacuo and the residue is recrystallized from isopropanol. This gives 7,8-dichloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo/2,1-a/isoindol-^-one with melting point 185-1-87°C.

Using the method described in steps a), b) and c), the reaction products written in the following 1 are reached using the n,r of the starting compounds described below:

7-Chloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a7isoindol-5-one.

a) 2-iodo^-chlorotoluene.

In a flask fitted with stirrups, drop funnel and reflux skirts

introduce ^1.*+ g (0.6 mol) sodium nitrite and K80 ml sulfuric acid. The contents of the flask are then heated for about 30 minutes at 70°C, then cooled in an ice bath to an internal temperature below 30°C and a solution of 85 g (0.6 mol) of 2-methyl-^f-chloroaniline in 250 ml is added acetic acid. The resulting mixture is filtered and the filtrate is added at room temperature to a solution of 100 g (0.6 mol) of potassium iodide in 250 ml of water. This mixture is stirred

nitrogen evolution is stopped and sodium bisulphite is then added until free iodine is removed. The oily mixture is then extracted with benzene. The benzene solution is washed with 250 ml of 10% aqueous sodium hydroxide solution, dried over magnesium sulphate, filtered and subjected to a distillation in vacuum, whereby 2-iodo-5-chlorotoluene with a boiling point of 88-90°C/0.35 mm Hg is then obtained.

b) 2-methyl-1-N-chlorobenzy;drol_.

In a flask, fitted with stirrups, reflux strainer, dropping funnel

and 3 g (0.11 mol) of magnesium shavings and 200 ml of anhydrous diethyl ether are introduced into the gas supply pipe. The flask is flushed with nitrogen. Then a solution of 25.3 g (0.1 mol) of 2-iodo-5-chlorotoluene in 50

ml of anhydrous diethyl ether to add dropwise at a rate such that gentle backflow takes place. The Grignard solution obtained is cooled in an ice bath and 10.6 g (0.1 mol) benzaldehyde dissolved in diethyl ether is added. The mixture is then stirred for 12 hours at room temperature, 25 ml of saturated aqueous ammonium chloride solution and then 25 g of anhydrous sodium sulphate are added. The salts are filtered off and the filtrate is evaporated in vacuo. After recrystallization of the residue from pentane, 2-methyl-^-chloro-benzhydrol is obtained.

c) 2-benzoyl-5-chlorobenzoate.

A mixture of 1500 ml of water, 18.5 g (0.075 mol) of 2-methyl-<1>+-chlorobenzhydrol, 2 g of sodium hydroxide and 5^ g of potassium permanganate is heated in a flask equipped with stirrers and reflux valves until boiling until the original coloring is gone. The hot solution is filtered off and the salts are extracted from the filtrate

200 ml of acetone. Acetone is removed from the extract in vacuum and the residue that remains is recrystallized from benzene/pentane. The 2-benzoyl-5-chlorobenzoic acid thus obtained melts at 173-75°C.

d) 7-chloro-9b-phenyl-1.,2,3,9b-tetrahydro-5H-imidazo/2,1-aj<7->isoindole;5z2Si

10 g of 2-benzoyl-5-chlorobenzoic acid, 1 g of ethylenediamine, 150 ml of toluene and 0.5 g of p-toluenesulfonic acid are introduced into a flask equipped with a water separator (according to Dean-Stark) and a reflux condenser. The reaction mixture thus obtained is heated for so long while stirring under reflux that no water is separated anymore. The solvent is then removed in a vacuum and the residue that remains is recrystallized from isopropanol. This gives 7-chloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo/2,1-a/isoindol-5-one with a melting point of 193-194°C.

Using the method described in steps a) to d) in the present example, the starting compounds described below are used to arrive at the reaction products described below:

8-trifluoromethyl-9-chloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo/ 2.1- a7isdndol-5-one.

a) 2,6-dichloro-3-trifluoromethylbenzoate.

In one with rudders, backflow skirts, drip funnel and thermometer

equipped flask, introduce 75 ml of a 15% solution of butyl-lithium into it

hexane (0.1 mol butyllithium). The contents of the flask are cooled in a carbonated ice-acetone bath to -50°C and then a solution is added

of 21 , k g (0.1 mol) of 2,^-dichloro-trifluoromethylbenzene in 250 ml of anhydrous diethyl ether. After about 1 hour of stirring at -50°C

introduce the contents of the flask into a mixture consisting of 150 g of powdered carbon dioxide and 200 ml of diethyl ether. The resulting solution is then allowed to stand until it has reached room temperature (20-25°C). The solvent is then evaporated in a vacuum and the thus obtained

residue is recrystallized from methanol/water.

b) 2j6-dichloro-3=trifluoromethylbenz

In a flask equipped with rudders, retrograde jolts and drop funnel

introduce 250 ml of anhydrous benzene and 25 g of anhydrous aluminum

chloride. The resulting mixture is added dropwise with stirring over the course of about an hour to a solution of 2,6-dichloro-3-trifluoromethyl-benzoyl chloride (obtained by reacting 25.8 g of 2,6-dichloro-3-trifluoromethylbenzoic acid and 150 ml of thionyl chloride) in 200 ml of benzene. Then heat while stirring little by little until boiling. Hydrogen chloride gas is thereby evolved, and after this has ceased it is cooled to room temperature (20-25°C). The contents of the flask are then introduced into a mixture consisting of

250 g of ice and 100 ml of concentrated hydrochloric acid. The organic phase is washed with water and then with saturated aqueous sodium chloride solution.

After drying over magnesium sulphate, filtration and distillation

2,6-dichloro-3-trifluoromethylbenzophenone is obtained from the filtrate.

c) 2-benzovi-3-chloro-H--trifluoromet^lbenzos^re_.

In a flask fitted with rudders, reflux skirts and thermometers

introduce 5.9 g (0.09 mol) potassium cyanide, 0.5 g copper chloride,

15) 9 g (0.05 mol) of 2,6-dichloro-3-trifluoromethylbenzophenone and 100 ml of anhydrous dimethylformamide. The mixture is heated to 75°C and held at this temperature for 2 hours. After cooling to room temperature (20-25°C), the mixture is poured into 750 ml of ice water. The organic phase is extracted with 200 ml of benzene, then dried over magnesium sulphate and freed from solvent. The 2-chloro~3-trifluoromethyl-6-cyanobenzophenone obtained as a residue is heated together with 250 ml of a 2N aqueous potassium hydroxide solution for 2 hours until boiling. The obtained solution is then acidified with concentrated hydrochloric acid. 2-benzoyl-3-chloro-If-trifluoro-

methylbenzoic acid as a precipitate which is filtered off.

d) 8-trifluoromethyl-9-chloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-i^i^§52^'?jll§Zi22i5§2iz5'ion_1_

In one with a water separator (according to Dean-Stark) and a return valve

supplied flask, introduce 10 g of 2-benzoyl-3-chloro-If-trifluoromethyl-

benzoic acid, h g ethylenediamine, 1 50 ml toluene and 0.5 g p-toluene-

sulfonic acid. The reaction mixture obtained is heated under ■

stirring until boiling, as the water that forms is separated. I. <H.>is complete water separation, the solvent is evaporated in vacuum and the residue is recrystallized from isopropanol, whereby 8-trifluoro-methyl-

9-chloro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one is obtained.

Claims (3)

1. Process for the preparation of 5-hydroxy-5-phenyl-2,3-dihydro-5H-imidazo/2,1-a^isoindoles of the general formula I in which R, R1 and R2 in the individual case stand for hydrogen, chlorine, fluorine, trifluoromethyl, alkyl or alkoxy each with 1-2 carbon atoms, although a) two neighboring substituents R, R2 and R2 do not simultaneously mean trifluoromethyl and b) if R and R2 stand for trifluoromethyl, R1 means hydrogen, chlorine or, fluorine, R^ means hydrogen, chlorine or fluorine, .<R>> and R^ in the individual case stand for hydrogen, chlorine, fluorine, trifluoromethyl, alkyl- or alkoxy with each 1-<*>+ carbon atoms, however, if one of the substituents R^ or R^ means trifluoromethyl, the other of the substituents R^ or R^ stands for hydrogen, chlorine or fluorine, or R^ and R^ together mean the -O-CH^-O group, R^ stands for hydrogen or fluorine, in each case at most two of the substituents R^, R^, R^ and R^ and in the individual case at most three of the substituents R, R^, R^, R^, R^, R^ and Rg have a meaning other than hydrogen, and the acid addition salts of the compounds, characterized in that 9b-phenyl-1,2,3,9b-tetrahydro -5H-imidazo/2,1-a/isaindol-5-one of the general formula II wherein R - Rg has the above meaning, in a straight chain or cyclic ether, preferably diethyl ether or tetrahydrofuran, and in an inert gas atmosphere at temperatures of at least M-5 C is treated with lithium aluminum hydride, the reaction products obtained are subjected to the influence of a mild oxidizing agent, preferably air, and the thus obtained compounds of formula I are optionally transferred in their acid addition alters. 2. Method as stated in claim 1, characterized in that air or oxygen is fed through the dissolution of the reaction products in a lower alcohol. 3. Method as stated in claim 1 or 2, characterized in that the residue of the reaction products after the splitting of the lithium aluminum hydride is filtered for the effect of the mild oxidizing agent. h. Procedure as stated in requirements 1-3? for the production of 5-(p-chlorophenyl)-5-hydroxy-2,3-dihydro 0-5H-imidazo/2,1 - aj - isoindole or acid addition salts thereof, characterized in that 9b-(p-chlorophenyl)-1, 2,3,9b-tetrahydro-5H-imidazo/2,1-a^isoindol-5-one is treated with lithium aluminum hydride, the reaction product is brought into contact with air and the compound obtained is optionally transferred in its acid ad dis j oras everything is .