IE47210B1 - Improvements in the production of heterocyclic benzamide compounds - Google Patents

Abstract

The process for the preparation of known imidazo[2,1-a]isoindoles of the formula (I) indicated in Claim 1 leads via intermediates, some of which are new, of the formula (II) indicated in Claim 1, which are reacted with appropriate alkylating agents, to salts of the formula (III) indicated in Claim 1; these salts are reacted with ethylene- diamine to give an intermediate of the formula (IV) indicated in Claim 1, which is finally hydrolysed to the title compound (I).

Description

The present invention relates generally to a novel process for making certain known biologically active heterocyclic benzamide compounds. More particularly, the present invention is concerned with a novel process for producing imidazo [2,1-a] isoindoles of the general formula I: wherein X represents hydrogen, halogen in particular fluorine, chlorine and bromine and lower alkoxy.

Imidazo[2,1-a]isoindoles of the general formula I and processes for their production are generally described, for example, in U.K. Patent Specifications Nos. 1,225,411, 1,225,412 and 1,225,413.

In these specifications such imidazo [2,J-a] isoindoles are described as being biologically active and are indicated as having utility as psychic energizers and anorectics. Probably the best known of such compounds at the present time is 5-(pchlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo [2,1-a] isoindole commonly referred to as mazindol.

The prior art discloses several processes for obtaining the compounds of formula I but these processes all leave something to be desired. For example, the processes disclosed in the above specification usually involve the reduction of an intermediate carbonyl compound followed by a very delicate oxydation. The process steps, and especially the latter, are very time consuming. Although the specifications teach that the oxydation step may be effected within a relatively short time by bubbling air or oxygen it should be noticed that the specifications emphasize, and all but one of the detailed specific examples illustrate, a very mild oxydation wherein the reaction mixture is merely contacted with air over a period of many, usually six, days. Since the simple procedure of bubbling a gas, especially air, through a reaction mixture generally presents few problems, the emphasis on the use of the very long oxydation step indicates that this procedure is highly preferred. The above processes also utilize lithium aluminum hydride as the agent to reduce the intermediate carbonyl function. This reagent is very expensive and, moreover, presents a significant fire hazard which, on a small scale, may be acceptable. However, the use of that reagent on a large, i.e. commercial, scale is very hazardous and involves significant inconvenience and expense. It may also be noted that the above specifications refer to process yields only in general terms and as being appreciable. There is no specific yield given in any of the said three specifications and, although a much later reference (J. Med.

Chem. 18, 177, (1975)) indicates that a yield of 65% is possible for the oxydation step, the present Applicant did not obtain a yield of even half that amount using the same process.

An object of the present invention is to provide an improved process for producing the compounds of formula I which process avoids the significant disadvantages of the prior art processes. 47310 According to the present invention there is provided a process for making imidazo [2,1-a) isoindoles of the general formula I: wherein X represents hydrogen, halogen in particular fluorine, chlorine and bromine and lower alkoxy, comprising reacting, optionally under an inert gas, for example, nitrogen, atmosphere and/or in the presence of a solvent, for example, methylene chloride a compound of formula II.

X wherein Rj, is lower alkyl (moieties having 1 to 6 carbon atoms); X is as defined above; and Y is -nr2r3 or—r4 wherein Rj, R3 and R4 are individually lower alkyl or aryl or and together represent pyrrolidinyl or piperidinyl with an alkylating agent selected from the group consisting of oxonium salts of the formula (Rl^0+Z~ and carbonium salts of the formula: / HCt \ Owherein R is methyl or ethyl; and Z is the fluoroborate, hexachloroantimonate or hexafluorophosphate ion, to form a corresponding salt of formula III III reacting optionally under an inert gas, for example, nitrogen, atmosphere and/or in the presence of a solvent, for example, methylene chloride said salt with ethylene diamine to form an intermediate represented by formula IV: which compound is hydrolysed in the presence of an acid to form the desired compound of formula I. The above reactions in methylene chloride may be effected at temperatures up to reflux of the reaction medium.

The dialkylamino lactams of formula Ila used as starting materials in the process of the present invention are novel compounds. They and the alkoxy lactams of formula lib may be conveniently obtained from the corresponding benzoyl benzoic acid derivatives, for example, as follows: wherein R^, R2, R^, R^ and X are as defined above. - 6 47210 The benzoyl benzoic acid derivatives of formula V are readily available (refer for example to W. Graf, E. Girod, E. Schmid and W.G, Stoll, Helv. Chim. Acta 42 1085 (1958)).

As an example, 2 - (4' - chlorobenzoyl) benzoic acid required as starting material in the production of mazindol is readily produced by the reaction of chlorobenzene with phthalic anhydride.

The present invention will be further described with reference to the following specific Examples but is not to be considered as limited thereto.

Examples 1—6 These examples illustrate the preparation of specific compounds of formula I utilizing the novel compounds of formula II. Examples 1—5 illustrate the production of the preferred compound mazindol.

Example 1 Preparation of Mazindol from Dimethylamino-LactanFormula lla: R =CH ; R =R =CH ; X=C1 3 2 3 3 Crystalline dimethylamino lactam II (60g; 0.20 mole) was added to a solution of 48g (0.25 mole) of triethyloxonium fluoroborate (the triethyloxonium fluoroborate was prepared in situ-ref. H. Meerwein, Org. Synthesis, Coll. Vol.V, 1080 (1973) in 80 ml of dry methylene chloride. The mixture was 2£ stirred at reflux under nitrogen for 5 hours, cooled to 0° and 30.6 g (0.51 mole) of ethylene diamine added over 30 minutes. This mixture was refluxed under nitrogen for 5 hours, cooled to 5° and made strongly acidic by the careful addition of 200 ml of 4N aqueous hydrochloric acid.

After 3 hours of reflux at 40° the methylene chloride was removed by distillation, and then the mixture was basified (pH 8-0— 8.5) with 45ml of 50% W/V sodium hydroxide. The voluminous white precipitate which formed was filtered and washed with two 100 ml portions of water. After drying at 25° 64 g of crude product was obtained. Recrystallization from methanolmethylene chloride (1:1) followed by suspension at reflux in the same solvent system yielded 35.3 g (62% theoretical from dimethylamino lactam Ila) of pure mazindol m.p. 201—202° with a setting of 6.5 in the Thompson-Hoover capillary melting point apparatus (lit. 20l—202° under similar conditions ref. P.

Aeberli et al. J. Med. Chem. 18 p. 177 (1975)). Analysis: %C SH SN SCI %0 15 Calculated 67.49 4.60 9.84 12.45 5.62 Found 67.25 4.69 9.74 12.42 5.62 The product was further characterized by the I.R. spectrum. Example 2 Preparation of Mazindol from Pyrrolidinyl Lactam — 2i Formula Ila: R =CH ; R with R =— (CH ) 7;X=C1 3 2 3 2 4 Pyrrolidinyl lactam (2.0 g; 6.1 mM) dissolved in dry methylene chloride (3 ml) was added to triethyloxonium fluoroborate (prepared as in Example 1) (2.4 g; 13mM) in methylene chloride (3 ml) and the mixture refluxed under nitrogen for 5 hours. After cooling to 0°, ethylene diamine (3.6 g; 60mM) was added and this mixture refluxed under nitrogen for 5 hours, and then stirred for 18 hours at 25°. Aqueous hydrochloric acid was added until the solution was strongly acidic (10 ml of 4NHC1) and the resulting mixture refluxed for -17 210 hours. After cooling, aqueous sodium hydroxide was added until the pH was 7.5 — 8.5 (~10ml 20% NaOH) and a large amount of white precipitate was observed. The reaction mixture was stirred at 0° for 30 minutes, filtered and the filtrate washed with cold water.

The so-obtained crude mazlndol was dried at 60° for 18 hours and then recrystaliized from methanol to give 0.8 g (46% theoretical) of pure mazindol characterized as in Example 1.

Example 3 Preparation of Mazindol from Piperidinyl Lactam — Formula Ha: R =CH ; R with R'—(CH) ; X=C1 1 3 2 3 2 5 A solution of 1.0 g (2.9 mM) of said lactam dissolved in 5 ml dry methylene chloride was added to 2.4 g (13 mM) of triethyloxonium fluoroborate (prepared as in Example 1) dissolved in 2 ml of dry methylene chloride. The mixture was refluxed under nitrogen for 5 hours and then cooled in an ice bath.

Ethylene diamine (3 g; 50mM) was added dropwise over 10 minutes and the mixture refluxed under nitrogen for 18 hours. After cooling the mixture to 25° aqueous hydrochloric acid (15 ml of 10% HCl) was added and the acidic mixture (pH=4) refluxed for 4 hours. Upon basification of the resulting solution with aqueous sodium hydroxide (15 ml of 10% NaOH) a voluminous white precipitate separates. The whole mixture was stirred in an ice bath for 20 minutes, filtered and washed well with cold water. After air-drying, the precipitate was suspended in cold ether, filtered and washed with cold ether to give 250 mg (30% theoretical) of crystalline mazindol shown by comparison to be the same product as obtained in Example 1.

Example 4 Preparation of Mazindol from Dimethylamino Lactam — Formula Ila: R^CHj,· R2=R3=CH3; X=C1 + Using Dimethoxycarbonium Fluoroborate ((CH^O)^Cll BF^Dimethoxycarbonium fluoroborate (5 g:31 mM) prepared in situ according to R.F. Borch, J. Org Chem., 34, 627 (1969) was suspended in 10 ml of methylene chloride under an atmosphere of nitrogen and 3 g (10 mM) of said dimethylamino lactam added thereto. The mixture was stirred at room temperature for 18 hours; the resulting yellow solution was cooled to 0° and 6.3 g (105 mM) of ethylene diamine was added over 15 minutes. This mixture was refluxed for 5 hours, recooled to 0°; 20 ml of 4M aqueous hydrochloric acid was added and the mixture refluxed at 40° for 5 hours. After cooling the mixture was partitioned and the organic fraction washed with 10 ml of 2N agueous hydrochloric acid. This aqueous wash liquor was combined with the previous aqueous layer and the mixture basified (pH — 9.0) with 10 ml of 50% sodium hydroxide. A precipitate resulted which was collected by filtration, washed with 20 ml of water and dried at 25°. The crude product was suspended in ethylacetate; filtered and washed with cold ethyl acetate to give 450 mg (16¾) of crystalline mazindol evaluated to be pure by comparison as previously. - 10 47210 Example 5 Preparation of Mazindol from Methoxy Lactam Formula lib: R =R =CH ; X=C1 13 A solution of 500 mg (17 mM) of the methoxy lactam dissolved in 5 ml of dry methylene chloride was added to a solution of 370 mg (1.9mM) of triethyloxonium fluoroborate in 2 ml of dry methylene chloride maintained under an atmosphere of nitrogen. The mixture was stirred at room temperature under nitrogen for 18 hours and then the resulting yellow solution (containing the corresponding methoxy imidate salt) was added over 15 minutes to a solution of 2 g (33mM) of ethylene diamine in 10 ml of methylene chloride kept at 0°.

This mixture was stirred at room temperature for 48 hours and then acidified strongly by the addition of 5% aqueous hydrochloric acid (50 ml). The mixture was refluxed at 40° for 5 hours and then partitioned. The organic layer was washed with 10 ml of 5% aqueous hydrochloric acid and the combined aqueous layers were basified (pH=8.0—8.5) by the addition of ml of 50% W/V sodium hydroxide. A precipitate resulted which was removed by filtration, washed with 20 ml of water and dried at 60°. The crude product was then suspended in cold ether, filtered and washed with cold ether to give 85 mg (17%) of cystalline mazindol, the product being characterized as previously. 4-7 210 Example 6 Preparation of 5-Phenyl-2,3 Dihydro-5-Hydroxy-5IIImidazo [2,la]isoindole from Dimethylamino Lactam— Formula XXa R.j=C2H5; R2=R3=CH3; X=H Triethyloxonium fluoroborate (12 g; 63 mM] (prepared as in Example 1) was dissolved in 7 ml of dry methylene chloride. A solution of 7.2 g (26 mM) of the dimethylamino-lactam in 10 ml of methylene chloride was added and the mixture stirred at reflux under nitrogen for 5 hours. After cooling to 0°, g (330 mM) of ethylene diamine was added over 15 minutes and the mixture stirred under N2 at room temperature for 18 hours. The mixture was cooled to 0° and made strongly acidic with 80 ml of 4N agueous hydrochloric acid. Following heating at reflux for 3 hours the mixture was cooled and then made basic by the addition of 10% aqueous sodium hydroxide. The voluminous white precipitate thus formed was filtered and washed twice with cold water. The crude product was dried at 60° and then recrystallized from methanol to give 4.4 g (68% theoretical) of the desired product in pure state, m.p. 200 -2020 (lit. 202—203°-P. Aeberli et al, J. Med.

Chem. 18, 177 (1975)).

The following examples illustrate the preparation of the novel lactams of formula IIi Example 7a Preparation of Pseudo Acid Chloride-Formula VI—X=H To a solution of 55.3 g (0.47 mM) of thionyl chloride in 100 ml of chloroform was added 100 g (0.44 mM) of o-benzoyl benzoic acid (V) and the mixture heated at reflux for 2 hours. Excess thionyl chloride and solvent was removed at reduced pressure to give 108 g (100% theoretical) of crude acid chloride VI. This material is used in subsequent reaction steps without further purification.

Example 7b Preparation of Hydroxy Lactam- Formula VII Rl=-C2H5; X=H A mixture of 110 ml of a 70% aqueous ethylamine (~1.7 mM of amine) and 100 ml of dioxan was prepared and cooled to 0°.

A solution of 24.5 g (0.10 mM) of crude acid chloride VI (from 7a) in 50 ml of chloroform was added thereto dropwise over 30 minutes. The resulting mixture was stirred at room temperature for 30 minutes and then all the solvents are removed at reduced pressure with warming. The crude solid remaining was recrystallized from benzene to give 19.9 g (79% theoretical) of white crystalline hydroxy-lactam VII m.p. 167—169° (lit. 168—170°, W. Graf, E. Girod, E. Schmid & K.G. Stoll, Helv.

Chim. Acta, 42 1085 (1959)).

Example 7c Preparation of Dimethylamino-Lactam —Formula 11a R =—C H ; R =R =CH X=H 1 2 5 2 3 3 To 15 ml of thionyl chloride was added portionwise over 20 minutes 10 g (39.5 mM) of hydroxy-lactam VII from (7b). The solution was allowed to stand at room temperature for 30 minutes and then the excess thionyl chloride was removed at reduced pressure. The resulting crude solid chloro-lactam VIII was dissolved in 20 ml of chloroform and that solution added to 30 ml of chloroform which had been saturated with dimethyl5 amine gas. After standing for 10 minutes, the mixture was washed with water and the organic layer dried over sodium sulfate. Removal of the solvent at reduced pressure yielded crude crystalline material which was suspended in hexane and then filtered to give 7.8 g (70% theoretical) of white crystalline dimethylamino-lactam 11a, m.p. 116—117°.

Example 8a-b Preparation of Pseudo Acid Chloride—Formula VI X=C1 and its Conversion to the Corresponding HydroxyLactam of Formula VII—R^=CH3; X—Cl To a suspension of 100 g (0.38 mole) of 2-(p-chlorobenzoyl) benzoic acid (v) and 2 g of dimethyl formamide in 250 ml of methylene chloride was added over a period of 15 minutes 51.2 g (0.43 mole) of thionyl chloride. The mixture was heated carefully to reflux and stirred at reflux for 3 hours resulting in the solution of the intermediate acid chloride VI. This solution was cooled to room temperature and added over 20 minutes at 0° to 100 g of a 40% aqueous solution of methylamine (1.29 mole of amine). The mixture was stirred at room temperature for 1 hour, recooled at Οθ and then made acidic with 6N aqueous hydrochloric acid (150 ml). Most of the methylene chloride was evaporated whereupon the product crystallized out. The crystals so obtained were filtered, washed with cold water and dried at 60° to give 102 g (97% theoretical) of the hydroxylactam VII, m.p. 190—194° (lit. 196—199.5°. W. Graf, E. Girod, E. Schmid & W.G. Stoll, Helv. Chim. Acta, 42, 1085 (1959)).

Example 8c(i) Preparation of Dimethylamino-Lactam of Formula Ila R =CHg; R2=R3=CH3; X=C1 To a suspension of 46 g (0.17 mole) of hydroxy-lactam VII (from 8b) in 140 ml of methylene chloride at 0° was added over 20 minutes, 24 g (0.20 mole) of thionyl chloride. Towards the end of the addition, a solution was obtained which was warmed to 25°, stirred for 1 hour and then recooled to 10°. To this solution (of chloro-lactam VIII) a stream of gaseous dimethylamine was introduced over a period of 15—20 minutes. The resulting mixture was washed twice with 50 ml portions of water and the organic layer was dried with sodium sulfate. The solvent and excess amine were removed at reduced pressure to yield a crude oily product. Trituration with cyclohexane gave 45 g (89%) of excellent crystalline dimethylamino lactam II, m.p. Ill—112°.

Example 8c(ii) Preparation of Pyrrolidinyl-Lactam of Formula Ila Rg=CH3; Rg with R3=—(CH.,)^; X=C1 To 10 ml of thionyl chloride was added portionwise 2 g (7.3 mole) of solid hydroxy-lactam VII (from 8b) and the mixture allowed to stand for 10 minutes at room temperature. Excess thionyl chloride was then removed at reduced pressure to yield crude solid chloro-lactam VIII which was dissolved in 10 ml of chloroform and 1.3 g (18 mole) of pyrrolidine in 5 ml of chloroform added. The resulting mixture was stirred at room temperature for 10 minutes and then washed with 10 ml of water. The organic layer was dried over sodium sulfate and the solvent was removed at reduced pressure to yield 2.2 g (92% theoretical) of the pyrrolidinyl lactam as an oil.

This material was used for the preparation of mazindol without further purification.

Example 8c(iii) Preparation of Piperidinyl-Lactam of Formula Ila R-^CHg,- Rg with R3=—(CHg)5; X=C1 To 6 ml of thionyl chloride was carefully added 1.0 g (3.7 mole) of solid hydroxy-lactam VII (from 8b). The mixture was maintained at room temperature for one hour and then excess thionyl chloride removed at reduced pressure to give crude solid chloro-lactam VIII which was dissolved in 5 ml of methylene chloride and 1.0 g (12 mole) of piperidine added thereto. After standing for 10 minutes at room temperature, the mixture was washed with 5 ml of water and the organic fraction dried over sodium .sulfate. Removal of the solvent at reduced pressure gave 1.2 g (96% theoretical) of oily piperidinyl lactam II. This material was used directly in the preparation of mazindol without further purification.

Example 9 Preparation of Methoxy Lactam —Formula lib R1=R4=CH3; X=C1 2’ 10 g (36.5 mM) of solid hydroxy lactam formula VII (from 8b) was added portionwise over 15 minutes with external cooling to 25 g (210 mM) of thionyl chloride. After completion of the addition the' mixture was stirred for a further 20 minutes at room temperature. The excess thionyl chloride 4721ο was removed at reduced pressure to give crude solid chlorolactam (Formula VIII—R3=CH3; X=C1). To the solid mass was carefully added 50 ml of methanol and the resulting solution was stirred at room temperature for one hour. The excess methanol was removed at reduced pressure and the residue was triturated with chloroform to yield 9.6 g (91% theoretical based on the hydroxy lactam VII) of crystalline methoxy lactam lib, m.p. 83—85° (m.p. 83—85° W. Graf, E. Girod, E. Schmid & W.G. Stoll, Helv. Chim. Acta 42 1085 (1959)). This material was used in the preparation of mazindol (refer Example 5) without further purification.

Throughout this text the term lower refers to organic moieties containing at most 6, and preferably at most 3, carbon atoms.

The present invention provides a process which utilizes readily available materials and avoids the use of an expensive and hazardous reducing agent. Moreover, the process of the present invention generally provides product yields which compare very favourably with those obtained in the prior art processes.

Claims (24)

CLAIMS:

1. Process for the preparation of imidazo [2,1-a] isoindoles of the general formula I, H0wherein X represents hydrogen, halogen, or lower alkoxy; comprising reacting a compound of formula II: Y -Ri II X wherein is lower alkyl; X is as defined above, and Y is NR 2 R 3 or — 0 — R^ , wherein R 2 , R 3 and R^ are individually lower alkyl, or R 2 and R 3 together represent pyrrolidinyl or piperidinyl with an alkylating agent selected from the group consisting of oxonium salts of the formula (R) 3 0 + Z“ and carbonium salts, of the formula 18 47210 O—R / HC' 7 \ O-R in which formulae R is methyl or ethyl; and Z~ is the fluoroborate, hexachloroantimonate or hexafluorophosphate ion to form a corresponding salt of formula III III reacting said salt with ethylene diamine to form an intermediate represented by formula IV: and hydrolysing, in the presence of an acid, said compound of formula XV to form the desired compound of formula I.

2. The process as claimed in claim 1 in which the compound of formula II is alkylated under an inert gas atmosphere.

3. The process as claimed in claim 1 or 2 in which the compound of formula III is reacted with ethylene diamine· under an inert gas atmosphere.

4. The process as claimed in claim 2 or 3 in which said inert gas atmosphere comprises nitrogen.

5. The process as claimed in any preceding claim in which X is fluorine, chlorine or bromine.

6. The process as claimed in claim 5 in which X is chlorine.

7. The process as claimed in any preceding claim in which the alkylation of the compound of formula II and/or the reaction of a compound of formula III with ethylene diamine is effected in the presence of an inert organic solvent.

8. The process as claimed in claim 7 wherein the organic solvent is methylene chloride.

9. The process as claimed in claim 8 wherein each or both the said reactions are effected at the reflux temperature of the methylene chloride.

10. The process as claimed in any preceding claim in which the alkylating agent is triethyloxonium fluoroborate. 20 47210

11. The process as claimed in any of claims 1 to 9 wherein the alkylating agent is dimethoxycarbonium fluoroborate.

12. The process as claimed in any preceding claim in which the starting compound of formula II has been prepared by treating a compound of formula VIII: VIII in which is lower alkyl; and X is hydrogen, halogen or lower alkoxy; with: 10 (a) an amine of formula HNR 2 R 3 in which R 2 and are individually lower alkyl or together represent pyrrolidinyl or piperidinyl; to form an amino lactam compound of formula Ila; or (b) an alcohol of formula R^—OH wherein is lower alky; whereby an alkoxy lactam of formula lib is obtained.

13. 15 13. The process according to claim 12 wherein the compound of formula 11 is prepared by reacting a compound of formula VIII VIII 4'< s> in which R^ is lower alkyl; and X is hydrogen, halogen or lower alkoxy with an amine of formula hnr 2 r 3 in which R 2 and R 3 are as defined in claim 12. 5 14. The process according to claim 13 wherein the compound of formula VIII is prepared by treating a compound of formula VII: SOCl 2 in which R^ is lower alkyl with thionyl chloride. 10 15. The process as claimed in claim 14 wherein the compound of formula VII is prepared by reacting a compound of formula VI: X in which X is hydrogen, halogen or lower alkoxy; with an amine 15 of formula HjNR^ in-which R^ is lower alkyl. 22 47210

14. 16. Process for the production of a compound of formula comprising reacting a compound of formula -N-R, II Cl 5 wherein R^ is lower alkyl; and Y is — NR^R^, wherein and R^ are individually lower alky or together represent pyrrolidiny1 or piperidinyl with an alkylating agent selected from the group consisting of oxonium salts of the formula (R) 3 0 + Z“ 1C and carbonium salts of the formula 0--R HC O-R in which formulae R is methyl or ethyl; and Z - is the fluoroborate, hexachloroantimonate or hexafluorophosphate ion; to form a corresponding salt of formula III reacting said salt with ethylene diamine to form an intermediate represented by formula IV: and hydrolysing said compound of formula IV to form the 10 desired compound of formula I.

15. 17. The process as claimed in claim 16 in which the compound of formula II is alkylated under an inert gas atmosphere.

16. 18. The process as claimed in claim 16 or 17 in which 15 the compound of formula III is reacted with ethylene diamine under an inert gas atmosphere.

17. 19. The process as claimed in claim 17 or 18 in which said inert gas atmosphere comprises nitrogen.

18. 20. The process as claimed in any preceding claim 16 to 19 in which the alkylation of the compound of formula II and/or the reaction of a compound of formula III with ethylene diamine is effected in the presence of an inert organic solvent.

19. 21. The process as claimed in claim 20 wherein the organic solvent is methylene chloride and each or both the said steps are effected at temperatures up to the reflux temperature of the methylene chloride.

20. 22. The process as claimed in any preceding claim 16 to 21 in which the alkylating agent is triethyloxonium fluoroborate or dimethoxycarbonium fluoroborate.

21. 23. The process as claimed in claim 1 substantially as hereinbefore described with reference to any of the foregoing Examples 1 to 6.

22. 24. Compounds of the formula I as defined in claim 1, whenever made by a process as claimed in any of claims ] to 15 and 23.

23. 25. The process according to claim 16 substantially as hereinbefore described with reference to any of the foregoing Examples 1 to 5.

24. 26. The compound 5 - (p - chlorophenyl)- 2,3 - dihydro 5 - hydroxy - 5H - imidazo 12,1-a]isoindole whenever prepared by the process of claims 16 to 22 and 25.