CA1105028A

CA1105028A - Production of heterocyclic benzamide compounds

Info

Publication number: CA1105028A
Application number: CA307,922A
Authority: CA
Inventors: Robert A. Dickinson
Original assignee: Canada Packers Inc
Current assignee: Maple Leaf Foods Inc
Priority date: 1977-07-22
Filing date: 1978-07-21
Publication date: 1981-07-14
Also published as: DE2831773A1; AR220143A1; BE869194A; CH642370A5; IE47210B1; IE781477L; GB1601701A; JPS5424894A

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention relates to a novel process for the preparation of certain known imidazo [2,1-a]
isoindoles of the general formula I:

Description

$~

BACKGR~UND F ~Ny~NTION

(a) Field of Inventi`on -The present invention reIates generally to a novel process for making certain known biologically active hetero-cyclic 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:

~

H0 ~ N
I ..~...I

~ .
X

wherein X repr~sents hydrogen, halogen in particular fluorine, chlorine and bromine, or lower alkoxy.

(b) _escription of Prlor Art Imidazo [2,1-a] isoindoles of the general formula I

and processes for their production are generally described, for example, in U.K. specifications Nos. 1,225,411, 1,225,412 and 1,225,~13.

In these specifications such imidazo ~2,1-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-(p-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo [2,1-a] isoindole commonly referred to as mazindol .

The prior art discla~se~ ~eyeral processe$ ~or obtain-ing 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 ~ollowed by a very delicate oxydation. The process steps, and especially the latter, are very time consuming. Although the specifications teach that the o~ydation 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 functi~n. 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 rea~ent 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 re~er 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 tJ. Med. Chem. 18/ 177, (1975)) indicates that a yield of 65~ is possible for the oxydation step, the presenL Applicant did not obtain a yield of even half that amount using the same process.

- - -~

An object o~ the p.resent inYention is to ~rovide an improved process fo~ producing the compounds of ~ormula I
which process avoids the significant disadvantages of the prior art processes.

Statement of Invention According to the present inven~ion there is provided a process for making imidazo [2,1~a] isoindoles of the general formula I:
~

H0 ~ -.

: X

; wherein X represents hydrogen, halogen in particular fluorine, chlorine and bromine or lower alkoxyl 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 XI~

~`~

5 ~ ~ ~
wherein Rl is lower alkyl;
X is as defined above; and Y is -NR2R3 or -O-R~ wherein R2l R3 and R~ are individually lower alkyl or R2 and R3 together repr0sent an alkylene chain of formula ~CH2)~n wherein _ is 4, 5 or 6 with an alkylating agent selected from the group consisting of oxonium salts of the formula (R)30~Z and carbonium salts o the formula: --.

~O-R
H~ Z
~O-R

wherein R is methyl or ethyl; and Z is the fluoroborate, hexachloroantimonate or hexafluorophosphate ion, to form a corresponding salt of formula _ _ ~ -R

~ ., ...... III

-- .
:
reacting under an inert ga~, for example, nitrogen, atmosphere `:

and/or in the presenae of a solvent, for example, methylene ~hloride.said 5alt wlth ethylene diamine to form an inter- ::
mediate represented by formula IV:
: - 5 -.

~ \N ~ ....................................... IV
X

.. . ~ ......

which compound lS hydrolysed in ~he presence of an acid to form the. desired compound Qf formula I. The above reactions in methylene c~loxide may be ef~ected at temperatures up to xeflux o the reaction medium.
The dialkylamino lactams of formula IIa ~elow used as starting materials in the process of the present invention are novel compounds and constitute a furt~er aspect of the present invention. They and the alXo~y lactams of formula IIb may be convenientIy obtained from the corresponding benzoyl benzoic :acid:derivatives, for example, as follows:

~COO~O ~ ,o ~0 ~ ~ ~ ~ Cl ~ O ~ HO ~ N -Rl ~J

~ V VI VII

~ 6 - :

'~ :

~o ~ ~o R23~ HNR~2R3 Cl ~N-Rl R40 ~N~R
R~.-OH

X X X

IIa VIII IIb 1 0 . , . ,, ,.,, _ ,_ _ " . .... . ... . --wherein R~, ~2, R3, R4 and X are as defined above.
The benzoyl benzoic acid derivatives o~ formula V

are readily available (re~er for example to W. Graf, E. Girod, E.s~Lia and W.G. Stoll, Helv. Chim. Acta, 42, 1085 (1959)).

As an example, 2-(4'~chlorobenzoyl~ben20ic acid requlred as starting material in the production o mazindol is readily produced by the reaction o~ chloroben2ene with phthalic anhydride .
The present invention will be urther described : with reference to the followi~g specific examples but is not to be considered as lLmited t~ereto.
Ex~ es 1._- 6 The~e examples illus~rate t.he prepara~ion o~ ~peciric compounds of fonmula I utilizing the no~el compounds or formula II. Examples 1- 5 illustrate .he ~roduction of : the preferred compound mazindQl~
Exam~le 1 Preparation of L~az ndol 'r~m ii=e~ m~ ctam - Formula IIa:

:~: : 30 Rl = CX3; R2 - R3 = C~3; X - Cl ~ Crys~alline dim2thylamino lactam II~(60 g; 0.20 mole) .
~ 7 was added to a solution of 48 g (O.25 mole) of triethyloxonium fluoroborate (the triethyloxonium fluoroborate was prepared in situ - ref. ~. ~eerwein, Org. Synthesis, Coll. Vol. V, 1080 (1973)) in 80 ml of dry methylene chloride. The mixture was 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.
~his mixture was refl~xed 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 distilla-tion, and then the mixture was basified (pH 8.0 - 8.5) with 45 ml of 50% W/V sodium hydroxide. The voluminous white precipltate which ronmed was ~iltered and washed with two 100 ml portions of water. After drying at 25~ 64 g of crude product was obtai.ned. Recrystallization from methanol~
.. . . .. _ .. .......... . .. . ... . .
meth~lene chloride ~ ollowed b~ suspension at re~lux in the same solvent syste~ yielded 35.3 g (62% theoretical ~rom dimethylamino lac~am IIa) o~ pure mazindol m.p. 201-202 with a setting o 6.5 in the Thompson-Hoover capillary melting point apparatus ~lit. 201 202~ und~r similar conditions ref.
P. Aeberli et al, J. Med. Chem. 18 p. 177 (1975)).

Analysls: %C %H ~N ~Cl ~0 Calculated 67.49 4.60 9.8~ L2~45S.62 Found 67.25 a.69 3.74 12.42 5.62 Example_2 Pre~ration or Mazindol from Pyrrolidinyl Lactam - Fo mula IIa:

The pyrrolldi~yl lact~ (2.0 g; 6.1 mM) dissolved in dry methylene chloride (3 mL) was added to triethyloxonium : rluoroborate (prepared as in Example l) (2~4 g; 13 mM) in m thylene chloride (3 ml) and the mixture refluxed und~r nitrogen fox S hours. After cooling to 0, ethylene diamine (3.6 g;
60 mM) was added and this mi~ure refluxed under nitrogen for S hours, and then stirred for 1~ hours at 25. Aqueous hydro-chloric acid was added until the solution was strongly acidic (10 ml of 4NHCl) and the resulting mixture refluxed for 3 hours.
Atex cooling, aqueous sodium hydroxide was added until the p~
was 7.5-8.5 (-10 ml 20% NaOH) and a large amount o white precipitate was observed. The reaction mixture was stirred at 0 for 30 minutes, filtered and the Eiltr~te washed with cold water. The so-obtained crude mazindol was dried at 60 for 18 hours and then recrystallized rrom methanol. to give _ _ . , . .. _. . . . . .,. ._ _ ._ . .
0.8 g (46% theoretical) of ~ure mazinc.ol characterized a~
in Example 1.
Example 3 Prepa _tion of Mazindol ~ro~ Piperidin~ll Lactam_- Formula IIa:
R~ - CH~; R2 with_R3 = -(CH2),; _ X - Cl A solution of 1.0 g (2.9 mM) or said lactam dissolved in 5 mL dry methylene chloride was added to 2.~ g (13 mM) of txi~thyloxonium 1uoroborate (prepared as in Example 1) dissolved in 2 ml of dry methylene chloride. The mix-ture was refluxed under nitrogen for S hours and ~llen cooled in an ice bath. Ethylene diamine (3 g; 50 mM) was added dropwise ovex 10 minutes and the mixture reeluxed under nitrogen for 18 houxs. After cooling the mixture to 25~ a~ueous hydro-~; chloric acid (lS ml of 10% HCl) was added and the acidic mixture (pH~l) refluxed for 4 hours. Upon basification of the ~esulting~solution with aqueous sodium hydroxide (lS ml of 10~ NaO~)~a volumlnous white precipitate separates. The whole mlxture~was stirred in an ice bat~ for 20 minutes, ~ 30 filter2d and washed well with oold water. A~ter air-dr~ing, .: - g _ 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 l).
E ample 4 Preparation of Mazindol from D~methylamino Lactam - Formula IIa:
Rl - C~3, R2 - R3 = CH3; X - Cl Using Dimethoxycarbonium ~luoroborate ((CH30)2~ BF~) Dimethoxycarbonium fluoroborate (5 g : 31 mM) prepared in situ according to R.F. Borch, J. Or~ Chem., 34, 627 (1969) was suspended in 10 ml of methylene chloride under an atm~sphere of nitroqen and 3 g (10 m~) o said dlmethylamino lactam added thereto. The mixture was stirred at room temperatura 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 4N aqueous hydrochloric acid was added and the mixture refluxed at 40 for 5 hours.
After cooling, the mixturQ was partitioned and the organic ~raction washed wi~h ].3 ~l of 2N aqueous hydrochloric acid.
~his aqueous wash liquox was combined with the pre~ious aque~us layer and the mixture basi~ied (pH~9.0) with 10 ml of 50% sodium hydroxide. A precipitate resulted which was collected by fiItration, washed with 20 ml of water and dried at 25. ~he crude product was suspended in ethyl acetate; filtered and washed with cold ethyl acetate to gi~e 450 mg (1~6%)~ of crystalline mazlndol evaluated to be : pure by comparison as previously.

3~

2~

Example S
Pre arat~on of Mazindol from MethoxY Lactam - Formula IIb:
p ~
R = Rl = CH3; X = Cl , A solution of 500 mg (1.7 mM) of the methoxy lactam dissolved ln 5 ml of dry methylene chloride was added to a solution or 370 mg ~l.9 ~M) of triethyloxonium fluoro-borate 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 svlution (containing the corresponding mekhoxy Lmidate salt) was added over 15 minutes to a solution o 2 g (33 mM) of ethylene diamine in 10 ml of methylene chloride kept at 0. This mixture was stirred at room temperature ~or 48 hours and then acidified strongly by the addition of 5~ aqueous hydrochloric acid (50 ml).
The mixture was re~luxed at 40~ for 5 hours and then partitioned. The orqanic 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 add~tion or 5 ml of ~50% W/V sodium hydroxlde. A precipitate resulted which : was remo~ved~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 e~her to give 85 mg (17%) of crystalli.rle mazindol, the ~roduct being charac~er-Lzed as previausly.
Example 6 :~
Preparation of S-Phenyl~2,3-Dihydro~ xdroxy-5H-Imida~o : ~2,1a]isoindole rom Dimethylam~no Lactam_- Formula IIa 30:~ Tri~ethyloxonium ~rluoroborate (12 g; 63 ~l) (prepared;as in~Example l) was dissolved in 7 ml of dry : ~:

methylene chloride. A solution of 7.2 g (26 m~) of the dimethylamino-lactam in 10 ml of methylene chloride was added and the mixture stirred at reflux under nitrogen for S hours. Ater cooling to 0, 20 g (330 mM) of ethylene diamine was added over 15 minutes a~d 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 4~ aqueous hydrochloric acld. FO11QWing heating at refl~x for 3 hours the mixture was cooled and then made basic by the addition of 10~ aqueous sodium nydroxide.
Ths voluminous white precipitate thus formed was filtered and washed twice with cold water. The crude product was dried at 60 and then recrystallized from me~hanol to give 4.4 g (68% theoretical) of the desired product in pure state, m.p. 200-202 (li~. 202-203 - P. ~e~erli et al, Med. Chem. 18, 177 (1975)1.
The following examples illustrate the production of the pre~erred compound mazindol using as alkylating agent triethyloxonlum hexachloroantimonate and triethyloxonium hexa1uorophosphate, respec~ively. The experiments wexe eL~ected purely to demonstrate the use of alternative alkylating agents and nc a~tempts were made ~o optimize reaction conditions, yield, etc.
Example 7 PreParation ~of ~azindol from Dimethlyamino Lactam- _ Formula IIa: ~ RI=CH3; ~2=R3=CH~,_X=Cl - Using Trlethyloxoni m ~exachLoroantlmona~e ((C2 1, ~O_OC__ Crystalline di~et~ylamino lactam IIa (6.4 g; 21 . 4mM) ~ 12 -:

was dissolved in 12 ml of dry methylene chloride and added at room ~emperature to a suspension o~ 11.9 g (27.2mM) of triethyloxoniumhexachloroantimonate in 12 ml of dry methylene chlorlde.
The mixture was stirred at reflux under nitrogen for 3 hours, cooled at 5 and 3.3 g t55mM) of ethylene diamine added ovex 5 minutes. The mixture was then refluxed under nitrogen for 5 hours, cooled to 5 and made strongly acidic by the addition of 20 ml of 4N aqueous hydrochloric acid. After a 2 hour reflux period the mixture was cooled and basified with aqueous sodium hydroxide (13 ml of 25% NaOH). The resulting light yellow solid was collected by filtration from the two-phase system after a 30 minute cooling period at 0. This crude mazinol was dried at 60 and then recrystallized from methanol-methylene chloride (1:1) to yield 0.7 g (11.5~ theoretical) of white crystalline mazindol shown by comparison to be the same product as obtained in Example 1.
Example 8 -Preparation of Mazindol from Dimethylamino Lactam-Formula IIa: R =CF~3; R2-R3CH3;X-Cl - Using Triethylox-onium Hexafluorophosphate (tC2H5)3O~F6).

A solution of 9.3 g (31 mM) of dimethylamino lactam IIa in 12 ml of dry methylene chloride was added at room temperature to a solution of 9.8 g (40mM) of triethyloxonium hexafluoro-phosphate. The mixture was heated at re1ux under nitrogen for 5 hours and then at room temperature for an additional 16 hours. After cooling to 0, 4.8 g (80mM~ of ethylene diamine was added over a lS minute period. The mixtu~e was then refluxed under nitrogen for 5 hours, cooled to 5 and made ~cidic with 34 ml of 4N aqueous hydrochloric acid. After ~nother reflux period of 15 minu~es the mixture was stlrred at room temperature for 16 hours. Upcn basification with aqueous sodium hydroxide (25 ml of 25~ NaOX) a vol~minous white precipitate separated. After cooling to 5 ror 30 minutes the white solid was collected by filtration. The crude product was dried at 60 and the~ recrystalli~ed from methanol-methylene chloride (1:1) to give 2.6 g (~9%
(theoretical)of crystalline mazindol shown by comparison to be the same produc~ as obtained in Example 1.
~ The following examples illustrate the prepa~ation of the novel lactams of formula II:
E
Preparaticn o Pseudo Acid Chloride -Formula VI - ~ - H
To a solutlon of 55.3 g (0.47 mM) of thionyl chloride in 100 ml of chloroform was added ln0 g (0.~4 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% theoreti-cal) of crude acid chloride VT. This material i~s used in subsequent reaction steps without further purification.
Ex~mple 9b pra aration cf ~Ydrox Lactam - ~ormula VII - Rl = -C7'~s;
:~ = H

A mixture o~ 110 ml of a 70~ aqueouC 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 9a) in 50 mL or chloroform ~as added thexeto dropwise over 30 minutes. The resulting mixture was stirred at room temperature for 30 minutes a~d then all the solvents are removed at reduced pressure with warming. The crude solid remalning was recrystalli~ed from benzene to give 19.9 g (79~ theoretical) of white crystalline hydroxy-lactam VII
lC m.p~ 167-169 ~lit. 168-170~, W. Graf, ~ Girod, E. Schmid &
... . ..
W.G. St~ll, Y-I. 5~ 38L:~ 42, lOS5 (195Q~).
: Exam~ 9c Preparation of ~imethylamino-Lac~am - Formula I~ - Rl - -C2H5, R~ = R3 = CH3 X = H
To 15 ml of thionyl chloride was added ~ortionwise over 2:0 minutes lO g (39.5 m~) of hydro~y-lactam VII from (gb)~. ~The solutio~n~waa allowed to stand at room temperature : ~ for 30~minutes aIld the~ the excess thiony~ chLoride ~as removed at reduced:pressure. ~he resulting crude solid chloro lactam VIII was dissolved in 20 ml o~ chloroform and that solution added ~o 30 ml of chloro~orm which had been saturated with , :
~ :~ dlmethy~lamine gas. :A~ter standing for 10 minutes, the mix~ure '~ was washed with water and the organic layer dried over sodium sulfate. ~emoval of ~he solvent at red~ced pressuxe yielded ~: :
crude crystalline material which was suspended in hexane and:then~flltered: to~give 7.8 g (70% ~heoretlcal) of white crystalLlne:dimethy~lamino-~lactam IIa, m.p. 116-117.

30~
} ~ -~ ~ :
:~ ~

, ~5`~Z~

Example lOa b Preparation of Pseudo Acid _C orlde - Formula VI - X - Cl and Lts Converslon to ~he Corresponding Hy~oxY Lactam of To a suspension of 100 g (0~38 mole) or 2-(p-chloro benzoyl)benzoic acid (V) and 2 g o~ dimethyl formamide in 250 ml of methylene chloride was added over a period of li minutes 51.2 g (0.43 mole) of thionyl chloride. The mixture was heated carefully to re~lux and stirred at reflux for 3 hours resulting in the solution o~ the inter-mediate acid chloride VI. This solution was cooled to room temperature and added over 20 minutes at 0 to 100 g of a 40~ aqueous ~olution o methylamine (1.29 mole o~ amine).
The mi~ture was stirred at room temperatura for 1 hour, recooled to 0 and the~ made acidic w~ith 6N aqueous hydro-chloric acid (1~0 ml). ~ost of the methylene chloride was evaporated whereupon the product crystallized out. The crystals 50 obtained were flltered, washed with cold water 2C and dried at 60 to give 102 g (97% theoretical) or t~e hydroxy lactam VII, m.p. 19C-194 (lit. 196 199.5, W. Graf, E. Girod, E. Schmid & W.G. Stoll, Helv. Chim. Acta, 42, 1085 (1959)) ~i) Pre~ ation of Dlmethylamino-Lactam of Formula IIa-R~ = CH3; R2 = R3 = CH3; X = Cl To a suspension of 46 g (0.17 mole~ of hydroxy-lactam VII (fromlob) in 140 ml of methylene chloride at 0 was added over 20 minutes, 24 g (0.20 mole) of thionyl chloride.
Towards the ~nd of the addition, a solution was obtained whlch was t~armed to 25, stirred for 1 hour and then re-; cooled to 10. ~o this solution (of chloro-lactam VIII) a stream of gasecus dimethylamine ~as introduced ovex a _ 16 -%~`

period of 15-20 minutes. The resulting mixtuxe 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. 111-112.

~3~ 'L:) Preparatlon of P~ olidinyl-Lactam of Formula IIa - Rl - C~3;
R2 with R3 = -(C~2) 4; X = Cl To 10 ml of thionyl chLoride was added portionwise 2 g (7.3 mole) of solid hydroxy-lactam VII (fromlob) and the mlxture allowed to stand ~or 10 minutes at room temperaturs.
Excess thion~yl chloride was then removed a-t 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 ternperature for 10 minutes and then washed with 10 ml of water. The organic layer was dried ov~r 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.
_3~ 2 ~
E~ tion of~P pe ldi~yl-Lactam of For~ula IIa - RI - CH3;
Rz w th ~3 = -(CH~)s; X = Cl To 6 ml of thionyl chloride was carerully added 1.0 g (3.7 mole) of solid hydroxy-lactam 'tII (rromlOb). The ; ~ 30 mix~ure was maintained at room ~emperature for one hour and then ~ 17 ~

the excess thionyl chloride removed at reduc~d 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 t room temperature, the mixture was washed with 5 ml of water and the organic fraction dried over sodium sulfate. ~emoval of the solvent at reduced pressure gave 1.2 g (96~ theoretical) of oily piperidinyl lactam TI. This material was used directly in the preparation o~ mazi~doL without further purification.

Exam~le 11 ..
Pre aration of Methoxv Lactam - Formula IIb P _ .
Rl- R4 = C~3;_ X - Cl 10 G (36.5 mM) or solid hydroxy lactam formula VII
(~rom la~ was added portionwlse over 15 minutes with ~sxternal cooling to 25 g (210 mM) of thionyl chloride~ Ater completion of the addition the mixture was stirred for a ~ further 20 minutes at room temperature~ The e~cess thionyl ; chloride was removed at reduced pressure to ~ive crude solid chloro-lactam (Formula VIII - Rl = CH3; ~ - Cl).

To the ~olid mass was carsfully added 50 ml of methanol and the resuLting solu~ion was stirred at room temperature ~or 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 ~II) or crystalline methoxy lactam IIb, m.p. 83-85 (m.p. 83-85~ -W. Gra~, E. Girod, E. Schmid & W~5. Stoll, Helv. Chim. Acta 42 1085 (195~)). This material was used in the preparation - of ma2indol (refer Example s) without further purification.
Throughout this text the term ''lower" refers to organic moi~stLes containins at most 6, and preferably at ~5~
most 3, carbon atoms.

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

.

'

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of imidazo [2,1-a]
isoindoles of the general formula I:

......I

wherein X represents hydrogen, halogen, or lower alkoxy;
comprising reacting a compound of formula II:

.....II

wherein R1 is lower alkyl;
X is as defined above, and Y is NR2R3 ox -O-R4 , wherein R2, R3 and R4 are individually lower alkyl or R2 and R3 together represent an alkylene chain of formula -(CH2)n - wherein n is 4, 5 or 6.

with an alkylating agent selected from the group consisting of oxonium salts of the formula (R)3O+Z-and carbonium salts of the formula Z-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:

.....IV
and hydrolysing said compound of formula IV
to form the desired compound of formula I.

2. The process according to claim 1 wherein the compound of formula II is alkylated under an inert gas atmosphere.

3. The process according to claim 1 wherein the compound of formula III is reacted with ethylene diamine under an inert gas atmosphere.

4. The process according to claim 2 wherein the compound of formula III is reacted with ethylene diamine under an inert gas atmosphere.

5. The process according to claim 1 wherein said inert gas atmosphere comprises nitrogen.

6. The process according to claim 2, 3 or 4 wherein said inert gas atmosphere comprises nitrogen.

7. The process according to claim 1, 2 or 3 wherein X is fluorine, chlorine or bromine.

8. The process according to claim 4 or 5 wherein X
is fluorine, chlorine or bromine.

9. The process according to claim 1, 2 or 3 wherein X is chlorine.

10. The process according to claim 4 or 5 wherein X
is chlorine.

11. The process according to claim 1, 2 or 3 wherein the alkylation of the compound of formula II is effected in the presence of an inert organic solvent.

12. The process according to claim 1, 2 or 3 wherein the alkylation of the compound of formula II is effected in the presence of methylene chloride.

13. The process according to claim 1, 2 or 3 wherein the alkylation of the compound of formula II is effected in the presense of methylene chloride and at a temperature up to the reflux temperature thereof.

14. The process according to claim 4 or 5 wherein the alkylation of the compound of formula II is effected in the presence of methylene chloride and at a temperature up to the reflux temperature thereof.

15. The process according to claim 4 or 5 wherein the alkylation of the compound of formula II is effected in the presence of methylene chloride.

16. The process according to claim 4 or 5 wherein the alkylation of the compound of formula II is effected in the presence of methylene chloride and at a temperature up to the reflux temperature thereof.

17. The process according to claim 1, 2 or 3 wherein the reaction of a compound of formula III with ethylene diamine is effected in the presence of an inert organic solvent.

18. The process according to claim 1, 2 or 3 wherein the reaction of a compound of formula III with ethylene diamine is effected in the presence of methylene chloride.

19. The process according to claim 1, 2 or 3 wherein the reaction of a compound of formula III with ethylene diamine is effected in the presence of methylene chloride and at a temperature up to the reflux temperature thereof.

20. The process according to claim 4 or 5 wherein the reaction of a compound of formula III with ethylene diamine is effected in the presence of an inert organic solvent.

21. The process according to claim 4 or 5 wherein the reaction of a compound of formula III with ethylene diamine is effected in the presence of methylene chloride.

22. The process according to claim 4 or 5 wherein the reaction of a compound of formula III with ethylene diamine is effected in the presence of methylene chloride and at a temperature up to the reflux temperature thereof.

23. The process according to claim 1, 2 or 3 wherein the alkylating agent is triethyloxonium fluoroborate or dimethoxycarbonium fluoroborate.

24. The process according to claim 4 or 5 wherein the alkylating agent is triethyloxonium fluoroborate or dimethoxycarbonium fluoroborate.

25. The process according to claim 1 wherein the starting compound of formula II has been prepared by reacting a compound of formula VIII:

.....VIII

in which R1 is lower alkyl; and X is hydrogen, halogen or lower alkoxy;
with:
(a) an amine of formula HNR2R3 in which R2 and R3 are individually lower alkyl together represent an alkylene chain of formula -(CH2)n - wherein n is 4, 5 or 6 to form an amino lactam compound of formula II; or (b) an alcohol of formula R4-OH
wherein R4 is lower alkyl;
whereby an alkoxy lactam of formula II is obtained.

26. The process according to claim 25 wherein the compound of formula II is prepared by reacting a compound of formula VIII:

....VIII

in which R1 is lower alkyl; and X is hydrogen, halogen or lower alkoxy with an amine of formula:

in which R2 and R3 are as defined above.

27. The process according to claim 26 wherein the compound of formula VIII is prepared by reacting a compound of formula VII:

....VII
SOCl2 in which R1 is alkyl with thionyl chloride.

28. The process as claimed in claim 27 wherein the compound of formula VII is prepared by reacting a compound of formula VI:

....VI

in which X is halogen or lower alkoxy, with an amine of formula H2NR1 in which R1 is lower alkyl.

29. A process for the preparation of a compound of formula Ib:

......Ib comprising reacting a compound of formula IIc:

.....IIc wherein R1 is lower alkyl; and Y is -NR2R3, wherein R2 and R3 are individually lower alkyl or together represent an alkylene chain of formula -(CH2)n - wherein n is 4, 5 or 6 with an alkylating agent selected from the group consisting of oxonium salts of the formula (R)3O+Z-and carbonium salts of the formula in which formulae R is methyl or ethyl; and Z- is the fluoroborate, hexachloroantimonate or hexafluorophosphate ion;

to form a corresponding salt of formula IIIa:

......IIIa reacting said salt with ethylene diamine to form an intermediate represented by formula IVa:

.....IVa and hydrolysing said compound of formula IVa to form the desired compound of formula I.

30. The process according to claim 29 wherein the compound of formula IIc is alkylated under an inert gas atmosphere.

31. The process according to claim 29 or 30 wherein the compound of formula IIIa is reacted with ethylene diamine under an inert gas atmosphere.

32. The process according to claim 29 or 30 wherein said inert gas atmosphere comprises nitrogen.

33. The process according to claim 29 or 30 wherein the alkylation of the compound of formula IIc is effected in the presence of an inert organic solvent.

34. The process according to claim 29 or 30 wherein the alkylation of the compound of formula IIc is effected in the presence of methylene chloride.

35. The process according to claim 29 or 30 wherein the alkylation of the compound of formula IIc is effected in the presence of methylene chloride and at a temperature up to the reflux temperature thereof.

36. The process according to claim 29 or 30 wherein the reaction of a compound of formula IIIa with ethylene diamine is effected in the presence of an inert organic solvent.

37. The process according to claim 29 or 30 wherein the reaction of a compound of formula IIIa with ethylene diamine is effected in the presence of methylene chloride.

38. The process according to claim 29 or 30 wherein the reaction of a compound of formula IIIa with ethylene diamine is effected in the presence of methylene chloride and at a temperature up to the reflux temperature thereof.

39. The process according to claim 29 or 30 wherein the alkylating agent is triethyloxonium fluoroborate or dimothoxycarbonium fluoroborate.

40. The process according to claim 1 for the prepara-tion of 5-phenyl-2,3-dihydro-5-hydroxy-5H-imidazo [2,1-a]
isoindole wherein 5-phenyl-5-dimethylamino-2-ethyl-1-isoindolinone is reacted with triethyloxonium fluoroborate, the so-obtained compound reacted with ethylene diamine and the resulting compound hydrolyzed with aqueous hydrochloric acid.

41. The process according to claim 29 for the prepara-tion of 5-(p-chlorophenyl)-2,3-dihydro-5 hydroxy-5H-imidazo [2,1-a] isoindole wherein 5-(p-chlorophenyl)-5-dimethylamino -2-methyl-1-isoindolinone is reacted with triethyloxonium fluoroborate, the so-obtained compound reacted with ethylene diamine and the resulting compound hydrolyzed with aqueous hydrochloric acid.