NO174346B - Process for Preparation of 5-aroyl-1,2-dihydro-3H-pyrrolo- (1,2- a) pyrrole-1-carboxylic acids and alkyl esters and salts thereof - Google Patents

Description

The invention relates to a new process for the production of 5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acids and alkyl esters and salts thereof.

5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acids, which are also called 5-aroyl-1,2-dihydro-3H-pyrrolizine-1 -carboxylic acids, and which have the formula I: 6 7

Ar^ lÅ 1 COOH

3 2

and the pharmacologically acceptable salts and esters thereof, are applicable as analgesic, anti-inflammatory and antipyretic agents for the treatment of humans and mammals.

They also act as relaxants for smooth muscles. Two examples of compounds currently under clinical investigation in humans are ketorolac, 5-benzoyl-l,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-l-carboxylic acid, (I, Ar = C6H5) and anirolac, 5-p-anisoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid,

(I, Ar = p-CH30-C6H5), both of which are described in US Patent No. 4,089,969. Other compounds, where the 5-aroyl substituent is substituted or unsubstituted benzoyl, furoyl, thenoyl or pyrroyl, and where the 6-position of the pyrrolo-pyrrole nucleus is optionally substituted with lower alkyl or halogen, and areas of use for these compounds, are described in a number of patent documents in the name of Syntex (U.S.A.) Inc., namely in US Patent Nos. 4,089,969, 4,087,539, 4,097,579, 4,140,698, 4,232,038, 4,344,943, 4,347,186, 4,458,081, 4,347,187 ,

4,454,326, 4,347,185, 4,505,927, 4,456,759, 4,353,829,

4,397,862, 4,457,941 and 4,454,151. In US Patent Nos. 4,511,724 and 4,536,512, in the name of Merck & Co., 5-(substituted pyrrole-2-oyl)-1, 2-dihydro-3H-pyrrolo-[1,2-a] is described respectively -pyrrole-1-carboxylic acid derivatives and 5-(1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrol-2-oyl)-1,2-dihydro-3H-pyrrolo-[1,2- a] - pyrrole-l-carboxylic acid derivatives, while in US patent no. 4,533,671, which is also in the name of Merck & Co., it is described

5-(1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrol-2-oyl)-2-pyrrolalkanoic acids and analogous compounds.

Many methods for the preparation of these pyrrolo-pyrroles are exemplified in the patent and chemical literature, and many of these make use of a common intermediate, 1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1 ,7-dicarboxylic acid, (II, R = H), or its dialkyl ester,

whose preparation from dimethyl-1,3-acetone-dicarboxylate, ethanolamine and haloacetaldehyde is described, e.g. in US Patent No. 4,089,969.

The reaction scheme set out in this patent document, namely:

includes reacting equimolar amounts of ethanolamine (III) and dimethyl-1,3-acetone dicarboxylate (IV) to form a solution of the hydroxyenamine (V), which is then, preferably in situ, treated in a suitable organic solvent (examples are given of aprotic solvents such as acetonitrile, dichloromethane, etc.) and under anhydrous conditions, with a 2-haloacetaldehyde at elevated temperatures to form N-(2-hydroxyethyl)-pyrrolene (VI). The compound (VI) is esterified with methanesulfonyl chloride to produce the mesylate (VII), which is optionally transferred to N-(2-iodoethyl)-pyrrole (VIII) by reaction with sodium iodide. One or the other of the compounds (VII) and (VIII) can be transferred to dimethyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylate (II, R = CH3 ) by treating with sodium hydride

in dimethylformamide. The dimethyl-1,2-dihydro-3H-pyrrolo-[1,2-a1-pyrrole-1,7-dicarboxylate thus obtained can then be selectively 7-decarboxylated and 5-aroylated according to methods such as those described in the above-mentioned patents and in US Patent No. 4,496,741, whereby a 5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid (I) is obtained. In a similar procedure, involving the reaction of ethanolamine, dimethyl-1,3-acetone dicarboxylate and a halomethylalkyl ketone, the hydroxyenamine (V) is bypassed, and the 4-alkyl analogue of (VI) is obtained directly. This compound can be transferred to the pyrrolo-pyrrole in the same way as above for the 4-unsubstituted compound.

A number of methods for the preparation of pyrroles are exemplified in the patent literature and the chemical literature. Methods for the preparation of 5-aroyl-N-R-pyrrole-2-acetic acid, where R is H, lower alkyl or benzyl, and analogous compounds are described in US patent documents no.

3,752,826, 3,865,840 and 3,952,012 (Carson). They involve - for the 4-alkyl substituted compounds, but not for the 4-unsubstituted compounds - reaction between a lower alkyl amine, a di-(lower alkyl)-1,3-acetone dicarboxylate and a chloromethyl lower alkyl ketone, "preferably in an aqueous medium", with subsequent pouring of the reaction mixture into ice-cold hydrochloric acid, whereby compounds of formula (IX) are obtained, where each of the substituents R, R' and R" is lower alkyl.

A similar method for the production of the 4-unsubstituted compounds (IX, R' = H), where chloroacetaldehyde is used, is described in US Patent No. 4,048,191.

In British patent application no. 2 034 304 A, in the name of Mallinckrodt, Inc., a method is described for the preparation of compounds of formula (IX), where R' can be hydrogen or alkyl, by either (a) forming a two- phase reaction medium of an aqueous solution of the alkylamine and an inert, water-immiscible organic solvent and adding the dicarboxylate and ketone (or aldehyde) substantially simultaneously, or (b) adding the dicarboxylate and ketone substantially simultaneously, with the ketone in excess, to an aqueous alkylamine. Preferably, the dicarboxylate and the ketone are added in excess to an alkylamine dispersion.

In a number of patents in the name of Ethyl Corporation, including US Patents 4,565,878, 4,565,879,

4,374,255, 4,388,468, 4,383,117, 4,455,433 and 4,333,878, other modifications of the Carson syntheses are described. US Patent No. 4,565,878 describes the addition of a water-immiscible co-solvent [a halogenated hydrocarbon with good solubility for both the di-(lower-alkyl)-1,3-acetone dicarboxylate and the product] to the mixture of chloromethyl lower alkyl ketone, dicarboxylate and aqueous lower alkyl amine. US Patent No. 4,565,789 mentions the use of an aromatic hydrocarbon as a co-solvent. US Patent No. 4,374,255 mentions the addition of "an amount of a lower alkanol which prevents the formation of solids" to the mixture of ketone, dicarboxylate and aqueous alkylamine. The reaction is usually carried out in the presence of a co-solvent, such as in US Patent No. 4,565,878 or 4,565,879. US Patent No. 4,388,468 describes a two-step process where (a) the ketone is added to a pre-mixed, cooled solution of the alkylamine and the dicarboxylate in a suitable solvent (e.g. aromatic hydrocarbons, chlorinated hydrocarbons, water or mixtures thereof) at a temperature below 60°C, after which (b) the reaction mixture is heated to 70-100° C. US Patent No. 4,383,117 describes the use of an anhydrous lower alkylamine instead of an aqueous solution, as well as the use of a non-aqueous single-phase reaction medium. US Patent No. 4,455,433 describes the addition of "a yield-enhancing amount of an acid with a dissociation constant of at least 1.3 x 10~<5> at 25°C" to a mixture of ketone, dicarboxylate and (preferably anhydrous) lower alkylamine, preferably in an organic solvent. In US patent document no; 4 333 878 describes the preparation of compounds of formula (IX) by reacting an enamine (X)

with a 2-carboxy-1-nitroalkane (XI, R<*> = lower alkyl, tolyl or benzyl). The enamine can be prepared by reacting a di-(lower alkyl)-1,3-acetone dicarboxylate with a lower alkylamine in "a suitable solvent, such as ethanol or methanol", with subsequent evaporation of the solvent and heating for to dehydrate the thus formed carbinolamine to the corresponding enamine.

US Patent No. 4,363,918 describes the preparation of compounds of formula IX where R is lower alkyl, R' is hydrogen or lower alkyl, and R" is H, by reacting 1,3-acetonedicarboxylic acid with CICH2COR and a lower alkylamine, preferably by slow addition of an aqueous solution of the lower alkylamine to an aqueous solution of the acid, with subsequent slow addition of the 1-chloro-2-alkanone, both additions preferably being made at a temperature below 20°C.

In European Patent Applications Nos. 92,487 and 105,664, in the name of Montedison S.p.A., the preparation of compounds of formula IX where R is CH3 and R" is H, and R' is CH3 (EP92487) or H (EP105664) is described by reaction of 1 ,3-acetone dicarboxylic acid or an alkali metal salt thereof with methylene amine and a halogen (ketone or aldehyde) in aqueous solution, preferably by adding the halogen ketone to an aqueous mixture of the methylamine and the dicarboxylic acid.

The known methods for the production of pyrrolo-pyrroles require large volumes of organic solvents, tend to lead to the formation of tars and are difficult to scale up to production quantities. A method for the production of certain pyrrolo-pyrroles has now been found which is carried out using aqueous solvents to a much greater extent than the previously known methods, and which can easily be used for production on a production scale.

The invention thus provides a method for the production of 5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acids with the general formula:

where Ar is substituted or unsubstituted phenyl, 2- or 3-furyl, 2- or 3-thienyl, or 2- or 3-pyrryl, which groups - if they are substituted - may have one or more lower alkyl, lower alkoxy or halogen groups in any available position on the ring, and pharmaceutically acceptable salts and alkyl esters of these compounds, where the alkyl group in the ester group has 1-12 carbon atoms, which method has the features in common with previously known methods that one

(a) esterifies a compound of the formula:

for the formation of a compound of the general formula XVIII:

where R is alkyl with 1-12 carbon atoms,

(b) decarboxylates the compound of formula (XVIII) to a compound of general formula (IX):

where R is as indicated above, and

(c) aroylates the compound of formula (IX) with an amide or morpholide to a compound of formula (I) or the corresponding alkyl ester where the alkyl group in the ester group has 1-12 carbon atoms, and that, when necessary, performing one or more of the following steps: (i) transferring a compound of formula (I) to a pharmaceutically acceptable salt, (ii) transferring a salt of a compound of formula (I ) to the corresponding free compound with formula

(IN),

(iii) esterification of a compound of formula (I) to an alkyl ester where the alkyl group in the ester group has 1-12 carbon atoms, (iv) transfer of an alkyl ester to the corresponding free compound of formula (I). These features are known, among other things, from Norwegian patent documents no. 147563 and 147564.

The new method is characteristic in that the compound with the formula (XII') is prepared by:

(1) a compound of the general formula XVI:

where R' is lower alkyl, and X is Br or Cl, is ring-closed with

a lithium-protected amine in an aprotic, polar solvent, preferably hexane and tetrahydrofuran, and the formed diester of formula (XII):

where R' is as indicated above, is saponified to the compound of formula (XII'),

or

(2) a compound of the general formula XVII:

where R' is lower alkyl, is reacted in aqueous solution with a 2-halogenactaldehyde, XCH2CHO, where X is halogen, and that the formed diester with the above formula (XII) is saponified to the compound of formula (XII').

Definitions

Unless otherwise stated, the following designations used in the description and claims have the following meanings: By "lower alkyl" is meant straight-chain, branched or cyclic, saturated hydrocarbon radicals with 1-6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, cyclopropylmethyl, pentyl, hexyl, cyclo-hexyl, etc. Preferred lower alkyl radicals are methyl,

ethyl and n-propyl, and a particularly preferred lower alkyl radical is methyl. If more than one alkyl radical is present in a given molecule, each of them, independently of the others, may be selected from "lower alkyl", unless otherwise stated.

By "lower alkoxide", "lower alkanol", "lower alkylamine", "lower alkyl ester" and similar terms are meant alkoxides, alkanols, alkylamines, alkyl esters, etc., where the alkyl radical or each alkyl radical is a "lower alkyl" radical, as above defined.

By "halogen", which is usually denoted by X, is meant chlorine, bromine or iodine. Preferred halogens are chlorine and bromine.

The term "aprotic polar solvent" includes organic solvents which may be either immiscible with water, such as e.g. halogenated hydrocarbons, e.g. methylene chloride, chloroform, etc., or miscible with water, such as e.g. tetrahydrofuran, dimethoxyethane, bis-(2-methoxyethyl)-ether (also known under the name diglyme), dimethylformamide, N-methylpyrrolidone, dimethylsulfoxyd, etc. The solvent can also contain smaller amounts of aprotic non-polar solvents, such as e.g. hydrocarbons, e.g. cyclohexane, toluene and the like, provided that the solvent properties are largely determined by the polar solvent.

The term "weak base" refers to the alkali metal or alkaline earth metal salt of a weak acid, e.g. sodium acetate, potassium bicarbonate, etc., or to a buffer mixture (such as NaH2PO4/Na2HPC<4) which gives a corresponding pH value.

The term "strong base" refers to bases such as alkali metal hydroxides, lower alkoxides, sterically hindered amines such as di(lower-alkyl)-amines and bis-(tri-lower-alkylsilyl)-amines, hydrides and the like, containing alkali metals including lithium, sodium, potassium, rubidium and cesium, e.g. sodium hydroxide, potassium hydroxide, potassium methoxyd, sodium methoxyd, potassium methoxyd, sodium ethoxyd, sodium hydride, lithium di-(isopropyl)amine, lithium bis-(trimethylsilyl)amine, etc.

"Mesyl" or "mesylate" denoted by Ms refers particularly to methanesulfonyl, but also includes other equivalent alkyl or arylsulfonyl compounds, such as e.g. ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, etc.

"Aryl" or "AR" refers to a substituted or unsubstituted monovalent unsaturated radical, e.g. phenyl, 2- or 3-furyl, 2- or 3-thienyl, or 2- or 3-pyrryl, which, if substituted, may have one or more lower alkyl, lower alkoxy or halogen groups in which any available position on the ring. Phenyl and p-methoxyphenyl are preferred.

The term "water miscible cosolvent" includes lower alkanols, di-(lower alkyl) ketones, tetrahydrofuran, dioxane, sulfolane, dimethylformamide, and the like. Preferred co-solvents are methanol, acetone and similar C-1 - or C2-alkyl alcohols and ketones.

The term "pharmaceutically acceptable salt" refers to salts derived from inorganic bases, including salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron (II), zinc, copper, manganese (II), aluminum, iron(III), manganese(III) etc. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic, non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-di-ethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic, non-toxic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

The term "pharmaceutically acceptable esters" refers to alkyl esters derived from branched or straight chain hydrocarbons of 1-12 carbon atoms. Typical alkyl ester groups are e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isoamyl, pentyl, isopentyl,

hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl.

The compounds with formulas (XVI) and (XVII) which are used as starting materials in the method according to the invention, can be prepared as shown in Reaction Core 1.

Dimethyl-1,3-acetonedicarboxylate is commercially available (Aldrich), and so is 1,3-acetonedicarboxylic acid, which is also known under the name 3-oxopentanedic acid. Other di-(lower alkyl)-1,3-acetone dicarboxylates can be readily prepared either from the dimethyl ester or - which is preferred - from the diacid, using esterification methods well known in the art. However, no particular advantages are obtained by varying the alkyl groups, so that the dimethyl ester (R = CH3) is preferred.

The compounds of formulas (XIII), (XIV), (XV) and (XVI) can be isolated, if desired, using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography and the like. These materials can be characterized in the usual way, e.g. using physical constants and spectral data.

The manufacturing steps in Reaction Scheme 1.

In step 1, a di-(lower alkyl)-3-(2-halogenethylamino)-2-pentenedioate ("halogenamine") is prepared from a di-(lower alkyl)-1,3-acetone dicarboxylate, either by direct reaction with a 2 -halogenethylamine hydrohalide salt or by reaction with 2-hydroxyethylamine (2-aminoethanol) with subsequent replacement of the hydroxy group with a halide.

In step 1, option I (which is preferred), the di-(lower alkyl)-1,3-acetonidicarboxylate is treated with a 2-haloethylamine hydrohalide salt in aqueous solution. The solution preferably has a pH of between 5 and 12, more preferably between 5 and 8. The pH value is usually regulated by using an aqueous solution of a weak base, e.g. sodium acetate, as reaction solvent, but also other pH regulation methods can be used, if desired. The reactants can be added simultaneously or one after the other, if this is desired, but it is desirable that the 2-haloethylamine hydrohalide is not placed in a base solution, unless this solution already contains acetone dicarboxylate, in order to

avoid formation of aziridines. Generally, the 2-haloethylamine hydrohalide and the acetone dicarboxylate are dissolved, either simultaneously or in the order indicated, in water, after which

a weak base is added in solid form to form the reaction mixture. The reaction is preferably carried out at a temperature between 0 and 35°C, more preferably at approximately room temperature, i.e. at a temperature between 20 and 30°C, during a time period which is preferably from 15 minutes to 24 hours, more preferably from 4 to 18 hours. The intermediate di-(lower alkyl)-3-(2-halogenethylamino)-2-pentenedioate "halogenamine" usually crystallizes out and can be isolated by filtration, as a mixture of the E and Z isomers. Each R is preferably methyl, while X is preferably Br or Cl, and sodium acetate is preferably used for regulating the pH value.

According to option II of step 1, the di-(lower alkyl)-1,3-acetone dicarboxylate is treated with 2-hydroxyethylamine-(2-aminoethanol) in an aprotic, polar solvent to form the hydroxyenamine (XIV), which is then transferred to the halogenenamine (XIII) via the mesylenamine (XV). The conversion can stop at the mesylenamine step, and the mesylenamine can be ring-closed directly (step 2, option II), if desired. Typically, the dicarboxylate is dissolved in the solvent, after which the 2-hydroxyethylamine is slowly added to the resulting solution and the water formed during the reaction is removed by azeotropic distillation. Although the hydroxyenamine can be formed under less stringent conditions (see e.g. US Patent No. 4,089,969), an anhydrous solution of the hydroxyenamine is required for the next reaction, and it is therefore appropriate to form the hydroxyenamine in a aprotic medium. The resulting solution contains a mixture of the E and Z isomers of the hydroxyenamine and can be used without purification in the next step. As in step 1, option I is a preferred R methyl. A preferred solvent is dichloromethane.

Esterification of the hydroxyenamine (XIV) with mesyl chloride in the presence of an organic base, such as e.g. a tertiary amine, optionally in the presence of an aprotic, polar solvent, takes place at a temperature between -10°C and room temperature, preferably between 0°C and 10°C. It is convenient to add the tertiary amine to the solution from the preceding reaction, after it has been cooled to the appropriate temperature, and the mesyl chloride is added slowly to the resulting solution over from 30 minutes to 10 hours, usually over 2- 5 hours. The solution of the resulting mesylenamine (XV) is added to water to stop the reaction, and the solvent is removed from the organic phase, whereby a mixture of the E and Z isomers of the mesylenamine (XV) is obtained, which can be used without further purification in the next reaction, although purification is preferred if the mesyl amine is to be ring-closed directly and not first transferred to the halogenenamine.

The mesylamine (XV). is transferred to the corresponding halogenenamine (XIII) by reaction with anhydrous alkali metal halide, preferably a bromide or iodide, which e.g. sodium iodide, lithium bromide, etc., in an aprotic, polar solvent at a temperature between room temperature and the solvent reflux temperature, e.g. at a temperature between 30 and 100°C, for 1-30 hours, e.g. for 5-20 hours, the time depending on the reagents and the reaction temperature. The halogenamine (XIII) can be easily isolated by adding water to the reaction mixture, washing the organic phase and removing the solvent, whereby a mixture of the E and Z isomers of the "halogenamine,

which can conveniently be purified by recrystallization.

In step 2, the halogenenamine (XIII) or the mesylamine (XV) from step 1 is cyclized with a strong base in an aprotic, polar solvent.

In step 2 (alternative I), the halogenenamine (XIII) is treated with a 2-haloacetaldehyde, XCH2CHO, where X is as indicated above. The method is preferably carried out in aqueous solution at a pH between 4.5 and 10, preferably between 5 and 8.5. The reaction is preferably carried out at a temperature between 0 and 65°C, more preferably at approximately room temperature, for 1-48 hours, preferably for 6-24 hours. X is preferably Br, and pH regulation is preferably carried out through the presence of a weak base, e.g. sodium acetate or sodium bicarbonate, in the solution. The method is preferably carried out in the presence of 10-50 vol% of a water-miscible co-solvent,

like for example. acetone.

To an aqueous solution of a weak base and 2-halogenacetaldehyde is added the halogenenamine (XIII). A water-miscible co-solvent is also preferably added. The mixture is stirred for the time necessary,

and the N-(2-halogenethyl)-pyrrole (XVI) is filtered off. The 2-haloacetaldehyde can be obtained commercially, or it can be prepared in any desired manner. With regard to the preferred 2-bromoacetaldehyde, acid hydrolysis of a 2-bromoacetaldehyde di-(lower alkyl) acetal, a lower alkyl 1,2-dibromethyl ether, 1,2-dibromethylacetate can be mentioned as examples of production methods. etc. Each of these methods results in an aqueous solution of 2-bromoacetaldehyde, to which the weak base can be added.

In alternative II of step 2 (which is preferred), the halogenenamine is usually dissolved in the solvent and from 1 to 2 equivalents, preferably from 1.1 to 1.5 equivalents, of the strong base in solid form is added. If

.the base is not soluble in the solvent, it may be desirable to add a phase transfer catalyst, e.g. a tetraalkylammonium halide, etc., to increase the reaction rate. The reaction preferably takes place at a temperature between 15 and 35°C, more preferably at approximately room temperature

trip, during from 1 to 30 hours. The resulting cyclic enamine (XVII) can be isolated, e.g. by extraction of the solution with water and evaporation of the solvent, and it can suitably be purified by distillation (e.g. Kugelrohr distillation) and/or recrystallization.

X is preferably Br, and preferred strong bases and solvents are sodium methoxy in dichloromethane, sodium hydroxide in tetrahydrofuran or dimethylsulfoxide, sodium hydride in tetrahydrofuran, etc. The E and Z isomers can, if desired, be separated from each other, but it is unnecessary to do this, as they are both usable as starting materials in the method according to the invention.

In step 2, alternative III (ring closure of the mesylamine (XV)) a procedure similar to that described above is carried out, but the amounts of base used are usually larger, e.g. up to 6 equivalents calculated on the mesylenamine, and the reaction conditions are stricter (higher temperatures, e.g. temperatures up to the solvent's reflux temperature, as well as longer reaction times). A preferred base/solvent combination is aqueous sodium hydroxide/dichloromethane, using a phase transfer catalyst.

The process according to the invention for the production of 5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acids with the general formula (I) is shown schematically in Reaction Scheme 2 below.

where R, R', X and Ar are as indicated above.

In step 1, alternative 1, the N-(2-halo-ethyl)-pyrrole (XVI) is ring-closed with from 1 to 2 equivalents, preferably from 1.1 to 1.5 equivalents, of a strong base in an aprotic, polar solvent . The obtained pyrrolo-pyrrol diester (XII) is then saponified in step 2 to the dicarboxylic acid (XII'). The saponification can conveniently be carried out in the solution of the diester obtained from the cyclization process.

A preferred X is Br or Cl. The strong base

is preferably a sterically hindered lithium amine, such as e.g. lithium di-(isopropyl)amine or lithium bis-(trimethylsilyl)amine, and the solvent is preferably tetrahydrofuran. Other examples of suitable combinations of strong base

and solvent is sodium hydroxide in dimethylsulfoxide

-and potassium methoxide in methanol (although the latter has a

tend to give an increased amount of the N-vinylpyrrole contaminant). The use of sodium hydride in dimethylformamide for ring closure of N-(2-iodoethyl)-pyrrole is known from e.g. US Patent No. 4,089,969.

The compound of formula (XVI) is dissolved in the aprotic polar solvent and a solution of the strong base is added slowly (ie over from 1 to 24 hours, e.g. from 2 to 8 hours) at a temperature of from

-10°C to 35°C, e.g. at room temperature, and the resulting solution is stirred to provide a solution of the pyrrolo-pyrrole diester (XII). The reaction temperature is preferably from 0 to 10°C when X = Br, and from 15 to 30°C when

X = Cl, when the strong base is lithium-di-(isopropyl)-amine. Compound (XII) can be recovered from the solution by removal

of the solvent and purification using conventional methods within organic chemistry and can - which is usually done - be transferred directly to the dicarboxylic acid (XII') in step 2.

In step 1, alternative 2, the pyrrole ring of the pyrrolo-pyrrole is formed by reacting the cyclic enamine (XVII) with

a 2-halogenacetaldehyde, XCH2CHO, where X is as above. The method is preferably carried out in aqueous solution at a pH value between 4.5 and 10, preferably between 5

and 8.5. The reaction is preferably carried out at between 15 and

35°C, more preferably at about room temperature, for 1-10

hours, preferably for 2-5 hours. X is preferably Br, and pH regulation is preferably carried out through the presence of a weak base, e.g. sodium acetate or sodium bicarbonate,

in the solution. The method is preferably carried out in the presence of from 10 to 50% by volume of a water-miscible co-solvent, e.g. methanol.

In typical cases, the cyclic enamine is set

(XVII) to an aqueous solution of the 2-haloacetaldehyde and

a weak base. A water-miscible co-solvent is also preferably added. The mixture is stirred for the time necessary and the resulting compound of formula (XII) can be isolated from the reaction mixture, e.g. by evaporation of the solvent, and purified as desired. The 2-haloacetaldehyde can be bought in, or it can be prepared in any way. As regards the preferred 2-bromoacetaldehyde, acid hydrolysis of a 2-bromoacetaldehyde di-(lower alkyl) acetal, a lower alkyl 1,2-dibromomethylether, 1,2-dibromoethylacetate, etc. can be mentioned as examples of production methods. Each of these methods results in an aqueous solution of 2-bromoacetaldehyde.

The dicarboxylic acid (XII<1>) is obtained by saponification of the compound of formula (XII) in step 2 using conventional chemical methods, i.e. by reaction with a strong base to remove the ester groups and treatment with acid to form the dicarboxylic acid. The diester is dissolved in an aqueous solution of alkali metal hydroxide or carbonate, e.g. a sodium hydroxide solution, which may also contain a water-miscible co-solvent, e.g. methanol, at a temperature between room temperature and the reflux temperature of the solvent for a period of from 30 minutes to 24 hours, e.g. in 1-4

hours. The cooled solution is then acidified with an aqueous, strong acid, e.g. 35% hydrochloric acid, and the dicarboxylic acid is precipitated and optionally recovered by filtration. The dicarboxylic acid can be purified in a conventional manner. In particular, it is appropriate to carry out recrystallization

from aqueous solution. Saponification can be carried out in isolation

material, but it can also suitably be carried out on the solution obtained by the ring-closing reaction described above. For example, water can be added to the solution, the aprotic, polar solvent is at least partially removed by distillation and a strong base, e.g. sodium hydroxide, is added directly to the resulting solution of the pyrrolo-pyrrole diester, the solvent is further partially removed (if desired or necessary) and an aqueous strong acid, e.g. Add 35% hydrochloric acid. The dicarboxylic acid precipitates from the solution and can be recovered by filtration. The dicarboxylic acid can be purified using conventional chemical methods. It is particularly appropriate to carry out recrystallization from an aqueous solution.

The acid group at C-1 in the resulting dicarboxylic acid (XII<1>) can then be selectively esterified in step 3 by treatment with a lower aliphatic alcohol, e.g. methanol, ethanol, isopropanol, n-butanol etc., in the presence of hydrogen chloride, to form the corresponding alkyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate-7-carboxylic acid with formula (XVIII). The reaction is carried out at a temperature of from 0°C to 50°C i

1-4 hours.

In step 4, the monoesterified compounds (XVIII) are decarboxylated to the corresponding compounds of formula (IX) by heating (XVIII) at an elevated temperature of the order of 230-280°C for a sufficiently long time for the reaction to be completed. The course of the reaction can be followed by means of the amount of carbon dioxide that is developed, and by means of thin-layer chromatography. The decarboxylation is usually completed within 45 to 90 minutes. The reaction product, i.e. alkyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate and its derivatives (XI), can be purified by chromatographic methods. Alternatively, and especially by decarboxylation of smaller portions of compound (IX), the reaction product (IX) can be distilled directly from the reaction vessel.

Condensation of a compound of formula (IX) can be carried out in one of two ways, namely with an amide or with a morpholide.

Condensation of a compound of formula (IX) with an amide of the formula

where R<1> is one of the above defined substituents, it gives the corresponding alkyl-5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-al-pyrrole-1-carboxylate (IA). This reaction is carried out in an inert, organic, aprotic solvent and in the presence of phosphorus oxychloride, at reflux temperature for 1-175 hours, under an inert atmosphere, followed by further refluxing in the presence of sodium acetate for 2-10 hours. Alternatively, other acid chlorides can be used instead of phosphorus oxychloride, such as e.g. phosgene or oxalyl chloride. In the preferred embodiment, this condensation is carried out by adding a solution of compound (IX) in a suitable solvent to a previously refluxed mixture of 1.1-5 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent, after which the the reaction mixture thus obtained is boiled with reflux cooling for 6-72 hours under an argon atmosphere. From 3 to 10 molar equivalents of sodium acetate are then added to the reaction mixture, after which further reflux is carried out for 4-6 hours. Suitable solvents for this reaction are the halogenated hydrocarbons, such as e.g. dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like, dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

Representative among the N,N-dimethylarylamides that can be used are: N,N-dimethyl-benzamide, N,N-dimethyl-o-toluamide, N,N-dimethyl-m-toluamide, N,N-dimethyl-p-toluamide , N,N-dimethyl-p-ethylbenzamide, N,N-dimethyl-o-propyl-benzamide, N,N-dimethyl-m-butyl-benzamide, N,N-dimethyl-o-methoxy-benzamide, N ,N-dimethyl-m-methoxy-benzamide, N,N-dimethyl-p-ethoxy-benzamide, N,N-dimethyl-p-isopropoxy-benzamide, N,N-dimethyl-o-chloro-benzamide, N,N -dimethyl-m-chloro-benzamide, N,N-dimethyl-p-chloro-benzamide, N,N-dimethyl-o-fluoro-benzamide, N,N-dimethyl-p-fluoro-benzamide, N,N-dimethyl -m-bromo-benzamide and N,N-dimethyl-p-bromo-benzamide. These amides are known compounds which are available commercially, or which can be prepared in a conventional manner from the corresponding acids, e.g. by transferring these to the acid chlorides and subsequent treatment with dimethylamine.

If an aroyl morpholide is used, the compound of formula (IX) is treated with an aroyl morpholide of the formula:

where Ar is as defined above, in the presence of an inorganic acid halide, such as e.g. POCl 3 , P0Br 2 ' SO 2 Cl 2 and the like, preferably POCl 3 . The quantity ratios are not of decisive importance. Optionally, an inert organic solvent, such as e.g. ethane dichloride, chloroform or carbon tetrachloride, but preferably methylene chloride, is incorporated into this mixture. However, the presence of the solvent is not particularly advantageous in all cases. The mixture is stirred, preferably stirred, for 0.5-36 hours, preferably 1-5 hours, at 30-50°C, preferably at 40-45°C.

A solution of the pyrrolo-pyrrole compound of formula (IX) in an inert solvent, most preferably CH 2 Cl 2 , is then added to the above-mentioned mixture. Here again, the quantity ratio between the reactants is not of decisive importance, but it is preferred that the molar quantity of the compound of formula (IX) is slightly less than the molar quantity of the reactant which is present in the smallest quantity in the prepared morpholide/halide mixture. The resulting reaction mixture is kept at 30-70°C, preferably 40-45°C, until the desired reaction has taken place, which usually takes from 1 to 8 hours, most often from 1.5 to 3 hours.

The entire procedure up to this point is carried out in an inert atmosphere to exclude water. Any anhydrous gas can be used, but it is preferable to use nitrogen. When the reaction is carried out on a larger scale, the problem of water in the surrounding air becomes less, because the available surface area becomes relatively smaller. However, it has proven to be a good practice to use nitrogen.

The intermediate product formed at this point can

cannot be isolated in any convenient way, but must be hydrolysed either to the alkyl ester of the acid of formula (I) or to the free acid of formula (I).

If it is desired to prepare a free acid of formula (I), a one-step process is preferred. In this embodiment, the reaction mixture is poured into a solution of a polar solvent, preferably aqueous, of a strong base, such as e.g. a mineral hydroxide or carbonate, preferably sodium hydroxide. A large surplus of the base is used. The mixture is then kept at 30-100°C, preferably at 40-60°C, until the reaction is complete.

Alternatively - if the two-step procedure is to be used, or an alkyl ester of the acid with formula (I) is to be prepared - from 3 to 10 molar equivalents of sodium acetate or another weak base can be added directly to the reaction mixture, with a subsequent additional reaction time of 4-6 hours, during which the mixture is refluxed. After this period, the alkyl ester of the acid of formula (I) has been formed.

If transfer to the acid of formula (I) is then desired, further hydrolysis is carried out in a conventional manner with an alkali metal hydroxide or carbonate in an aqueous solution or an aqueous solution of a lower aliphatic alcohol (methanol, ethanol, etc.). The temperature is from room temperature to the reflux temperature, and the reaction time is from 15 minutes to 3 hours. The hydrolysis is preferably carried out with aqueous, methanolic potassium carbonate at reflux temperatures and for approx. 30 minutes.

After alkaline hydrolysis of the alkyl ester group in an alkyl ester of the acid of formula (I), the corresponding free acid of formula (I) is obtained. This hydrolysis is carried out in a conventional manner, with an alkali metal hydroxide or alkali metal carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., in an aqueous, lower aliphatic alcohol, e.g. methanol, ethanol, etc., at a temperature from room temperature to the reflux temperature, for a period of from 15 minutes to 2 hours, under an inert atmosphere. In the preferred embodiment, this hydrolysis is carried out with aqueous, methanolic potassium carbonate, at reflux temperature and for approx. 30 minutes.

The free acids of formula (I) can be transferred to

other alkyl esters with 1-12 carbon atoms by conventional methods, e.g. by treatment with (a) the alcohol corresponding to the desired ester, in the presence of a strong mineral acid, (b)

an ethereal dazoalkane or (c) the desired alkyl iodide in the presence of lithium carbonate.

The salt derivatives of the compounds of formula (I) are prepared by treating the free acids with a suitable amount of a pharmaceutically acceptable base. The reaction is carried out in water or in a combination of water with an inert, water-miscible organic solvent, at a temperature from 0°C to 100°C, preferably at room temperature. Typical inert, water-miscible organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane and tetrahydrofuran. The molar ratio between the compounds of formula (I) and the base used is chosen so that the quantity ratio desired for the salt to be produced is achieved.

It should be noted that the steps 2-5 described above for the preparation of compounds of formula I have previously been described in e.g. Norwegian patent documents no. 147563 and 147564 and in US patent documents no. 4,089,969 and 4,353,829.

The method according to the invention is illustrated in the following examples.

Concrete examples of the production of the starting materials used with formulas (XVI) and (XVII) will be found in Norwegian patent application no. 169,124 and Norwegian patent application no. 903995, respectively.

Example 1. Preparation of 5-p-toluoyl-1,2-dihydro-3H-pvr-rolo-fl,2-al-pyrrole-1-carboxylic acid (I) and alkyl esters and salts thereof.

A. Preparation of 1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid (XII') (Steps 1 and 2 = characteristic of the claim).

Eel. From a compound of formula (XVI) (Alt. 1 of step 1).

Under a nitrogen atmosphere, 75 ml of 1.3M n-butyllithium (98 mmol) in hexane was added slowly and with stirring at a temperature from -5 to 0°C to a solution of 13.8 ml (10.0 g; 98 mmol) of diisopropylamine in 50 ml dry tetrahydrofuran. The resulting solution was transferred to an addition funnel and added, under nitrogen and at a temperature of 0 to 5°C, to a stirred slurry of 20.0 g (66 mmol) methyl-N-(2-bromomethyl-3-methoxycarbonyl-2 -pyrrole acetate in 100 ml of dry tetrahydrofuran. A slight rise in temperature occurred, and complete dissolution occurred after the addition of about two-thirds of the lithium di-(isopropyl)amine solution. The resulting solution was stirred for two hours, under heating to 10°C, and was then diluted with 100 ml of water under gentle heat generation. The solvents were evaporated by distillation at atmospheric pressure. 240 ml were collected, with a bottom temperature of 80°C, giving a solution of dimethyl-1 , 2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylate The diester can be isolated at this point by addition of water, extraction into an organic solvent such as ethyl acetate and evaporation of the solvent, with subsequent purification after conv national methods. However, it is also appropriate to saponify the diester into the dicarboxylic acid, without isolation from the solution.

The bottom solution obtained above was cooled to 50°C, and 6.0 g (150 mmol) of sodium hydroxide was added. Methanol was then removed by distillation at atmospheric pressure until a bottom temperature of 97°C. The bottom solution was cooled to 5°C and acidified with 18 mL of 12M hydrochloric acid (216 mmol), resulting in an increase in temperature to 15°C. The resulting mixture was cooled to 5°C and filtered, and the eluate was washed with 50 ml of cold water and dried to give 11.4 g of impure 1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid.An examination of the impure material showed that it contained 91.4% 1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid (and 7.0% N-vinyl-3-carboxy-2-pyrroleacetic acid ).

A2. From a compound of formula (XVI) (Alt. 1 of step 1).

295.5 ml of 2.6M n-butyllithium (0.77 mol) in hexane was added dropwise at 0-3°C and with stirring to a solution of 109.3 ml of diisopropylamine (78.9 g; 0.78 mol) in 200 ml of freshly distilled tetrahydrofuran. The resulting solution was transferred to an addition funnel and then added dropwise and at room temperature to a stirred solution of 150.0 g (0.58 mol) N-(2-chloroethyl)-3-methoxy-carbonyl-2-pyrrole acetate in 750 ml dry tetrahydrofuran. The addition took four hours, and the temperature was maintained in the range from 23 to 27 °C. The resulting solution was stirred for 16 hours and then diluted with 500 ml of water spread over 10 minutes, with an accompanying slight evolution of heat. The solvents were evaporated by distillation at atmospheric pressure to a bottom temperature of 75°C. The bottom solution was cooled to 50°C, and 53.0 g (1.33 mol) of sodium hydroxide was added. Then methanol was removed by distillation at atmospheric pressure to a bottom temperature of 95° C. A total of 1370 mL of solvents was collected. The bottom solution was cooled to the range of -3 to 0° C. and acidified with 180 mL of 12M hydrochloric acid (216 mmol), resulting in an increase in temperature to 18° C. The resulting mixture was cooled to the range of -3 to 0° C., aged for 30 minutes at this temperature and filtered, and the supernatant was washed with 300 ml of ice-cold water and dried to give 107, 8 g of impure 1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid An examination of the impure material indicated that it contained 96.6% 1,2-dihydro-3H -pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid.

A3. From a compound of formula (XVII) (Alt. 2 of step 1).

1.70 g (10 mmol) of 2-bromoacetaldehyde dimethyl acetal, 0.25 ml of 48.5% hydrobromic acid (2 mmol) and 2.5 ml of water were refluxed for 75 minutes, whereby a solution of 2- bromoacetaldehyde. The solution was cooled to room temperature and 0.50 g of sodium acetate was added. The resulting solution was added over three hours to a stirred solution of 1.00 g (5 mmol) methyl-3-methoxycarbonyl-2-pyrrolidinylidenecarboxylate, 3.10 g sodium acetate, and 2 ml water in 10 ml methanol. The mixture was stirred for an additional hour and most of the solvents were removed by evaporation in vacuo. The residue was dissolved in 100 ml of dichloromethane, and the solution was washed with 2 x 25 ml of aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. On removal of the solvent by evaporation, 1.26 g of dimethyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylate were obtained.

1.26 g (5 mmol) of dimethyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylate and 1.00 g (25 mmol) of sodium hydroxide were refluxed in 10 ml of water for one hour. The resulting solution was cooled to 0°C and acidified with 21M hydrochloric acid to pH 1. 0.70 g of 1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid (71, 4% yield) was filtered off and dried.

B. Preparation of isopropyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate-7-carboxylic acid (XVIII) (Step 3 = step (a) of claim).

A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, is saturated with gaseous hydrogen chloride, the reaction the temperature of the mixture is kept below 50°C. The ice bath is then removed, and the reaction mixture is stirred for 1.5 hours at room temperature and evaporated to dryness under reduced pressure. 10 ml of benzene are added to the residue, and the solution is evaporated once more under vacuum. This process is repeated a total of three times, to completely remove the excess of hydrogen chloride. 1.58 g of isopropyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate-7-carboxylic acid (96%) are thereby obtained, which after crystallization from methanol-ethyl acetate has a melting point of 144-145°C. C. Preparation of isopropyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate (IX) (Step 4 = step (b) of claim). 1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate-7-carboxylic acid is heated to 240-250°C in a dry 10 ml round bottom flask, the reaction product being distilled directly from the reaction flask. In this way, 745 mg of isopropyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-l-carboxylate (87%) are obtained in the form of a pale yellow oil with the following physical constants: 07 Xmtks 215 ™ (£ 6020)' IR V<max3> 1725 cm"1 ' NMR ^Ms'3 ^22 (d. J= 7 Hz, 6H), 2.40-2.90 (m, 2H), 3.60 -4.20 (m, 2H), 4.65-5.2 (m, 1H), 5.73-5.92 (m, 1H), 6.10 (t, J= 3 Hz, 1H), 6.43-6.53 ppm (m, 1H). D. Preparation of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid (I) (Step 5 = step (c) of the requirement).

A solution of 179 mg of N,N-dimethyl-p-toluamide and 0.11 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is boiled with reflux for 30 minutes. To this solution is added a solution of 193 mg of isopropyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is refluxed under an argon atmosphere for eight hours, treated with 405 mg of sodium acetate and refluxed for a further five hours. The resulting mixture is then evaporated to dryness, and the residue is chromatographed on 12 g of silica gel eluting with hexane:ethyl acetate (3:1), whereby 208 mg of isopropyl-5-p-toluoyl-1,2-dihydro-3H- pyrrolo-[1,2-a]-pyrrole-l-carboxylate (66%) in the form of an oil and with the following physical constants: UV Aj^g 256, 312 nm (e 8700, 19 500), IR 1735, 1620,

1605 cm-1, NMR 6% jj£} 3 1.23 (d, J = 7, Hz, 6H), 2.38 (s, 3H),

2.5-3.0 (m, 2H), 3.75-4.10 (m, 1H), 4.2-4.60 (m, 2H), 4.85-

5.20 (m, 1H), 5.95 (d, J= 4 Hz, 1H), 6.70 (d, J = 4 Kz, 1K), 7.10 (d, J = 8 Hz, 2H) , 7.60 ppm (d, J = 8 Hz, 2H).

A solution of 336 mg of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution of 690 mg of potassium carbonate in 5 ml of water. The reaction mixture is refluxed under a nitrogen atmosphere for 30 minutes, cooled and evaporated to dryness. The residue is taken up in 10 ml of 10% aqueous hydrochloric acid and 50 ml of water, and the resulting mixture is extracted with 2 x 50 ml of ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate-hexane yields 238 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid (89%) with a melting point of 182 183°C.

E. Preparation of alkyl esters and salts of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid (I).

A solution of 300 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo, and the residue is purified by chromatography on aluminum oxide, whereby isoamyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate available.

To a solution of 300 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of sodium hydroxide, in the form of a 0, 1N solution. The solvent is then evaporated under reduced pressure, and the residue is taken up in 2 ml of methanol, after which it is swept up with ether, whereby an impure sodium-5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2 -α]-pyrrole-1-carboxylate which can be crystallized from ethyl acetate hexane.

To a solution of 175 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid in 5 ml of methanol is added 1 molar equivalent of potassium hydroxide, in the form of a 0, 1N solution, whereby a solution is obtained containing potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate. A solution of 40 mg of calcium carbonate dissolved in the smallest amount of 1N hydrochloric acid necessary to dissolve the calcium carbonate is buffered with 100 mg of solid ammonium chloride, after which a further 5 ml of water is added. The buffered calcium solution thus obtained is then added to the solution of potassium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate, and the precipitate that forms is filtered off , washed with water and dried in air, whereby calcium 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate is obtained.

A solution of 200 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropylamine. The solution is allowed to cool to room temperature and the product is filtered off, washed with ether and dried to give the isopropylamine salt of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid .

Example 2. Preparation of 5-benzoyl-1,2-dihydro-3H-pyrrolo-T1,2-al-pyrrole-1-carboxylic acid (I).

By proceeding as indicated in example 1, A-D, but using 1.1-5 molar equivalents of N,N-dimethyl-benzamide instead of N,N-dimethyl-p-toluamide under point D and monitoring the course of the reaction by thin-layer chromatography, isopropyl-5 is obtained -benzoyl-l,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-l-carboxylate, a pale yellow oil with the following physical constants: UV AMepK 245, 311 nm (e 7230, 17 800), IR v CHC13 1735

max max

1620 cm"<1>, NMR 6^°g<13> 1.24 [d, 6H, (CH3)2CH1, 2.50-3.13

(m, 2H, H-3), 3.97 (dd, 1H, H-1), 4.18-4.70 (m, 2H, H-3),

5.00 [sept., 1H, (CH3)2CH], 6.00 (d, 1H, H-7), 6.86 (d, 1H, H-6), 7.10-7.90 ppm ( m, 5H, phenyl protons), M.S.: m/e 297

(M+).

After hydrolysis of the isopropyl ester group in a similar manner as in example ID, 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid is obtained, with a melting point of 160-161°C.

Preparation of an alkyl ester.

A solution of 200 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is kept at room temperature for 30 minutes. The solvents and excess reagent are removed under reduced pressure, and the residue is crystallized from ethyl acetate-methanol, whereby methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate available.

Preparation of the free acid.

100 mg of sodium 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylate are dissolved in 50 ml of water. 10 ml of concentrated hydrochloric acid are added while stirring at room temperature. The aqueous solution is then extracted with 2 x 50 ml of ethyl acetate, after which the organic extracts are combined, dried and evaporated. The product, 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid, is recrystallized from ethanol/ether. Melting point 160-161°C.

Claims (1)

Process for the preparation of 5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acids with the general formula: where Ar is substituted or unsubstituted phenyl, 2- or 3-furyl, 2- or 3-thienyl, or 2- or 3-pyrryl, which groups - if they are substituted - may have one or more lower alkyl, lower alkoxy or halogen groups in any available position on the ring, and pharmaceutically acceptable salts and alkyl esters of these compounds, where the alkyl group in the ester group has 1-12 carbon atoms, wherein one: (a) esterifies a compound of the formula: for the formation of a compound of the general formula XVIII: where R is alkyl of 1-12 carbon atoms, (b) decarboxylates the compound of formula (XVIII) to a compound of the general formula (IX): where R is as indicated above, and (c) aroylates the compound of formula (IX) with an amide or morpholide to a compound of formula (I) or the corresponding alkyl ester where the alkyl group in the ester group has 1-12 carbon atoms, and that, when necessary, performing one or more of the following steps: (i) transferring a compound of formula (I) to a pharmaceutically acceptable salt, (ii) transferring a salt of a compound of formula (I ) to the corresponding free compound of formula (I), (iii) esterification of a compound of formula (I) to an alkyl ester where the alkyl group in the ester group has 1-12 carbon atoms, (iv) transfer of an alkyl ester to the corresponding free compound with formula (I), characterized in that the compound with the formula (XII') is prepared by: (1) a compound with the general formula XVI: where R' is lower alkyl, and X is Br or Cl, is ring-closed with a lithium-protected amine in an aprotic, polar solvent, preferably hexane and tetrahydrofuran, and the formed diester of formula (XII): where R' is as indicated above, is saponified to the compound of formula (XII'), or (2) a compound of the general formula XVII: where R' is lower alkyl, is reacted in aqueous solution with a 2-halogenactaldehyde, XCH2CHO, where X is halogen, and that the formed diester with the above formula (XII) is saponified to the compound of formula (XII').