HU213614B - Process for producing 5-aroyl-1,2-dihydro-3h-pyrrolo [1,2-a]pyrrole-1-carboxylic acides and their alkylesters - Google Patents

Abstract

The present invention relates to a novel process for the preparation of compounds of the general formula (IA) and (I): wherein Ar is a phenyl group monosubstituted with C 1-4 alkyl or alkoxy, R is alkyl, starting from a compound of general formula (IV), (XV), (XVI), and (XVII) and the known intermediates of formula (XII) (wherein Ar and R are as defined above, X is halogen and Ms is mesyl), and the compound of formula (XII) is as follows: further processing of the compound in a known manner. COOR COOR (IV) HN COOR COOR (XVH) HU 213 614 B Scope of the description: 19 pages (including 5 sheets)

Description

The present invention relates to a novel process for 5-aroylpyrrolo [1,2-a] pyrrole derivatives, namely 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids and alkyl- for the preparation of their esters.

The 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids of formula (I), which are 5-aroyl-1,2-dihydro-3H-pyrrolizine-1- Carboxylic acids are also known and their pharmaceutically acceptable salts and esters are used as analgesics, anti-inflammatory and antipyretic agents in the treatment of humans and mammals, and also as mild muscle relaxants. Two compounds which are subject to human clinical trials are exemplified, for example, ketorolac, which is 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid of formula (I) wherein Ar is phenyl. aniroaco, which is 5- (p-anisoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid corresponding to formula (I) wherein Ar is p-methoxyphenyl. Both compounds are described in U.S. Patent 4,089,969 to Muchowski et al. Further compounds having a 5-aroyl substituent substituted or unsubstituted with a benzoyl, furoyl, tenoyl or pyrrolyl group and optionally substituted at the 6-position by a lower alkyl group or a halogen atom and their use are described in 4,089,969, 4,087. 539, 4,097,579, 4,140,684, 4,232,038, 4,334,943, 4,347,186, 4,458,081, 4,347,187, 4,454,326, 4,347,185, 4,505,927, 4,456,759, 4,353,829, U.S. Patent Nos. 4,397,862, 4,457,941, and 4,454,151 to SYNTEX. Merck Company Nos. 4,511,724 and 4,536,512. United States Patent Nos. 5,197, 5, 5 (substituted pyrrol-2-oil) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives, and 5- (1,2-dihydro) -3H-pyrrolo [1,2-a] pyrrol-2-oil) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid derivatives; U.S. Pat. No. 5,123,115 discloses 5- (1,2-dihydro-3H-pyrrolo [1,2-a] pyrrol-2-oil) -2-pyrroloalkanoic acids and analogs thereof.

The pyrrolopyrrole derivatives of the above preparation is described in the patent and scientific literature different ways, of which a large number of common intermediates, R-1,2-dihydro-3H-pyrrolo ¹ is a hydrogen atom (II) of formula [1,2- a) pyrrole-1,7-dicarboxylic acid or the dialkyl esters of formula II having two R ¹ alkyl groups. The preparation of compounds of formula (II) having two R @ ¹ methyl groups from dimethylacetone dicarboxylic acid, aminoethanol and a haloacetaldehyde is described, for example, in U.S. Patent No. 4,089,969. U.S. Pat. The preparation procedure is illustrated in Scheme (A). The method comprises reacting an equimolar amount of the aminoethanol (III) and dimethyl ester of acetone dicarboxylic acid (IV) with the methyl groups and then reacting the resulting solution containing hydroxyamine (V), preferably without isolation, in a suitable organic solvent, e.g. in aprotic solvents such as acetonitrile, dichloromethane and the like, under anhydrous conditions, 2-haloacetaldehyde is added at elevated temperature to form N- (2-hydroxyethyl) pyrrole of formula (VI). The compound of formula (VI) is esterified with methanesulfonyl chloride and the resulting mesylate of formula (VII) is converted, if desired, by reaction with sodium iodide to form N (2-iodoethyl) pyrrole of formula (VIII). Both the compounds of formula (VII) and (VIII) are reacted with sodium hydride in dimethylformamide with 1,2-dihydro-3H-pyrrolo of formula (II) having two R ¹ groups in the methyl group [1,2-a]. can be converted to pyrrol-1,7-dicarboxylic acid dimethyl ester. The 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid dimethyl ester thus obtained is disclosed in the aforementioned patents and in U.S. Pat. No. 4,496,741. according to the methods described in Doherty, U.S. Pat. No. 7, it can be selectively decarboxylated at the 7-position and aroylated at the 5-position to yield 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole of formula (I). -1-carboxylic acids are obtained. By a similar procedure, the reaction of aminoethanol, acetyldicarboxylic acid dimethyl ester and a halomethylalkyl ketone directly yields the 4-alkyl analogue of compound (VI), avoiding the formation of hydroxyamine (V). This compound can be converted to the corresponding pyrrolopyrrole derivative as described above for the 4-unsubstituted compound.

Many processes for the preparation of pyrrole derivatives are described in the literature. The preparation of 5-aroyl-N- (R) -pyrrol-2-acetic acid (wherein R is hydrogen, lower alkyl or benzyl) and analogs thereof are described in U.S. Pat. Nos. 3,752,826, 3,865,840 and 3,952,012. in U.S. Patents (Carson). According to this method, 4-alkyl substituted compounds are prepared instead of 4-unsubstituted compounds by preparing a (lower) alkylamine, an acetondicarboxylic acid di (lower alkyl ester) and a chloromethyl (short) The reaction mixture is poured into an ice-cold hydrochloric acid solution to give compounds of formula IX wherein R, R 'and the two Rs are lower alkyl.

The preparation of the 4-unsubstituted compounds of formula IX wherein R 'is hydrogen using chloroacetaldehyde is described in U.S. Patent No. 4,048,191. (U.S. Patent No. 4,198,125 to Carson).

A 2,034,304 As. United Kingdom Publication (Mallinckrodt) discloses that compounds of formula IX wherein R 'is hydrogen or alkyl may be prepared by:

(a) a biphasic reaction medium is prepared from an aqueous solution of an alkylamine and an inert water-immiscible organic solvent and the dicarboxylate and the ketone (or aldehyde) are added substantially simultaneously; or

b) the dicarboxylate and the excess ketone are added substantially simultaneously to an aqueous solution of the alkylamine. Preferably, the dicarboxylate and the excess ketone are added to the dispersion of the alkylamine.

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Ethyl Corporation has several patents, including 4,565,878, 4,565,879, 4,374,255, 4,338,468,4,838,117,4455,433, and 4,333,878. U.S. Pat. No. 4,565,878. U.S. Pat. dicarboxylate and a lower alkylamine aqueous solution. No. 4,565,789. U.S. Pat. No. 4,374,255. According to the process described in U.S. Pat. No. 4,129, a small amount of lower alkanol is added to the mixture of ketone, dicarboxylate and aqueous alkylamine solution to prevent solid formation. The reaction is generally carried out in the presence of a co-solvent as described in U.S. Pat. No. 4,565,878 or 4,565,879. See U.S. Patents. No. 4,388,468. U.S. Pat

(a) the ketone is added to a pre-cooled solution of the alkylamine and dicarboxylate in a suitable solvent such as an aromatic hydrocarbon, chlorinated hydrocarbon, water or mixture thereof at a temperature below 60 ° C, and

b) heating the reaction mixture to 70-100 ° C.

No. 4,383,117. U.S. Pat. No. 4,455,433. In the process according to U.S. Pat. No. 4, an acid having a dissociation constant of at least 1.3 x 10 ^-5 is added at 25 ° C to a mixture of ketone, dicarboxylate and preferably anhydrous (lower) alkylamine to increase the yield. preferably carried out in an organic solvent.

No. 4,333,878. United States Patent No. 5,400,900 for the compounds of formula IX, the enamines of formula X, and the compounds of formula XI.

Discloses the preparation of 2-carboxy-1-nitroalkanes (wherein R * j is lower alkyl, tolyl or benzyl) by reaction. Enamine is prepared from a di (lower) alkyl ester of acetone dicarboxylic acid by reaction of a lower alkylamine with a suitable solvent such as ethanol or methanol, followed by evaporation of the solvent and heating of the resulting carbinolamine to the corresponding enamine. by dehydration.

Albert et al., U.S. Patent No. 4,363,918. U.S. Patent lower alkyl, ^R1 is hydrogen or lower alkyl with a compound of formula two wherein R is hydrogen (IX) propose a synthesis for preparing wherein R is that acetonedicarboxylate a C1CH ₂ COR compound and reacting with a lower alkylamine preferably by slowly adding an aqueous solution of a lower alkylamine to an aqueous solution of the acid followed by slowly adding the 1-chloro-2-alkanone. Both operations are preferably carried out at a temperature of 20 ° C or lower.

Nos. 92,487 and 105,664. Acetone dicarboxylic acid according to methods recommended for the preparation of compounds of Formula IX in European Patent Publication (Montedison SpA), wherein R is methyl, two R are hydrogen and R 'is methyl (92 487) or hydrogen (105 664). or an alkali salt thereof, with an aqueous solution of methylamine and a halogenated ketone or aldehyde, preferably by adding the halogenated ketone to an aqueous mixture of methylamine and acetonitrile.

Known processes for the preparation of pyrrolopyrrole derivatives require large amounts of organic solvents, often result in tar products and are difficult to make for large scale production due to their technological difficulties. In contrast, the novel process of the present invention, which is partially novel to intermediates not previously described in the literature, requires substantially less organic solvent in a more aqueous medium under technologically advantageous conditions, is also well suited for large-scale enlargement. .

The 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids of formula (I) and their alkyl esters of formula (IA) are, according to the invention, (B) and (C). ), starting from a compound of formula (IV), the new compounds of formula (XIII), (XV) and (XVII) and the above-mentioned U.S. Patent 4,089,969 (II). via intermediates of formula (XII); in the formulas (B) and (C), Ar, X and R are as defined in the following paragraph, and M is a methanesulfonyl group.

Accordingly, the present invention provides a novel process for the preparation of 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids of formula (I) and alkyl esters of formula (IA): in these formulas

Ar is optionally C 1 -C 4 alkyl or

Phenyl substituted with C1-C4 alkoxy;

R is selected from the group consisting of dialkyl esters of acetone dicarboxylic acid of formula (IV) and the known 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 of formula (XII), Via dialkyl esters of 7-dicarboxylic acids, wherein R is as defined above; according to the procedure

a) reacting an acetone dicarboxylic acid dialkyl ester of formula IV wherein R is C 1 -C 4 alkyl in both solutions with an hydrogen halide of a 2-haloethylamine;

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the resulting 3- (2-haloethyl) amino-2-pentenedioic acid dialkyl ester of formula (XIII), wherein R is as defined above and X is halogen, a 2-halo compound of formula (XX); with acetaldehyde wherein X is halogen;

- cyclizing the resulting N- (2-haloethyl) -pyrrole dicarboxylic acid dialkyl ester of formula (XVI), wherein R and X are as defined above, to a strong base in an aprotic organic solvent; obsession

b) reacting an acetyldicarboxylic acid dialkyl ester of formula (IV) wherein each R is a C 1-4 alkyl group in an aqueous solution with a hydrogen halide of a 2-haloethylamine;

- reacting the resulting 3- (2-haloethylamino) -2-pentenedioic acid dialkyl ester of formula (XIII) wherein R is as defined above and X is halogen in an aprotic polar solvent with a strong base ;

reacting the resulting 3-alkoxycarbonyl-2-pyrrolidinylidene carboxylic acid alkyl ester of formula XVII in aqueous solution with 2-haloacetaldehyde of formula XX where X is halogen; obsession

c) reacting an acetone dicarboxylic acid dialkyl ester of formula (IV) wherein each R is a C 1-4 alkyl group in an aprotic polar solvent with ethan-2-olamine;

the resulting 3- (2-hydroxyethylamino) -2-pentenoic acid dialkyl ester of the formula (XIV): wherein R is the same as methanesulfonyl chloride as defined in the preceding paragraph;

the resulting 3- (2-methanesulfonyloxyethyl) amino-2-pentenoic acid dialkyl ester of formula XV

- where R is as defined above and Ms is methanesulfonyl - cyclized with a strong base in an aprotic polar solvent;

reacting the resultant compound of formula XVII, wherein R is as defined above, with an aqueous solution of 2-haloacetaldehyde of formula XX, wherein X is halogen; obsession

d) reacting an acetone dicarboxylic acid dialkyl ester of formula (IV) wherein each R is C 1-4 alkyl in an aprotic polar solvent with ethan-2-ol;

the resulting 3- (2-hydroxyethylamino) -2-pentenoic acid dialkyl ester of the formula (XIV): wherein R is the same as methanesulfonyl chloride as defined in the preceding paragraph;

the resulting 3- (2-methanesulfonyloxyethylamino-2-pentenoic acid dialkyl ester of formula XV, wherein R is as defined above and Ms is methanesulfonyl) in an organic solvent with an alkali metal halide, preferably lithium bromide; or reacting with sodium iodide;

the resulting 3- (2-haloethylamino) -2-pentenedioic acid dialkyl ester of formula (XIII) wherein R is as defined above and X is halogen in an aprotic polar solvent in a strong reacting with a base;

- the resulting compound of formula XVII, wherein R is as defined above, is reacted in aqueous solution with 2-haloacetaldehyde of formula XX, wherein X is a halogen, followed by a), b), c) and d) above; The compound of formula (XII) obtained according to any one of the processes wherein R is as defined above is hydrolyzed to the corresponding free dicarboxylic acid in a known manner (for example, as described in United States Patent 4,089,969, cited above). Esterifying it with a monoester of formula (XVIII) having a C4 alkyl group; then decarboxylating the resultant compound of formula XVIII to the corresponding compound of formula XIX and converting the resultant compound of formula XIX into the corresponding ester of formula IA with an appropriate aroylamide, optionally to a free carboxylic acid, wherein Ar and R are as defined above.

The reaction scheme of the above described procedures is illustrated in the accompanying drawings in Schemes (A), (B) and (C). In Step 1 of the processes, the di (lower alkyl) 3- (2-haloethylamino) -2-pentenedicarboxylic acid ester ("haloamine") is prepared from the di (lower) alkyl ester of acetone dicarboxylic acid or directly by reaction with the hydrohalide salt of 2-haloethylamine or by first reacting with 2-aminoethanol and subsequently replacing the hydroxy group with a halogen atom.

In Variant I, Step 1, the di-lower alkyl ester of acetone dicarboxylic acid is preferably reacted in aqueous solution with the hydrohalide salt of 2-haloethylamine.

The pH of the solution is preferably from 5 to 12, more preferably from 5 to 8. The pH is generally controlled by the use of an aqueous solution of a weak base such as sodium acetate as the reaction medium, but other pH control methods may also be employed. The reaction partners may be added simultaneously or sequentially, but it is desirable that the hydrogen halide salt of 2-haloethylamine is not added to the basic solution until the solution contains the acetyl dicarboxylic acid ester to avoid the formation of aziridines. Generally, the 2-haloethylamine and the acetone dicarboxylic acid ester are dissolved simultaneously or in the order indicated in water and the weak base is added in solid form to the reaction mixture. The reaction is preferably carried out at 0-35 ° C, more preferably at room temperature, for example 20-30 ° C, preferably 15 minutes to 24 hours, more preferably 4-18 hours. The intermediate 3- (2-haloethylamino) -2-pentenedicarboxylic acid di-lower alkyl ester ("haloamine") usually crystallizes and can be isolated by filtration as a mixture of E and Z isomers. Intermediates of formula (XIII) wherein R is methyl and X is bromo or chloro are preferred and sodium acetate is preferably used to adjust the pH.

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II. In step 1, the di-lower alkyl ester of acetondicarboxylic acid is reacted with 2-amino-ethanol (also known as 2-hydroxyethylamine) in an aprotic polar solvent to form the hydroxy enamine XIV ) is converted to the corresponding haloethylamine of formula XIII via mesyloxyethylamine. The reaction may be terminated during the formation phase of the mesyloxyethylamine and the mesyloxyethylamine formed, if desired, can be prepared as described in Method II. Alternatively, it can be cyclized directly according to step 2.

The reaction is generally carried out by dissolving the dicarboxylate in the solvent and then slowly adding 2-hydroxyethylamine to the resulting solution and azeotropic distillation of the water formed during the reaction. The preparation of hydroxyenamine can be carried out under less stringent conditions (cf., for example, U.S. Patent No. 4,089,969), but the subsequent reaction requires an anhydrous solution of hydroxyamine, so it is expedient to prepare it in an aprotic medium. The resulting solution contains a mixture of the E and Z isomers of hydroxyamine and can be used in the next step without purification. As in Variant I, Step 1, the compound containing R is preferably methyl.

The esterification of hydroxyamines of formula XIV is preferably carried out in the presence of an organic base such as a tertiary amine and optionally an aprotic polar solvent with mesyl chloride at a temperature of -10 ° C to room temperature, preferably 0-10 ° C. The tertiary amine is suitably added after cooling to the appropriate temperature from the previous reaction and mesyl chloride is added slowly over a period of 30 minutes to 10 hours, usually 2-5 hours. The dissolution of the mesyloxyethylamine (XV) is quenched by the addition of water and the solvent is removed from the organic phase, and the mixture of the E and Z isomers of the mesyloxyethylamine can be used in the next step without further purification. If the ethylamine is directly cyclized without conversion to the haloamine, purification is advantageous.

The mesyloxyethylamine (XV) is converted to the haloamine (XIII). The reaction is carried out under anhydrous conditions in an aprotic solvent at a temperature ranging from room temperature to reflux temperature, for example 30-100 ° C, depending on the reagents and the temperature used.

The reaction is carried out for 1 to 30 hours, for example 5 to 20 hours, with anhydrous alkaline halide, preferably bromide or iodide such as sodium iodide or lithium bromide. The resulting haloamine is easily isolated by addition of water to the reaction mixture, the organic phase is washed and the solvent is removed to give a mixture of the E and Z isomers of the haloamine, which can be purified by recrystallization.

Preparation of Compounds of Formula XII

In Step 2, the haloamine (XIII) or mesyloxyethylamine (XV) obtained in Step 1 is cyclized with a strong base in an aprotic polar solvent.

In Variant I, Step 2, a haloamine (XIII) is reacted with 2-haloacetaldehyde (XX), wherein X is as defined above. The reaction is preferably carried out in aqueous solution at a pH of 4.5 to 10, preferably at a pH of 5 to 8.5, preferably at 0 to 65 ° C, more preferably at room temperature for 1 to 48 hours, preferably 6 to 24 hours. Preferably X is a bromine atom and pH control is achieved by the presence of a weak base such as sodium acetate or sodium bicarbonate. The reaction is preferably carried out in the presence of 10 to 50% by volume of a water miscible co-solvent such as acetone.

To the aqueous solution of the weak base and 2-haloacetaldehyde is added the haloamine (XIII) and preferably a water miscible co-solvent. The reaction mixture is then stirred for a sufficient time and the resulting N- (2-haloethyl) pyrrole (XVI) is isolated by filtration. The 2-haloacetaldehyde is commercially available or may be prepared by any desired route. Preferred 2-bromoacetaldehyde is selected from the group consisting of 2-bromoacetaldehyde di (lower) alkylacetal, lower alkyl 1,2-dibromoethyl ether, 1,2-dibromoethyl acetate and the like. is acidically hydrolyzed and the weak base is added to an aqueous solution of the resulting 2-bromoacetaldehyde.

Preferably, the compound of formula II is used. Alternatively, the haloamine is generally dissolved in the solvent and 1-2 equivalents, preferably 1.1-1.5 equivalents, of the strong base are added in solid form. If the base is insoluble in the solvent, a phase transfer catalyst, such as tetraalkylammonium halide or the like, may be added to the reaction mixture to facilitate the completion of the reaction. The reaction is preferably carried out at 15-35 ° C, more preferably at room temperature, for 1-30 hours. The resulting cyclic enamine (XVII) can be isolated, for example, by aqueous extraction of the solution and purified by ball-tube distillation and / or recrystallization. The E and Z isomers may be separated if desired, but this is not necessary since both react in Step 3. Preferably, X is bromine, and the base and solvent are preferably sodium hydroxide in dichloromethane, sodium hydroxide in tetrahydrofuran, or dimethyl sulfoxide, sodium hydride in tetrahydrofuran, and the like.

In III. Step 2, i.e. the cyclization of the mesyloxyethyl amines of formula (XV) is carried out in a similar manner to that described above, however, more bases, such as up to 6 equivalents of the base per mesyloxyethylamine, are generally employed and the reaction is more stringent. such as reflux and for a longer period of time. The mixture of the base and the solvent is preferably a mixture of aqueous sodium hydroxide solution and dichloromethane in the presence of a phase transfer catalyst.

Finally, in Step 3, in Variant I, an N- (2-haloethyl) pyrrole derivative of formula (XVI)

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It is cyclized with a solution of 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents, of a strong base in an aprotic polar solvent. In this process, the diester may be saponified to form the dicarboxylic acid of formula XII wherein R is hydrogen. The saponification is preferably carried out in a solvent for the cyclization reaction.

Preferably X is chlorine or bromine. The strong base is preferably a lithium atom-hindered amine, such as lithium diisopropylamine or lithium bis (trimethylsilyl) amine, and the solvent is preferably tetrahydrofuran. Other suitable strong bases and solvent mixtures are, for example, sodium hydroxide and dimethyl sulfoxide or mixtures of potassium methoxide and methanol, although the latter may result in significant amounts of N-vinylpyrrole impurities. The cyclization reaction of N- (2-iodoethyl) pyrrole in sodium hydride solution with dimethylformamide is described, for example, in U.S. Patent No. 4,089,969. U.S. Pat.

The compound of formula (XVI) is dissolved in an aprotic polar solvent and a solution of a strong base is added slowly, for example 1-24 hours, preferably 2-8 hours at -10-35 ° C, for example at room temperature, and then stirring to promote the formation of the pyrrolopyrrole diesters of formula (XII). The reaction is preferably carried out at 0 to 10 ° C for compounds of formula XVI where X is bromine and preferably 15 to 30 ° C for compounds where X is chlorine, if the strong base is lithium diisopropyl ) amine. The compounds of formula (XII) are isolated from the solution by removal of the solvent, and can be purified by conventional organic chemistry or, more generally, directly converted to the corresponding dicarboxylic acids of formula (XII) wherein R is hydrogen.

II. Alternatively, in Step 3, the pyrrole ring of the pyrrolopyrrole compound is formed by the reaction of a cyclic enamine of formula XVIII with a 2-haloacetaldehyde of formula XX in which X is as defined above. The reaction is preferably carried out at pH 4.5-10, more preferably 5-8.5 in aqueous solution. The cyclization reaction is preferably carried out at 15-35 ° C, more preferably at room temperature for 1-10 hours, preferably

2-5 hours. Preferably X is bromine and pH control is preferably achieved by the presence of a weak base such as sodium acetate or sodium bicarbonate. The process is preferably carried out in the presence of 10 to 50% by volume of a water miscible co-solvent such as methanol.

The cyclic enamine of formula (XVII) is usually added to an aqueous solution of 2-haloacetaldehyde and a weak base, preferably with a water miscible co-solvent. After stirring for a suitable period of time, the resulting compound of formula (XII) may be isolated from the reaction mixture, for example by evaporation of the solvent, and purified if desired. The 2-haloacetaldehyde can be purchased commercially or prepared in any desired manner. For example, the preferred 2-bromoacetaldehyde is prepared by 2-bromoacetaldehyde di (lower alkyl) acetal, a (lower) alkyl 1,2-dibromoethyl ether, 1,2- dibromoethyl acetate, etc. acidic hydrolysis to give an aqueous solution of 2-bromoacetaldehyde in each case.

If the dicarboxylic acids of formula (XII) in which R is hydrogen are to be prepared, the diesters may be saponified by conventional chemical means, for example, by removal of the ester groups with a strong base and addition of an acid to promote dicarboxylic acid formation. The diester is dissolved in an aqueous solution of an alkali metal hydroxide or carbonate, such as sodium hydroxide, which may also contain a water miscible co-solvent such as methanol, and at room temperature to reflux temperature for 30 minutes to 24 hours, preferably 1- Allow to stand for 4 hours. The cooled solution is then acidified with an aqueous solution of a strong acid, such as 35% aqueous hydrochloric acid, and the precipitated dicarboxylic acid precipitate can be removed by filtration. The dicarboxylic acid may be purified by conventional means, preferably by recrystallization from an aqueous solution. The saponification may also be carried out on the isolated material, but may also be carried out in the solution formed in the cyclization reaction described above. For example, water may be added to the solution, the aprotic polar solvent may be partially removed by distillation, and a strong base such as sodium hydroxide may be added directly to the resulting pyrrolopyrrol diester solution, followed by partial removal of the solvent and an aqueous solution of a strong acid for example, 35% hydrochloric acid is added. The dicarboxylic acid precipitate precipitates out of solution and can be removed by filtration. The dicarboxylic acid may be purified by conventional chemical methods, preferably by recrystallization from an aqueous solution.

The acidic group at the 1-position of the resulting dicarboxylic acid of formula XII wherein R is hydrogen can be selectively esterified with a lower aliphatic alcohol such as methanol, ethanol, isopropanol, n-butanol, and the like, 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1- (carboxylic acid alkyl ester) -7-carboxylic acid is obtained. The reaction is preferably carried out at 0-50 ° C for 1-4 hours.

The decarboxylation of the monoesterified compounds of formula (XVIII) to the compounds of formula (XIX) is accomplished by heating a compound of formula (XVIII) at a high temperature, such as 230 to 280 ° C, for the time necessary to complete the reaction. The completion of the reaction can be monitored by the degree of evolution of carbon dioxide and by thin layer chromatography, with decarboxylation generally taking place within 45-90 minutes. The resulting product, i.e., the 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid alkyl ester of formula (XIX), can be purified by chromatography. During the decarboxylation of a small amount of the compound of formula XVIII, the compound of formula XIX can also be directly distilled from the reaction vessel.

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The condensation of the compound of formula XIX can be accomplished in two ways, either by reaction with an amide or with a morpholide.

Reaction of a compound of formula (XIX) with an amide of formula Ar-CO-N (CH ₃ ) ₂ (wherein Ar is one of the substituents listed above) provides the corresponding 5-aroyl-1,2-dihydro-3H of formula (IA). leading to an alkyl ester of pyrrolo [1,2-a] pyrrole-1-carboxylic acid. This reaction is preferably carried out in an inert organic aprotic solvent in the presence of phosphorus oxychloride at reflux for 1 to 175 hours in an inert atmosphere and then in the presence of sodium acetate for 2 to 10 hours. Other acid chlorides such as phosgene or oxalyl chloride may be used instead of phosphorus oxychloride. The condensation is preferably carried out by adding a solution of a compound of formula (XIX) in a suitable solvent to a preformed mixture prepared by dissolving 1.1-5 molar equivalents of the desired amide and phosphorus oxychloride in the same solvent and refluxing the mixture was refluxed under argon for 6-72 hours and then 3-10 molar equivalents of sodium acetate were added and refluxed for 4-6 hours. Suitable solvents for the reaction include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like, dimethoxyethane and tetrahydrofuran. Preferably, 1,2-dichloroethane is used.

Examples of applicable Ν, Ν-dimethylaryl amides include:

Ν, Ν-dimethylbenzamide, N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, N, N-dimethyl-p-toluamide, NN-dimethyl-p-ethylbenzamide, N, N-dimethyl-o-propyl-benzamide, N, N-dimethyl-m-butyl-benzamide, N, N-dimethyl-o-methoxybenzamide, N, N-dimethyl-m-methoxybenzamide, N, N- dimethyl p-ethoxybenzamide, N, N-dimethyl p-isopropoxybenzamide.

These amides are known compounds and are commercially available, but can be prepared in a conventional manner from the corresponding acids, for example by converting the acids to acid chlorides and then reacting with dimethylamine.

When an aroyl morpholide is used, a compound of formula XIX is reacted with an aroyl morpholide in the presence of an inorganic acid halide such as POCl ₃ , POBr ₃ , SO ₂ Cl ₂ or the like, preferably POCl ₃ . Quantitative ratios of reacting compounds are not critical. Suitable inorganic organic solvents such as dichloroethane, chloroform or carbon tetrachloride, preferably methylene chloride, may also be used. However, the presence of a solvent is not always preferred. The reaction mixture is shaken and preferably stirred for 0.5-36 hours, preferably 1-5 hours at 30-35 ° C, preferably 40-45 ° C.

A solution of the pyrrolopyrrole compound (XIX) in an inert solvent, preferably dichloromethane, is added to the above mixture. The ratio of the compounds involved in the reaction is not critical here, but it is preferred that the molecular weight of the substrate is slightly lower than the lower molar amount of reagent in the prepared morpholide / halide mixture. The resulting reaction mixture is kept at 30-70 ° C, preferably 40-45 ° C, until the desired reaction is complete, which is usually 1-8 hours, more often 1.5-3 hours.

The whole process so far is carried out under inert atmosphere to exclude the presence of water. Any anhydrous gas can be used for this purpose, but nitrogen gas is most preferred. As the reaction progresses, the problem of water in ambient air becomes less important due to the smaller accessible surface area, but it is prudent to use nitrogen routinely.

The intermediate formed in this step cannot be well isolated but must be hydrolyzed to either the corresponding ester of formula IA or the free acid of formula I.

If a compound of formula (I) is to be prepared, it is preferable to use a one-step process. In this case, the reaction mixture is poured into a solution of a polar solvent, preferably an aqueous solution of a strong base such as mineral hydroxides or carbonates, preferably sodium hydroxide. The base is used in large excess. The mixture is then maintained at 30-100 ° C, preferably 40-60 ° C, until the reaction is complete.

Alternatively, if the process is carried out in two steps or if the compounds of formula IA are to be prepared,

3-10 molar equivalents of sodium acetate or other weak base are added directly and the reaction mixture

Reflux for 4-6 hours. The product obtained is the corresponding compound of formula IA.

Subsequently, if the products obtained are to be converted into compounds of formula I, the hydrolysis is conveniently carried out with an alkali metal hydroxide or carbonate in aqueous solution or with a lower aliphatic alcohol such as methanol, ethanol and the like. in aqueous solution. The reaction is carried out at room temperature to reflux temperature for 15 minutes to 3 hours. The hydrolysis is preferably carried out in an aqueous solution of potassium carbonate in methanol at reflux for 30 minutes.

Alkali hydrolysis of the alkyl ester group of the compounds of formula IA yields the corresponding free acids of formula I. This hydrolysis is conventionally carried out using an alkali metal hydroxide or carbonate such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, lower aliphatic alcohols such as methanol, ethanol and the like. aqueous solution at room temperature to reflux temperature for 15 minutes to 2 hours under inert atmosphere. The hydrolysis is preferably carried out in potassium carbonate in aqueous methanol at reflux for 30 minutes.

The resulting free acid of formula (I) can be converted to other C 1 -C 12 alkyl esters by conventional methods, e.g.

HU213 614Β

a) reacting with the alcohol corresponding to the desired ester in the presence of a strong mineral acid;

b) reacting with an ethereal diazoalkane;

c) reacting with the appropriate alkyl iodide in the presence of lithium carbonate.

Salts of the compounds of formula (I) may be prepared by reacting the free acid with an appropriate amount of a pharmaceutically acceptable base. The reaction is carried out in water or in a mixture of water and an inert water-miscible organic solvent at 0-100 ° C, preferably at room temperature. Such inert, water-miscible organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane or tetrahydrofuran. The molar ratio of the compound of formula (I) to the base is chosen to correspond to the desired ratio of the salt of choice.

Methods for further processing of intermediates of formula (XII) into the final product for the preparation of compounds of formula (IA) and (I) are described, for example, in U.S. Patent Nos. 4,089,969 and 4,353,829.

Practical embodiments of the process of the invention are illustrated by the following examples.

Example 1

Preparation of 3- (2-Bromoethylamino) -2-pentene dicarboxylic acid dimethyl ester - Procedure I, Step I

A) 2-Bromoethylamine hydrobromide (12.35 g, 60 mmol) was dissolved in water (30 mL) with stirring at room temperature (20 ° C) followed by acetone dicarboxylic acid (10.0 g, 57 mmol). dimethyl ester is added. After 5-10 minutes, solid anhydrous sodium acetate (14.35 g, 175 mmol) was added and stirring continued. After about 80 minutes, precipitation of 3- (2-bromoethylamino) -2-pentene dicarboxylic acid dimethyl ester begins and the solution is stirred at room temperature for 17 hours. The slurry is then diluted with 20 ml of cold water, kept at 0-5 ° C for 30 minutes, filtered, and the precipitate is washed with 50 ml of cold water 0-5 ° C and dried to constant weight. 13.9 g of 3- (2-bromoethylamino) -2-pentene dicarboxylic acid dimethyl ester are obtained in the form of a white solid. Yield: 86%. M.p. 71-72 ° C.

NMR (CDCl ₃ ): δ: 8.80 (1H, broad); 4.60 (1H, s); 3.85 (3H, s); 3.77 (3H, s); 3.35-3.72 (4H, broad m); 3.25 (2H, s).

B) In place of 2-bromoethylamine hydrobromide, 10.8 g of 3- (2-chloroethylamine hydrochloride) were treated with 7.0 g (60 mmol) of 2-chloroethylamine hydrochloride. chloroethylamino) -2-pentene dicarboxylic acid dimethyl ester was obtained as a white solid. Yield: 80%. M.p. 75-76 ° C.

NMR (CDCl ₃ ): δ: 8.80 (1H, broad); 4.60 (1H, s); 3.75 (3H, s); 3.65 (3H, s); 3.60 (4 H, m); 3.27 (2 H, s).

C) The procedure of Example E, A or B was followed, but using the following starting materials instead of the acetone dicarboxylic acid dimethyl ester:

acetone dicarboxylic acid diethyl ester, acetone dicarboxylic acid dipropyl ester, acetone dicarboxylic acid di (isopropyl) ester, or acetone dicarboxylic acid di (t-butyl) ester, to give the following products:

3- (2-bromoethyl) -2-penten-dicarboxylic acid diethyl ester,

3- (2-bromoethyl) -2-penten-dicarboxylic acid dipropyl ester;

3- (2-bromoethyl) -2-penten-dicarboxylic acid di (iso-propyl) ester,

3- (2-bromoethyl) -2-pentenoic acid di (t.butil) ester,

3- (2-chloroethyl) -2-penten-dicarboxylic acid diethyl ester,

3- (2-chloroethyl) -2-penten-dicarboxylic acid dipropyl ester;

3- (2-chloroethyl) -2-penten-dicarboxylic acid di (iso-propyl) ester,

3- (2-chloroethyl) -2-pentenoic acid di (t.butil) ester.

Example 2

Preparation of 3- (2-bromoethylamino) -2-pentene dicarboxylic acid dimethyl ester - Part II. procedure variant, step 1

A) Place 196.1 g (1.13 mL) of dimethyl acetone dicarboxylic acid in a 3 L three-necked flask with a stir bar and a water extractor fitted with a reflux condenser and a dosing funnel and purge with nitrogen. The water extractor was filled with dichloromethane and 800 ml of dichloromethane was added to the flask. 68.8 g (1.13 moles) of amino-ethanol was added dropwise to the flask over 10 minutes via the addition funnel, and the mixture was heated to 30 ° C and refluxed for 24 hours. Subsequently, thin layer chromatography showed very little dicarboxylate remaining and 20 ml of water collected in the water extractor.

A solution of 3- (2-hydroxyethylamino) -2-pentene dicarboxylic acid dimethyl ester was cooled to 0 ° C and triethylamine (170.6 g, 235 mL, 1.69 mol) was added in one portion. . Then, 168.8 g (1.47 moles) of methanesulfonyl chloride is added dropwise over a period of 3.75 hours to a temperature of 5-7 ° C. The medium yellow suspension darkens to orange-yellow when the last 10 ml of methanesulfonyl chloride is added. The mixture was stirred at 0 ° C for an additional 2 h and water (250 mL) was added. The organic layer was washed with water (4 x 500 mL), brine (250 mL) and dried over anhydrous magnesium sulfate overnight. After filtration, the solvent was removed by rotary evaporation under reduced pressure at 50 ° C. 310.0 g of 3- (2-methanesulfonyloxyethylamino) -2-pentene dicarboxylic acid dimethyl ester are obtained in the form of a red oil. Yield: 93%. The mesyloxyethylamine can be purified or converted, if necessary or desired, to a haloamine according to the following procedure or as described in Scheme II. version 2 directly.

156.3 g (529 mmol) of dimethyl 3- (2-methanesulfonylethylamino) -2-pentene dicarboxylate in a 2 liter, 3-neck, mechanical stirrer, thermometer and

21 Place in a flask fitted with a condensation vessel connected to the reflux condenser. Dichloromethane (750 mL) was added to the flask and stirred until the mesylate was completely dissolved, then 69.0 g (794 mmol) of anhydrous lithium bromide was added and the mixture was stirred at 35 ° C for 19 hours. The mixture was cooled to 0 ° C, water (250 ml) was added, the mixture was stirred for 5 minutes and the layers were separated. The organic layer was washed with water (3 x 250 mL) and brine (150 mL) and dried over anhydrous potassium carbonate for 15 min. The solvent was removed by rotary evaporation under reduced pressure at 50 ° C to give 128.4 g of crude 3- (2-bromoethylamino) -2-pentene dicarboxylic acid dimethyl ester as a yellow oil which solidified rapidly to a yellow solid. . The crude product was purified by extraction with hot hexane (5 x 750 mL) and recrystallized from hexane to give a total of 90.8 g of dimethyl 3- (2-bromoethylamino) -2-pentene dicarboxylate as a white mirror. form. Yield: 61.2%. The NMR spectrum (CDC1 ₃₎ the ratio of Z / E isomers of 19: 1 was: 1 CDC1 ₃ solution and again three days later, when measuring the ratio of Z / E isomers 4th The two isomers were not separated.

B) Following the procedure of Example 2, Part A, but using light iodine 3- (2-iodoethylamino) -2-pentene dicarboxylic acid, sodium iodide instead of lithium bromide and using dichloromethane instead of acetone or acetonitrile dimethyl ester is obtained which can be purified by conventional means.

C) According to the procedure of Example 2, A, but using lithium chloride instead of lithium bromide, 3- (2-chloroethylamino) -2-pentene dicarboxylic acid dimethyl ester is prepared.

D) Similar to the procedures of Example 2, Steps A-C, but using other acetone dicarboxylic acid di (lower) alkyl esters, the corresponding 3- (2-chloroethylamino) -2-pentene dicarboxylic acid di (lower) alkyl esters are obtained.

Example 3

Preparation of N- (2-bromoethyl) -3-methoxycarbonyl-2-pyrroloacetic acid methyl ester -1. procedure variant, step 2

A) 2-Bromoacetaldehyde diethyl acetal (42.2 g, 214 mmol) was placed in a 100 mL, three-necked flask equipped with a mechanical stirrer, a condenser and a thermometer attached to the reflux condenser. A solution of hydrobromic acid (4.0 mL, 36 mmol) in water (9 mol) in water (16 mL) was added and the mixture was refluxed for 1 hour and cooled to room temperature to give a solution of 2-bromoacetaldehyde.

Sodium acetate (41.0 g, 500 mmol) was added to a solution of 2-bromoacetaldehyde and refluxed for 5 minutes to pH 6. The flask was placed in a cold tap water bath and 3- (20.0 g, 71 mmol) was added. 2-Bromoethylamino) -2-pentene dicarboxylic acid dimethyl ester was added followed by 40 ml of isopropanol and the solution was stirred at room temperature at 25 ° C. After about 35 minutes, the solids completely dissolve and after 90 minutes, a precipitate begins to form. After stirring at room temperature for 1 hour, the solution was cooled to 0 ° C and stirred at this temperature for 1 hour, then filtered through a coarse glass filter. The precipitate was washed with 400 mL of ice-cold water and 150 mL of ice-cold isopropanol. 15.7 g of crude yellow-brown solid N- (2-bromoethyl) -3-methoxycarbonyl-2-pyrroloacetic acid methyl ester are obtained. Yield: 72%. 129-130.5 ° C.

NMR (CDCl ₃ ): δ: 6.58 (2H, q); 4.20 (2H, tr); 4.10 (2 H, s); 3.75 (3H, s); 3.65 (3H, s); 3.50 (2 H, tr).

B) Place 20.9 g (106 mmol) of 2-bromoacetaldehyde diethyl acetal in a 100 mL three-necked flask with stirring bar, condenser and thermometer, followed by 17.7 g (106 mmol) of hydrobromic acid in 54 mL 48.5% solution in water was added and the mixture was stirred at 40 ° C for 3 hours, then cooled to room temperature and extracted with 100 ml of hexane.

A solution of 2-bromoacetaldehyde was obtained.

The solution was stirred for 1 hour at 0 ° C

Add 17.8 g (212 mmol) of sodium acetate as a thick suspension in 15 ml of water and stir for a further 10 minutes. 3- (2-Chloroethylamino) -2-pentene dicarboxylic acid dimethyl ester (20.0 g, 85 mmol) was added followed by acetone (50 mL) and the solution was allowed to warm to room temperature and stirred for 20 hours. . The resulting slurry was cooled to 0 ° C and held at this temperature for 4 hours, then filtered through a coarse glass filter. The precipitate was washed with water (300 ml) and dried. 19.9 g of N- (2-chloroethyl) -3-methoxycarbonyl-2-pyrroloacetic acid methyl ester are obtained in the form of white crystals. Yield: 90%. 110-111 ° C.

NMR (CDCl 3): δ: 6.65 (2H, q); 4.25 (2H, tr), 4.18 (2H, s); 3.82 (3H, s); 3.75 (2H, tr); 3.73 (3 H, s).

C) By following the procedures of Example E, A or B, but using 2-chloroacetaldehyde diethyl acetal instead of 2-bromoacetaldehyde diethyl acetal, the following products are obtained:

N- (2-bromoethyl) -3-methoxycarbonyl-2-pyrrol-acetic acid methyl ester,

N- (2-chloroethyl) -3-methoxycarbonyl-2-pyrrol-acetic acid methyl ester.

D) Following the procedures described in Example E, A to C, but other than the corresponding compounds, other 3- (2-haloethylamino) -2-pentene dicarboxylic acid di (lower alkyl) esters, e.g. Dimethyl ester of (2-iodoethylamino) -2-pentene dicarboxylic acid or diethyl ester of 3- (bromoethylamino) -2-pentene dicarboxylic acid, and the like. using other N- (2-haloethyl) -3-alkoxycarbonyl-2-pyrroloacetic acid alkyl esters such as N- (2-iodoethyl) -3-methoxycarbonyl-2-pyrrole. methyl acetic acid, N- (2-bromoethyl) -3-ethoxycarbonyl-2-pyrrole acetic acid ethyl ester, and the like. we produce.

Example 4

Preparation of 3-methoxycarbonyl-2-pyrrolidinylidene-carboxylic acid methyl ester —II. procedure variant, step 2

A) 3- (2-Bromoethylamino) -2-pentene dicarboxylic acid dimethyl ester (5.00 g, 17.8 mmol) in a stirred solution

Transfer to a 100 ml flask containing 50 ml of dichloromethane and stir until complete dissolution is achieved. Sodium methoxide (1.92 g, 35.5 mmol) was then added over a period of 18 minutes while developing heat.

After stirring at room temperature for 23 hours, the reaction mixture was extracted with water (4 x 50 mL) and brine (50 mL), then dried over anhydrous magnesium sulfate. After rotary evaporation of the solvent, 2.27 g of a pale yellow solid are obtained, which are separated by three thin layer chromatography. The largest amount of product was recrystallized from hexane to give crystalline (Z) -3-methoxycarbonyl-2-pyrrolidinylidene-carboxylic acid methyl ester.

84-85 ° C.

NMR (CDCl ₃ ): δ: 7.8-8.0 (1H, bs); 4.70 (1H, d, J = 0.67 Hz); 3.75 (3H, s); 3.64 (3H, s); 3.5-3.8 (3 H, m); 2.1-2.5 (2 H, m).

A smaller amount of (E) -3-methoxycarbonyl-2-pyrrolidinylidene carboxylic acid methyl ester was isolated as an oily product.

NMR (CDCl ₃ ): δ: 7.8-8.0 (1H, bs); 4.64 (1H, s); 4.08 (1H, d, J = 11Hz); 3.77 (3H, s); 3.65 (3H, s); 3.55 (1H, d, J = 11Hz); 3.5-3.9 (1H, m); 2.0-2.4 (2 H, m).

3- (1-Aziridinyl) -2-pentene dicarboxylic acid dimethyl ester was isolated as a very small amount of oily product.

B) To a solution of 4.71 g (20 mmol) of dimethyl 3- (2-chloroethylamino) -2-pentene dicarboxylate in 50 ml of dichloromethane at room temperature was added 1.62 g (30 mmol) of sodium methoxide. we give you four equal portions over 45 minutes. The reaction mixture, which turns slightly yellowish and precipitates, is stirred for 27 hours and then worked up as described in part A of this example to give 2.8 g of a yellow oily product which is characterized by thin layer chromatography and NMR (Z). and (E) -3-methoxycarbonyl-2-pyrrolidinylidene-carboxylic acid methyl ester.

C) To a solution of 3- (2-iodoethylamino) -2-pentene dicarboxylic acid dimethyl ester (3.3 g, 10 mmol) in distilled tetrahydrofuran (20 mL) was added tetrabutylammonium bromide (0.32 g, 1 mmol). and 0.41 g (10.3 mmol) of sodium hydroxide particles were added and the resulting mixture was stirred at room temperature for 5.5 hours. Dichloromethane (30 mL) and water (20 mL) were added and the mixture was stirred for 5 minutes to give a light brown upper aqueous phase and a pale yellow lower organic phase. The organic layer was separated and the aqueous layer was washed with dichloromethane (2 x 20 mL). The post-wash solutions were combined with the organic phase and the resulting mixture was washed with water (2 x 20 mL) and brine (20 mL), and the solvent was evaporated by rotary evaporation. 1.8 g of a light brown oil are obtained which solidifies on standing. Yield: 90%. Thin layer chromatography and NMR determined large and small amounts of (Z) - and (E) -3-methoxycarbonyl-2-pyrrolidinylidene-carboxylic acid methyl ester and very small amounts of 3- (vinylamino) -2 pentene dicarboxylic acid dimethyl ester is formed.

D) Similarly, using other 3- (2-haloethylamino) -2-pentene dicarboxylic acid di (lower alkyl) esters and optionally other strong bases and / or aprotic polar solvents, in the present Example A) -C), other 3- (lower) alkoxycarbonyl-2-pyrrolidinylidenecarboxylic acid (lower) alkyl esters are prepared.

Ε) III. process

To a 1 liter, 3 liter, 3-necked stirrup flask equipped with a condenser attached to the reflux condenser, add 32.0 g (800 mmol) of sodium hydroxide and 32.0 mL of water, and stir until complete dissolution is achieved. . Dichloromethane (640 mL) followed by dimethyl ester of 3- (2-methanesulfonyloxyethylamino) -2-pentene dicarboxylic acid (40.12 g, 136 mmol) and tetrabutylammonium (6.57 g, 20 mmol) were added. Place bromide in the flask. The reaction mixture is heated at reflux for 7 hours, at which point a small amount of the starting mesyloxyethylamine can be detected by thin layer chromatography. The reaction mixture was therefore stirred for an additional 14 hours, at which time no residue of mesyloxyethylamine was detected by TLC. The mixture was washed with water (3 x 200 mL) and brine (200 mL) and dried over anhydrous magnesium sulfate to give a yellow solution. The solvent was rotary evaporated under reduced pressure to give a red liquid which was distilled in a ball-tube distillate at 0.3 mm Hg at 50-55 ° C. 19.74 g of (Z) - and (E) -3-methoxycarbonyl-2-pyrrolidinylidene carboxylic acid methyl ester are obtained in the form of a clear, colorless oil. Yield: 72.9% distilled.

F) Using other 3- (2-mesyloxyethylamino) -2-pentene dicarboxylic acid di (lower alkyl) esters and optionally other strong bases and / or aprotic polar solvents as described in Section E of this Example The process for the preparation of other 3- (lower) alkoxycarbonyl-2-pyrrolidinylidenecarboxylic acid (lower) alkyl esters.

Example 5

Dimethyl ester of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7- Preparation of dicarboxylic acid - Step 3

A) Procedure I A solution of n-butyllithium (1.3 mmol) in n-butyl lithium (1.3 M in hexane) was slowly stirred at -5 to 0 ° C under nitrogen with 10 g (13.8 mL, 98 mmol) of di (isopropyl). ) to a solution of the amine in 50 ml of dry tetrahydrofuran. The resulting solution was added to a funnel and N-2-bromoethyl-3-methoxycarbonyl-2-pyrroloacetic acid methyl ester (20 g, 66 mmol) was added under nitrogen with stirring at 0-5 ° C. It is added to a thick suspension of 100 ml of dry tetrahydrofuran. Slight heating is observed and dissolution is complete after the addition of two thirds of the lithium di (isopropyl) amine solution. The resulting solution was stirred at 10 ° C for 2 hours and then with 100 ml of water

HU213 614Β is diluted while little heat is generated. The solvents were removed by atmospheric distillation: 240 mL was collected at 80 ° C to facilitate dissolution of the 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid dimethyl ester. . The diester may be isolated at this point by interrupting the reaction with water and extracting with an organic solvent such as ethyl acetate and evaporating the solvent. The purification is carried out by standard methods; mp 76-77.5 ° C. Alternatively, the diester is not isolated from the solution but saponified to give the corresponding carboxylic acid.

The solution from the previous section in the vessel was cooled to 50 ° C and 6.0 g (150 mmol) of sodium hydroxide was added. The methanol was then removed at atmospheric pressure at a vessel temperature of 97 ° C. The resulting solution was cooled to 5 ° C and acidified with 12 ml of 12M hydrochloric acid (18 ml, 216 mmol) while the temperature rose to 15 ° C. The resulting mixture was cooled to 5 ° C, filtered and the precipitate was washed with cold water (50 mL). After drying, 11.4 g of crude 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid are obtained, m.p. 195.5-197 ° C (dec). The crude product was found to contain 91.4% 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and 7.0% N-vinyl-3-carboxy-2-pyrroloacetic acid. .

Β) Procedure I

A solution of n-butyllithium (295.5 ml, 0.77 mol) in hexane (2.6 mol) was stirred at 0-3 ° C with 78.9 g (0.78 mol, 109.3 ml) of di (isopropyl) ) -amine is added dropwise to a solution of 200 ml of freshly distilled tetrahydrofuran. The resulting solution was charged to a funnel and stirred at room temperature with 150.0 g (0.58 mol) of methyl N- (2-chloroethyl) -3-methoxycarbonyl-2-pyrroloacetic acid in 750 ml of dry tetrahydrofuran. solution. The addition was continued for 4 hours and the temperature was maintained at 23-27 ° C. The resulting solution was stirred for 16 hours and then diluted with 500 ml of water for 10 minutes while developing little heat. The solvents were removed by atmospheric distillation until the vessel reached 75 ° C. The resulting solution was cooled to 50 ° C and 53.0 g (1.33 mol) of sodium hydroxide were added and the methanol was removed by atmospheric distillation until the temperature of the vessel reached 95 ° C. A total of 1370 ml of solvent was collected. The solution in the vessel was cooled to -3 -0 ° C and acidified with 12 ml hydrochloric acid (180 mL, 216 mmol) while the temperature rose to 18 ° C. The resulting mixture was cooled to -3 -0 ° C, kept at this temperature for 30 minutes, then filtered and the precipitate was washed with ice-cold water (300 ml). After drying, 107.8 g of crude 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid are obtained. The crude product was found to be 96.6%

It also contains 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid.

C) I. live price version

By following the procedure of Sections A and B of this example, but using N- (2-bromoethyl) -3-methoxycarbonyl-2-pyrroloacetic acid methyl ester or N- (2-chloroethyl). Instead of -3-methoxycarbonyl-2-pyrroloacetic acid methyl ester

N- (2-iodoethyl) -3-carbomethoxy-pyrrole-2-acetic acid methyl ester,

N- (2-chloroethyl) -3-ethoxycarbonyl-2-pyrroloacetic acid ethyl ester and the like

The following products were prepared using N-haloethyl-3-lower alkoxycarbonyl-2-pyrroloacetic acid lower alkyl esters:

1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid dimethyl ester or 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7- dicarboxylic acid,

1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid diethyl ester or 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and similar

1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid di-lower alkyl esters or 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 , 7-dicarboxylic acid.

D) II. process

A mixture of 2-bromoacetaldehyde dimethylacetal (1.70 g, 10 mmol), 48.5% hydrochloric acid (0.25 mL, 2 mmol) and water (2.5 mL) was heated at reflux for 75 min. a solution of bromoacetaldehyde is obtained. The solution was cooled to room temperature and 0.50 g of sodium acetate was added. The resulting solution was added under stirring over 3 hours to a mixture of 1.00 g (5 mmol) of methyl 3-methoxycarbonyl-2-pyrrolidinylidenecarboxylic acid, 3.10 g of sodium acetate and 2 ml of water in 10 ml of methanol. . The mixture was stirred for an additional hour and most of the solvents were evaporated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with aqueous sodium bicarbonate (2 x 25 mL) and dried over anhydrous magnesium sulfate. After evaporation of the solvent, 1.26 g of dimethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate are obtained.

E) II. process

Using 2-chloro-diethyl-acetal instead of 2-bromo-acetaldehyde-methyl-acetal, the following product was prepared according to the procedure of Section D of this Example:

1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid dimethyl ester.

F) IL variant

Similarly, other lower alkyl esters of 3- (lower) alkoxycarbonyl-2-pyrrolidinylidene carboxylic acids, e.g.

3-ethoxycarbonyl-2-pinOlidinilidén-carboxylic acid ethyl ester,

3-Propoxycarbonyl-2-pyrrolidinylidene-carboxylic acid (-n-propyl) ester and the like. Using the procedures of Sections D and E of this Example, other 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid di (lower) alkyl esters, e.g. following:

Diethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid,

1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid di (n-propyl) ester and the like.

HU 213 614 Β

Example 6

Preparation of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid

A) 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 in 10 ml of water The mixture was refluxed for one hour. The resulting solution was cooled to 0 ° C and acidified to pH 1 with 12M hydrochloric acid. After filtration and drying, 0.70 g

1.2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid is obtained; yield 71.4%.

B) By the procedure of Section A of this Example, the

In place of 1,2-hydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid dimethyl ester

1,2-Dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid diethyl ester and the like

The following compound is also prepared using 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid di (lower alkyl esters):

1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid.

Example 7

Preparation of 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acids

A) A cooled solution of 1.34 g of 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol was cooled with hydrogen chloride gas while maintaining the reaction temperature at 50 ° C. below. The ice bath was removed and the mixture was stirred at room temperature for 1 hour and then concentrated to dryness under reduced pressure. Benzene (10 mL) was added to the residue, and the solution was again evaporated in vacuo and this was repeated three times to completely remove excess hydrogen chloride gas. 1.58 g of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1- (carboxylic acid isopropyl ester) -7-carboxylic acid are obtained, which is recrystallized from a mixture of methanol and ethyl acetate. Yield: 96%. 144-145 ° C.

B) 1.054 g of 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1- (carboxylic acid isopropyl ester) -7-carboxylic acid was heated to 240-250 ° C in a 10 mL dry round flask. distilling the reaction product directly from the reaction vessel. The product is obtained in the form of a pale yellow oil, 745 g of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid ester. Yield: 87%.

Physical characteristics are as follows:

U.V. λ McOH up 215nm (c 6020) IRISH. v CHCl, up 1725 cm ^-1 NMR δ CDCl, TMS 1.22 (d, J = 7Hz, 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 = 3Hz, 1H), 6.43-6.53 ppm (m, 1H).

C) In a 100 ml round-bottomed flask equipped with condenser, nitrogen inlet and bubbling gas, 5.0 g of 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid isopropyl ester. -7-Carboxylic acid. The device is flushed thoroughly with nitrogen gas and then the nitrogen inlet is eliminated. The apparatus was immersed in an oil bath at 270 ° C and the reaction was monitored by the evolution of carbon dioxide gas (bubbling) and silica gel TLC (90: 10: 1 benzene: dioxane: acetic acid). After 45 minutes, the reaction is substantially complete. After 1 hour, remove the flask from the oil flask and transfer the contents of the flask to a 500 ml round bottom flask containing acetone. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (100 g silica gel). The fractions were eluted with 70: 30 hexane: benzene and 50:50 hexane: benzene. 2.77 g of isopropyl ester of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are obtained. Yield: 68%.

D) A solution of 179 mg of N, N-dimethyl-p-toluene amide and 0.11 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane was heated under reflux for 30 minutes. To this solution is added a solution of 193 mg of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole carboxylic acid isopropyl ester in 2 mL of dichloromethane. The reaction mixture was refluxed under argon for 8 hours, then sodium acetate (405 mg) was added and refluxed for an additional 5 hours. The resulting mixture was evaporated to dryness and the residue was chromatographed on a column of silica gel (12 g), eluting with 3: 1 hexane: ethyl acetate. 208 mg of isonropyl ester of 5- (p-toluoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid are obtained in the form of an oil.

Yield: 66% Lx ^H

Physical characteristics:

UV λ θ ^Η 256, 312 νμ (ε 8700, 19,500)

IRISH. v 1735, 1620, 1605 cm- '

NMR δ 1.23 (d, J = 7Hz, 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 = 4Hz, 1H), 6.70 (d, J = 4Hz) ), 7.10 (d, J = 8Hz, 2H), 7.60 ppm (d, J = 8Hz, 2H).

E) To a solution of 336 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid isopropyl ester in 10 ml of methanol, a solution of 690 mg of potassium carbonate in 5 ml of water added. The reaction mixture was refluxed for 30 minutes under a stream of nitro, then cooled and evaporated to dryness. The residue was partitioned between 10 ml of 10% aqueous hydrochloric acid and 50 ml of water, and the resulting mixture was extracted twice with 50 ml of ethyl acetate each time. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. Recrystallization from a mixture of ethyl acetate and hexane gave 238 mg of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. Yield: 89%. Mp 182-183 ° C.

F) 250 mg of isopropyl ester of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid in 8 ml of methanol.

A solution of HU213 614 Β was treated with a solution of sodium hydroxide (200 mg) in water (1 mL) under a stream of nitrogen while maintaining the reaction mixture at room temperature for 1.5 hours. The methanol was then removed under reduced pressure and the remaining basic solution was diluted with water (5 mL) and extracted with ether to remove the unsaponifiable product. The aqueous solution was acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts were dried and evaporated to dryness under reduced pressure. Recrystallization from ethyl acetate / hexane gave 5-p-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid.

G) Using the above procedure, but using 1.1-5 molar equivalents of Ν, Ν-dimethylbenzamide instead of N, N-dimethyl-p-toluamide, the following product is obtained in the form of a pale yellow oil while monitoring the progress of the reaction:

5-Benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid isopropyl ester.

Physical characteristics:

UV λ ^C ° ^H 245, 311 nm (ε 72,30,17,800)

IR δ ™ '1735, 1620 cm ^-1

NMR δ "I ¹ '1.24 (d, 6H, (CH _{3) 2} CH), 2.50 to 3.13 (m, 2H, H-2), 3.97 (dd, IH, Hl); 4.18-4.70 (m, 2H, H-3), 5.00 (Sept, 1H, (CH ₃ ) ₂ CH), 6.00 (d, 1H, H-7), 6.86 (d, 1H, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons)

MS: m / e 297 (M < ^{+ >} ).

Hydrolysis of the isopropyl ester group according to the method described above gives 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 160-161 ° C.

H) 1.45 g (7.90 mmol) of benzmorpholide are placed in a 25 mL round bottom flask and 1.25 mL (13.4 mmol) of phosphorus oxychloride are added. The mixture was heated in an oil bath at 40 ° C with stirring for 2.5 hours. A solution of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid methyl ester (1.00 g, 6.10 mmol) in dichloromethane (3.4 mL) was added and the The reaction was continued for 1 hour while the reaction was determined to be complete by TLC. The reaction mixture was carefully added to a solution of sodium hydroxide (3.09 g, 77.2 mmol) in water (10 mL) and the dichloromethane was allowed to reflux and the mixture was heated. An additional 1.30 g (32.5 mmol) of sodium hydroxide was then added. TLC showed that the hydrolysis was complete after 15 minutes. The reaction mixture was cooled and extracted with dichloromethane (2 x 10 mL). The aqueous phase was acidified by addition of concentrated hydrochloric acid (3.30 mL, 39.6 mmol) to give a milky liquid. The mixture was extracted with dichloromethane (5 x 10 mL). 1-4. The extracts were dried over sodium sulfate and filtered over Darco 660 charcoal. The resulting solution was evaporated to give a mixture of all the benzoyl isomers as a reddish brown solid. The solid was dissolved in 10 mL of 2-propanol and 10 mL of hexane was added to slowly crystallize. The first product was purified by TLC 0.90 g of pure 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid; yield: 58.5%.

160-161 ° C.

I) The procedure described in Section H) is followed except that an equimolar amount of 4-methoxybenzmorpholide is used instead of benzmorpholide. There was thus obtained 5- (4-methoxybenzoyl) -1,2-dihydro-3H-pyrrolo [3,2-a] pyrrole-1-carboxylic acid, m.p. 187-187.5 ° C.

Claims (3)

A process for preparing alkyl 5-aroyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid esters of formula IA Ar is phenyl optionally substituted with C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R is C 1 -C 4 alkyl and the corresponding free carboxylic acids of formula (I) wherein Ar is as defined above for the preparation of a dialkyl ester of acetone dicarboxylic acid of formula IV wherein R is as defined above for 1,2-dihydro-3H-pyrrolo of formula XII [1, 2-a] pyrrole-1,7-dicarboxylic acid dialkyl ester - where R is as defined above - hydrolyzing the ester groups of the latter compound, esterifying the 1-carboxyl group of the resulting free dicarboxylic acid and decarboxylating the resulting compound of formula XVIII where R is as above; , 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid alkyl esters, where R is as defined above, with an aryldimethylamide of the formula Ar-CO-N (CH ₃ ) ₂ - where the meaning of Price is the same as the one given above, characterized in that a) reacting an acetone dicarboxylic acid dialkyl ester of formula IV wherein R is C 1 -C 4 alkyl in both solutions with an hydrogen halide of a 2-haloethylamine; the resulting 3- (2-haloethylamino) -2-pentenedioic acid dialkyl ester of formula (XIII), wherein R is as defined above and X is halogen, a 2-halo compound of formula (XX): with acetaldehyde wherein X is halogen; the resulting N- (2-haloethyl) pyrrole dicarboxylic acid dialkyl ester of formula XVI - wherein R and X are as defined above - are cyclized with a strong base in an aprotic organic solvent; obsession b) reacting an acetone dicarboxylic acid dialkyl ester of formula (IV) wherein R is C 1 -C 4 alkyl in each aqueous solution with a hydrogen halide of a 2-haloethylamine; the resulting 3- (2-haloethylamino) -2-pentenedioic acid dialkyl ester of formula (XIII), wherein R is as defined above, X is halogen, in an aprotic polar solvent with a strong base reacted; HU213 614 Β reacting the resulting 3-alkoxycarbonyl-2-pyrrolidinylidene carboxylic acid alkyl ester of formula XVII in aqueous solution with 2-haloacetaldehyde of formula XX wherein X is halogen; obsession c) reacting an acetone dicarboxylic acid dialkyl ester of formula (IV) wherein each R is a 1 M alkyl group in an aprotic polar solvent with ethan-2-olamine; the resulting 3- (2-hydroxyethylamino) -2-pentenoic acid dialkyl ester of the formula (XIV): wherein R is the same as methanesulfonyl chloride as defined in the preceding paragraph; cyclizing the resulting 3- (2-methanesulfonyloxyethyl) amino-2-pentenoic acid dialkyl ester of formula XV wherein R is as defined above and Ms is methanesulfonyl in an aprotic polar solvent with a strong base; reacting the resulting compound of formula XVII wherein R is as defined above with an 2-haloacetaldehyde of formula XX where X is halogen in an aqueous solution; obsession d) reacting an acetone dicarboxylic acid dialkyl ester of formula IV wherein R is C 1 -C 4 alkyl in an aprotic polar solvent with ethan-2-ol; the resulting 3- (2-hydroxyethylamino) -2-pentenoic acid dialkyl ester of the formula (XIV): wherein R is the same as methanesulfonyl chloride as defined in the preceding paragraph; - the 3- (2-methanesulfonyloxyethylamino) -2-pentenoic acid dialkyl ester of formula XV thus obtained - wherein R is as defined above, and Ms represents a methanesulfonyl group - in an organic solvent, by reaction with an alkali metal halide, preferably lithium bromide or sodium iodide; the resulting 3- (2-haloethylamino) -2-pentenedioic acid dialkyl ester of formula (XIII), wherein R is as defined above, X is halogen, in an aprotic polar solvent, reacting with a base; - reacting the resultant compound of formula XVII wherein R is as defined above with an 2-haloacetaldehyde of formula XX where X is halogen in aqueous solution, followed by a), b), c) above. and d) the compound of formula (XII) obtained according to any one of the processes, wherein R is as defined above, via the appropriate intermediates of formula (XVIII) and (XIX) to give the desired compound of formula (IA) converted; and, if desired, hydrolyzing the ester of formula (IA) obtained by any of the above processes to the corresponding free carboxylic acid of formula (I). Process for the preparation of 5-benzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and C 1 -C 4 alkyl esters according to Claim 1, characterized in that the corresponding starting compounds are used in the process of claim 1. 3. A process according to claim 1 for the preparation of 5-p-anisoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and C 1 -C 4 alkyl esters, characterized in that starting materials containing substituents are used in the process of claim 1.