HU187137B - Process for producing esters of 1-alkyl- orl,4-dialkyl-1h-pyrrol-acetic acid - Google Patents

Abstract

The invention relates to a new process for the preparation of 1-alkyl- or 1,4-dialkyl-1H-pyrrole- -2-acetic acid, esters of the general formula (I) < IMG > (I) wherein R1 is hydrogen or an alkyl group having from 1 to 4 carbon atoms, R2 and R3 each independently represent an alkyl group having from 1 to 4 carbon atoms, by selective desalkoxycarbonylation of the corresponding 1-alkyl- and 1,4-dialkyl-3-alkoxycarbonyl-1H-pyrrole- -2-acetic acid esters of the general formula (II) < IMG > (II) wherein R1, R2 and R3 have the same meaning as defined above, by heating in the presence of a concentrated mineral acid or an aliphatic or aromatic sulfonic acid. Compounds of the general formula (I) are known pharmaceutically active materials, which can be prepared by this process in a single reaction step selectively, without the formation of by-products.

Description

The present invention relates to a novel process for the preparation of 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid esters of formula (I)

R ^{1 is} hydrogen or C 1-4 alkyl,

R ² and R ³ each independently represent a C 1 -C 4 alkyl group by selective desalkoxy carboxylation of the corresponding 1-alkyl or 1,4-dialkyl-3-alkoxycarbonyl-1 H -pyrrol-2-acetic acid esters of formula II.

The 5-aroylated derivatives of 1-alkyl- and 1,4-dialkyl-1H-pyrrole-2-acetic acid, such as the anti-inflammatory and anti-rheumatic 1-methyl-5- (4-methyl) derivatives, have been used successfully in medicine in recent years. benzene) -1H-pyrrole-2-acetic acid (tolmetin) and in particular 1,4-dimethyl-5- (4-chlorobenzoyl) -1H-pyrrole-2-acetic acid sodium salt (zomepirac) as non-narcotic analgesics.

Important intermediates for the synthesis of these compounds are the 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid esters of formula (I) which are known in the art. Chem. 1973, 172-174; No. 3,865,840 United States of America and U.S. Pat. Federal Republic of German Patent Specification] As the (A) is a reaction diagram illustrated in the corresponding R ¹ -CO- CH2C1 alpha-chloro carbonyl compound obtained ^R2 -NH2 alkylamine and acetonedicarboxylate diester cyclizing condensation of the formula (Formula They are prepared by the removal of the 3-position alkoxycarbonyl group of the diester of formula II. However, this last operation has only a very cumbersome and complex fashion, the (B) Reaction Scheme been produced as shown in a multistage process (in this reaction scheme, R ^1, R ² and R ³ are as hereinbefore defined): (II) The diester of the formula (I) was first completely saponified in an alkaline medium and the resulting salt was deacarboxylated, partially esterified with the corresponding alcohol (R ³ -OH) to give the desired compound of formula (I) by decarboxylation of the resulting overall yield (about 50%).

In addition to the complexity of this multi-step operation, the relatively poor yield of partial esterification (about 70% for R ³ = C ₂ H ₅ ) was another disadvantage. This latter disadvantage is disclosed in U.S. Patent No. 879,539. According to a Belgian patent, although the use of a cation exchange resin as an esterification catalyst has been reduced (total yield about 64%), the preparation of the compounds of the general formula directly from the diester of the formula II has not yet been simplified.

This object is solved by the present invention, which is based on the proper recognition that diesters of formula II can be directly desaturated directly by desaturation in concentrated acids, especially in phosphoric acid, without damage to other parts of the molecule and other undesirable side reactions. 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid esters of formula (I). Such a procedure has not been described in prior literature.

Although it is known in the chemistry of pyrrole compounds that alkoxycarbonyl groups directly attached to the ring are present in sulfuric acid, 85% phosphoric acid (II Farmaco, 1972, 621-626) and polyphosphoric acid [J. Org. Chem. 1970, 3122-3126], but this method did not appear to be at all appropriate for diesters of the type II. J. Org. Chem., Cited above, states that if the pyrrole carboxylic acid ester also contains an alkoxycarbonyl group in the side chain, although desalkoxycarbinylation occurs in polyphosphoric acid, the removal of the ester group attached to the ring results in the inter . However, it was not at all expected that the dicarboxylic acid esters of the type of formula (II) having an additional esterified carboxyl group in the side chain would remain unchanged under the reaction conditions leading to the removal of the ring-linked esterified caboxyl group.

The present invention thus provides a novel process for the preparation of 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic esters of formula (I) as defined above (corresponding 1-alkyl or 1-4-dialkyl of formula II) By selective decarboxylation of -3-alkoxycarbonyl-1H-pyrrole-2-acetic acid esters], wherein the 1-alkyl or 1,4-dialkyl-3-alkoxycarbonyl-1H of the general formula (II) containing the desired substituents R ¹ and R ² The pyrrole-2-acetic acid ester, where R ³ is as defined above, is heated in concentrated mineral acid, preferably sulfuric acid or phosphoric acid, or in an aliphatic or aromatic sulfonic acid, preferably methanesulfonic acid or p-toluenesulfonic acid.

It is particularly advantageous to carry out the selective desalkoxycarboxylation of the starting compound (II) in 100% phosphoric acid containing 5-10% free phosphorus pentoxide. No organic solvent or other diluent is used in the process. The reaction is conveniently carried out at a temperature of from 70 ° C to 130 ° C, preferably from about 100 ° C to about 110 ° C, using from 6 to 12 moles, preferably 7-9 moles, of acid per mole of diester (II). The reaction time may be from 1 to 6 hours, and the completion of the reaction is indicated by the cessation of gas evolution or depletion of the retention compound; the latter can be verified by thin layer chromatography. Upon completion of the reaction, the reaction mixture is conveniently poured onto crushed ice or water and the resulting monoester (I) obtained as the reaction product is isolated by extraction with a water immiscible organic solvent, preferably an aromatic or chlorinated aliphatic hydrocarbon. The thus obtained 1-alkyl and / or 1-alkyls

The 1,4-dialkyl-1H-pyrrole-2-acetic acid ester can be purified by vacuum distillation; however, the crude product obtained by the process of the invention and isolated by extraction as described above is

187,137 (95-97%) which can be used without further purification for the synthesis of the above 5-aroylated derivatives.

Thus, as opposed to the three reaction steps known in the literature, the process according to the invention converts the diester (II) directly into the desired monoester (I) in a single step. In addition to the substantially shorter reaction time, better equipment utilization, reduced labor and better yields, the process of the present invention provides the following additional advantages over the following:

- the product of the dicarboxylic acid of formula (VI) formed as an intermediate in the known process is difficult to filter and to dry due to its crystalline structure; the water content of the filter wet product is about three times the dry solids content;

- the decarboxylation of the dicarboxylic acid semi-ester of formula (VII) at high temperature (about 200 ° C) requires a special device, and the reaction requires a great deal of caution due to the sudden foaming;

- because of the known heat and light sensitivity of the α-substituted pyrrole compounds, intermediates of formulas VI and VII are readily degraded and, therefore, the product of formula I obtained by the known three-step process is highly shows color purity sufficient for further processing only after distillation under high vacuum due to coloring; the process according to the invention is free from all these disadvantages and difficulties due to the direct selective desalkoxycarbinylation of the starting diester.

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

Example 1

To 5 g (0.02 mol) of ethyl 1,4-dimethyl-3-ethoxycarbonyl-1H-pyrrole-2-acetic acid (25 g) is added 25 g of p-toluenesulfonic acid and the mixture is stirred for 1 hour at 110 ° C. The reaction mixture was cooled to room temperature and triturated with dichloromethane (80 mL); The crystalline p-toluenesulfanoic acid (about 20 g) is isolated by filtration, the filtrate is washed with 40-40 ml of 5% aqueous sodium bicarbonate solution, twice with 40 ml of water, dried over anhydrous sodium sulfate and then concentrated. The resulting 1,4-dimethyl-1H-pyrrole-2-acetic acid ethyl ester was purified by vacuum distillation; 2.17 g of ethyl 1,4-dimethyl-1H-pyrrole-2-acetic acid (60% of theory) are obtained as the main product by distillation over 0.2 mm Hg at 76-80 ° C: njj = 1.486.

EXAMPLE 2 Ethyl ester of 1,4-dimethyl-3-ethoxycarbonyl-1H-pyrrole-2-acetic acid (g, 0.04 mol) was treated with 85% phosphoric acid (32 ml) and stirred at 90 ° C for 4 hours. The reaction mixture was poured onto 60 g of crushed ice and the aqueous mixture was extracted three times with 70-70 ml of dichloromethane. The organic phases are combined. The reaction mixture was washed with 50 ml of 5% aqueous sodium bicarbonate solution, twice with 30 ml of water, dried over anhydrous sodium sulfate and evaporated. 4g of crude product (55%) are obtained; after purification by vacuum distillation as described in Example 1

The ethyl ester of 1,4-dimethyl-1H-pyrrole-2-acetic acid weighs 3.25 g (45% of theory).

Example 3

Dissolve 55 g of phosphorus pentoxide in 120% (70 ml) of 85% phosphoric acid, cool to 40 ° C and stir with 50.6 g (0.2 mol) of 1,4-dimethyl-3-ethoxycarbonyl-1 ethyl pyrrole-2-acetic acid was added and the reaction temperature was raised to 100 ° C over half an hour. The resulting solution was maintained at this temperature for 3 hours (during which time the gas evolution at the beginning of the reaction ceased), then cooled to 30'C and poured into 300 mL of 5-10'C water. The aqueous mixture was extracted with benzene (4 x 100 mL), and the combined organic layers were washed with 5% aqueous sodium bicarbonate (80 x 80 mL), water (2 x 40 mL), and the resulting benzene solution was evaporated under water evaporated. 32.6 g of ethyl 1,4-dimethyl-1H-pyrrole-2-acetic acid (90% of theory) are obtained in the form of a hot, yellow, mobile liquid at a pressure of 0.2 mmHg at 76-80 ° C. . The crude product thus obtained was 95-97% pure by authentic spectral and gas chromatography and was prepared and purified according to the literature.

Example 4

The procedure described in Example 3 was followed except that instead of starting the 1,4-dimethyl-3-ethoxycarbonyl-1H-pyrrole-2-acetic acid ethyl ester mentioned therein, 3-ethoxycarbonyl-1-methyl-1H-pyrrol-2-acetic acid was used. ethyl ester (47.2 g) was used. Yield: 30 g (90% of theory) of 1-methyl-1H-pyrrole-2-acetic acid; Φθ, 05 mmHg · 47-55 C.

Claims (3)

A process for the preparation of 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid alkyl esters of formula (I) wherein: R ^{1 is} hydrogen or C 1 -C 4 alkyl, R ² and R ³ are independently C 1 -C 4 alkyl - 1-alkyl or 1,4-dialkyl-3-alkoxycarbonyl-1 H -pyrrol-2-acetic acid (II) alkyl esters wherein R ¹ , R ² and R ³ are as defined above, characterized in that a 1-alkyl or 1,4-dialkyl-3-alkoxycarbonyl-1 pyrrole-23 The alkyl acetic acid ester, where R ¹ , R ² and R ³ are as defined above, is heated in concentrated mineral acid or in an aliphatic or aromatic sulfanoic acid. 2. The process of claim 1, wherein the acid is p-toluenesulfonic acid or phosphoric acid containing 85-100%, optionally containing 5-10% free phosphorus pentoxide. 3. The process according to claim 1 or 2, wherein the heating is carried out at a temperature of 70-130'C, preferably 100-110'C.