FI77023C - PROCEDURE FOR FRAMSTATION OF AV 1-ALKYL-ELLER 1,4-DIALKYL-1H-PYRROL-2-ACETIC XYRAESTRAR. - Google Patents

Description

77023

Process for the preparation of 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid esters

The invention relates to a new process for the preparation of the general formula (I) 5 R1 \ - i 1 (i) CIIoC00R3

10 I

for the preparation of 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid esters according to u2, in which R 1 is hydrogen or an alkyl group having 1 to 4 carbon atoms, 2 3 R and R independently of one another denote 1 to 4 carbon atoms. by an alkoxy-containing alkyl group, by desalkoxycarbonylation selectively corresponding to 1-alkyl or 1,4-dialkyl-3-alkoxycarbonyl-1-alkyl or 1,4-dialkyl-3-alkoxycarbonyl of formula (II) 20 RL COOR3 2 1H-pyrrole-2-acetic acid ester, wherein R, R and R3 are as defined above.

In recent years, 5-aroylated derivatives of 1-alkyl and 1,4-dialkyl: 1H-pyrrole-2-acetic acid have been used, such as the anti-inflammatory and antirheumatic 1-methyl-5-. (4-methylbenzoyl) -1H-pyrrole-2-acetic acid (tolmetin) and in particular 1,4-dimethyl-5- (4-chlorobenzoyl) -:. 35 sodium salt of 1H-pyrrole-2-acetic acid (zomepirac: ia), a non-narcotic analgesic, with excellent results in therapy.

2 77023

The 1-alkyl or 1,4-di-12,3-alkyl-1H-pyrrole-2-acetic acid esters of general formula (I) (R, R and R are as defined above) are valuable intermediates in the synthesis of these compounds. The compounds of general formula (I) 5 are prepared according to known syntheses as shown in Scheme A. 1 of the formula α-chlorocarbonyl-2 ά ...

ring closure condensation of the compound, alkylamines of formula R 1 -N 2 and an acetonodicarboxylic acid diester followed by a diester of general formula (II). 8-a1okoks b o n y y 1 i r y hmä n e 1 imi. This latter step has hitherto been able to be carried out in a very complex and cumbersome manner by the multi-step method shown in Scheme B. 3 in which in the diagram R, R and R have the same meaning as above. The diester of general formula (II) is completely saponified, the resulting salt is liberated with dicarboxylic acid and then partially esterified with the corresponding alcohol (R 1 -OH) to give the semi-ester from which the desired compound of general formula (I) is obtained by decarboxylation n. 200 ° C.

A further disadvantage of this complex process is the relatively low yield of partial esterification (if r3 = C2H5, the yield is about 70%). According to BE patent 879,539, an attempt has been made to reduce this disadvantage by using a cation exchange resin as the esterification catalyst.

EP-A-514-2 discloses that a pyrrole-2-acetic acid ester containing a carboxyl group in the 3-position in the form of a carboxylic alkoxycarbonyl or salt form decomposes in an acidic medium by heat (thermolysis), whereby the 3-position substituent cleaves from the compound and is replaced by a hydrogen atom.

The problem to be solved in this case has been to achieve the highest possible conversion and to avoid side reactions 35 as completely as possible.

According to the reference, this problem is solved by reacting a compound of general formula (II) with a mixture of a strong mineral acid, a lower alkanol and water. Efforts have been made to optimize the composition of the reaction mixture by numerous experiments. From the optimization experiments performed, the inventors concluded that all three components, acid alkanol and water, are needed (see lines 7-10 on page 12).

Instead, the alkanol-containing reaction mixture is not used in the process according to the invention. The present invention is based on the surprising finding that diesters of general formula (II) can be desalkoxycarbonylated directly to the desired 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid esters of general formula (I) by heating in concentrated acids. , preferably in phosphoric acid. Reaction 15 is selective, no other parts of the molecule are damaged and no undesired side reactions occur. There is no representation of similar reactions in the prior art.

Although it is known in the chemistry of pyrrole derivatives that alkoxycarbonyl groups attached directly to the ring can be eliminated by heating in sulfuric acid, 85% phosphoric acid (Il Parmaco, 1972, 621-626) or polyphosphoric acid (J. Org. Chem. 1970, 3122-3126), ; this method has been considered inappropriate for general formula (II). : In the case of diesters such as 25. In J. Org. Chem. according to the article in which the pyrrole carboxylic acid ester has one alkoxycarbonyl group also in the side chain, although the desalkoxycarbonylation takes place in the presence of polyphosphoric acid, together with the elimination of the ester group attached to the ring, the ring is acylated in the liberated position and It has not been foreseen that under the reaction conditions which cause the elimination of the esterified carboxylic acid attached to the ring of the dicarboxylic acid esters of the general formula (II), the esterified carboxylic acid in the side chain remains unchanged.

„77023

The invention therefore relates to a new process for the preparation of compounds of general formula (I) in which the substituents have the meaning defined above by selectively decarboxylating the corresponding 1-alkyl and 1,4-dialkyl-3-alkoxycarbonyl-1H-compounds of general formula 5 (II). pyrrole-acetic acid esters according to which 1-alkyl or 1,4-dialkyl-3-alkoxycarbonyl-1H-2-acetic acid esters of the general formula (II), 1.2 in which R and R in the final product denote the desired substituents, R1 is the same as above, heated in 85 to 100% phosphoric acid containing 5 to 10 SS of free phosphorus pentoxide

According to a preferred embodiment of the invention, the starting materials of general formula (II) are selectively decarboxylated in 100% phosphoric acid containing 5-10% free phosphorus pentoxide. The process is performed without any organic solvent or other diluent. The reaction temperature is about 70 ° to 130 ° C, preferably 100 ° to 110 ° C, and 6 to 12 moles, preferably 7 to 9 moles of acid are used per mole of the diester of general formula (II).

The reaction time may be 1 to 6 hours. Completion of the reaction is indicated by cessation of gas evolution or depletion of the starting compound, which can be determined by thin layer chromatography. After completion of the reaction, the reaction mixture is poured onto crushed ice or water, and the resulting monoester of general formula (I) is isolated by extraction with a water-immiscible organic solvent, preferably an aromatic or chlorinated aliphatic hydrocarbon. The 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid ester product of general formula (I) can be purified by vacuum distillation; however, the crude product prepared according to the invention and isolated by extraction as described above is generally sufficiently pure (95-97% by gas chromatography) to be used in the synthesis of the corresponding 5-aroylated compounds without prior purification.

5,77023

When, according to the literature, three steps are used in the synthesis of the compounds of general formula (I), according to the invention these monoesters can be obtained directly from the corresponding diesters of general formula (II) in a single reaction step. In addition to a substantially shorter reaction time, better utilization of the equipment, reduced laboratory requirements and higher yields, the process according to the invention has the following advantages over the known synthesis 10: Dicarboxylic acid according to general formula (VI) rl cooh (Over) 15 / _ch / nch2-coorj 20, obtained in a process known as an intermediate, is difficult to filter and dry due to its crystalline structure, and contains about three times the amount of water relative to the dry matter content of the filtration-dry product.

- General formula (VII)

30 r1 COOH

N- (I | (VI)

\ Jf .x · '1' ·· CH2-COOH

Decarboxylation of the dicarboxylic acid semester of R 35 6 77023 at elevated temperature (about 200 ° C) requires special equipment and the reaction should be carried out with extreme caution due to the possible occurrence of sudden foaming, which causes difficulties in operating on a large scale.

- due to the known thermal and photosensitivity of α-unsubstituted pyrrole compounds, the intermediates of general formulas (VI) and (VII) are readily degraded, so that the compounds of general formula (I) prepared according to a known method reach a satisfactory degree of purity only after tar the crude product is distilled under high vacuum.

Since the process according to the invention is based directly on the selective desalkoxycarbon-20 of the starting diester compound, it does not suffer from these disadvantages and difficulties.

Further details of our invention are set forth in the following examples which illustrate the invention.

Example 1 55 g of phosphorus pentoxide are dissolved in 120 g (70 ml) of phosphoric acid, the solution is cooled to 40 ° C and 50.6 g (0.2 mol) of 1,4-dimethyl-3-ethoxycarbonyl-1H -pyrrole-2-acetic acid-30 ethyl ester. The temperature of the reaction mixture is raised to 100 ° C in half an hour, the solution is kept at this temperature for three hours (during which time the gas evolution at the beginning of the reaction ceases) and then cooled to 30 ° C and poured into 300 ml of water at 5-10 ° C. ° C.

35 The aqueous mixture is extracted with four 100 ml portions of benzene, the organic phases are combined and washed 7 77023 with two 80 ml portions of 5 l of aqueous sodium hydrogen carbonate solution and then with two 40 ml portions of water. From the resulting benzene solution, the solvent is distilled off under a water-jet vacuum to give 32.6 g (90%) of 5,4-dimethyl-1H-pyrrole-2-acetic acid ethyl ester as a yellow, pale liquid boiling at 76 ° -80 ° C 0.2 at a pressure of mmHg. The purity of the obtained crude product is 95-97% according to the spectral and gas chromatographic analysis performed compared to the sample prepared and purified according to the prior art method.

Example 2

According to the procedure of Example 1, but substituting 47.2 g of 1,4-dimethyl-3-ethoxycarbonyl-1H-pyrrole-2-acetic acid ethyl ester for 3-ethoxycarbonyl-1-methyl-1H-pyrrole-2-acetic acid ethyl ester, 30 g of g of (90¾) 1-methyl-1H-pyrrole-2-acetic acid ethyl ester. Boiling point: 47 ° -55 ° C / 0.05 mmHg.

Claims (3)

8 77023 1. Method of general formula (I) For the preparation of 1-alkyl or 1,4-dialkyl-1H-pyrrole-2-acetic acid esters according to R1__ (I) H * '' * 3 Λ CH.-COORJ I * 10 r2, in which R * is hydrogen or 1- Alkyl group having 4 carbon atoms, R and R 1 independently of one another denote an alkyl group having 1 to 4 carbon atoms, characterized in that 20 rL of COOR 3 / TTX N_ / K} ΓΊ -COOR 3 of general formula (II) are heated 1-alkyl or 1,4-dialkyl-3-alkoxycarbonyl-1 according to R 2. 2H-pyrrole-2-acetic acid esters, wherein R and R are as desired in the final product and R 1 is as defined above, in 85-100 phosphoric acid containing 5-10% free phosphorus pentoxide. Process according to Claim 1, characterized in that the heating is carried out at a temperature of 70 ° to 130 ° C. Process according to Claim 1 or 2, characterized in that the heating is carried out at a temperature of 100 ° to 110 ° C.