Process for the Preparation of Etodolac

The present invention regards a process for the preparation of etodolac.

1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-bis]indole-1-acetic acid, better known with the common name etodolac, is an active principle having high anti-inflammatory activity. In U.S. Pat. No. 3,843,681 compounds are described that are analogues of etodolac and fall within the following general formula (A): ##STR1## in which R.sup.1 is H, a lower alkyl, lower alkenyl, lower cyclo-alkyl, phenyl, benzyl, or thienyl; R.sup.2, R.sup.3, R.sup.4, and R.sup.5, which may be the same or different from each other, are H or a lower alkyl; R.sup.6, is a lower alkyl, lower cyclo-alkyl, hydroxy, alkoxy, benzyloxy, alkanoyloxy, phenyl, nitro, halogen, mercapto, alkylthio, trifluoromethyl, amino, or sulphamoyl; R.sup.7 is H, a lower alkyl, or lower alkenyl; X is O or S; Y is --CO--, --CR.sup.8 (R.sup.9)--CR.sup.10 (R.sup.11)--CO--, --CR.sup.8 (R.sup.9)--CR.sup.10 (R.sup.11)CR.sup.12 (R.sup.13)--CO--, in which R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R .sup.3, which are the same or different from each other, are H or a lower alkyl; Z is OH, a lower alkoxy, a lower alkylamino, or a lower dialkylamino. These products, and in particular those in which X=O and Z=OH (and therefore etodolac falls within this definition), are prepared by means of condensation of the indole derivative having the following formula (B): ##STR2## in which R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meanings indicated above and X' is a hydroxy, with a B-keto ester of formula R.sup.1 --CO--Y--Z, in which Y has the aforesaid meanings and Z is a lower alkoxy in an apolar solvent, such as benzene or toluene, in the presence of catalytic quantities of para-toluenesulphonic acid, under reflux for a period of time ranging between half an hour and several hours. The patent U.S. Pat. No. 4,585,877 describes an improved process for the specific preparation of etodolac as compared to the process described in the foregoing patent, since the condensation of the tetrahydropyran ring on the indole derivative (7-ethyl-tryptophol in the specific case regarding the preparation of etodolac) is carried our at room temperature and no longer under reflux, using, instead of B-keto ester (the methyl 3-oxo-pentanoate in the specific case of etodolac), the corresponding protected form, i.e., the enol ether of formula (C): ##STR3## in the presence of BF.sub.3.Et.sub.2 O in anhydrous methylene chloride at room temperature. However, the use of catalysts, such as boron trifluoride etherate for industrial production processes causes considerable problems on account of its notable toxicity, and hence for disposal of waste liquor. In addition, this type of catalyst is stable only in a perfectly anhydrous environment, and it is thus difficult to manage.

The need is felt for having available an alternative process for the preparation of etodolac which does not involve the drawbacks presented by the processes of the known art.

The applicant has now surprisingly found a process for the preparation of etodolac which does not present the drawbacks of the known art in so far it is conducted at lower temperatures than the reflux temperature of the solvent and in the absence of BF.sub.3.Et.sub.2 O.

This process, which comprises:

a) reacting 7-ethyl-tryptophol of formula (II) ##STR4## with methyl 3-oxo-pentanoate of formula (III) ##STR5## in an apolar solvent thereby obtaining methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-bis]indole-1-acetate of formula (IV) ##STR6## and b) subsequently hydrolysing the intermediate product of formula (IV) to etodolac (I) ##STR7## wherein step (a) is carried out in the presence of high quantities of a concentrated mineral acid, the molar ratio of the inorganic acid to 7-ethyl-tryptophol being comprised between 0.5 and 5, and at a temperature of between -20.degree. C. and +50.degree. C.

The inorganic mineral acid used in the process according to the present invention is any acid, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric or polyphosphoric acid. Preferably, gaseous hydrochloric acid is used dissolved in a C.sub.1 -C.sub.5 alcohol, or concentrated sulphuric acid is used. According to a preferred solution, the alcohol in which the gaseous hydrochloric acid is dissolved is isobutanol. According to a particularly preferred solution, the concentration of the hydrochloric acid in isobutyl alcohol is 20% by weight. The hydrochloric acid is preferably present in a molar ratio of 3:1 with respect to 7-ethyl tryptophol.

Also when the reaction is conducted in the presence of sulphuric acid, isobutanol is preferably added as co-solvent. The sulphuric acid is preferably present in a molar ratio of 3:1 with respect to 7-ethyl tryptophol.

The reaction solvent of step (a) is generally an aromatic hydrocarbon; preferably, toluene is used.

The reaction temperature is preferably kept at 0.degree. C.

The hydrolysis of methyl 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-bis]indole-1-acetate (IV) is conducted with conventional methods, such as by addition of aqueous potassium hydroxide to a methanol solution of the above-mentioned intermediate (IV).

7-ethyl tryptophol, i.e., the compound of formula (II) of the process according to the present invention, is prepared according to conventional methods, such as by reaction of 2,3-dihydrofuran with the phenylhydrazine hydrochloride in dioxane at 95.degree. C.

The following examples are given to provide non-limiting illustrations of the process according to the present invention.

105.8 g of methyl 3-oxo-pentanoate (0.813 mol) are added to 1000 g of a toluene solution containing 128.0 g of 7-ethyl tryptophol (0.676 mol). The solution is brought to a temperature of approximately 0.degree. C. Keeping this temperature, 74.0 g (2.029 mol) of gaseous hydrochloric acid dissolved in 20% by weight isobutyl alcohol are added drop by drop.

Once the addition is completed, the mixture is poured into a solution of 10% potassium bicarbonate, and the phases are separated. The organic phase is concentrated until 302 g of residue are obtained, which are then re-diluted and re-crystallised using 420.0 ml of methyl alcohol, to obtain 145.0 g of etodolac methyl ester with HPLC purity degree higher than or equal to 97.5%.

112 g of isobutyl alcohol and 41.3 g (0.3169 mol) of methyl 3-oxo-pentanoate are added to 469.4 g of a toluene solution containing 50.0 g of 7-ethyl tryptophol (0.2641 mol).

The solution is brought to a temperature comprised between 0 and 5.degree. C. Keeping this temperature range, 80.9 g (0.7923 mol) of concentrated sulphuric acid (98%) are added drop by drop.

Once the addition is completed, the mixture is poured into a solution of 10% potassium bicarbonate, and the phases are separated. The organic phase is concentrated until 148.0 g of residue are obtained, which are then re-diluted and re-crystallised using 130.0 g of methyl alcohol, to obtain 40.5 g of raw etodolac methyl ester.