The compounds of formula (I) are described in the patent application WO 98/03484 (Merck Frosst Canada Inc.).

An improved process for the synthesis of the compounds of formula (I), recently described in the patent application WO 99/15503 (Merck & Co., Inc.), is characterized by the synthesis of the compound of formula as key intermediate for the preparation of the COX-2 inhibitors of formula (I).

The synthesis of the intermediates (II) essentially consists of the reaction between a Grignard compound of formula

wherein X is chlorine, bromine or iodine; and an amide (Weinreb amide) of formula to yield a compound of formula and of the subsequent oxidation.

This synthesis is undoubtedly advantageous in comparison with the known syntheses mainly because it avoids coupling reactions which require the use of expensive catalysts.

However, the used reagents, that is the Grignard compound and especially the amide, have several drawbacks.

The Grignard compound must be prepared in situ from the corresponding 4-methylthio- benzyl halide.

Also the amide must be suitably prepared by reacting 6-methyl-nicotinic acid methyl ester with N, O-dimethyl-hydroxy-amine and isopropyl magnesium chloride in tetrahydrofuran, at -10°C.

It is clear that the process is not of easy industrial applicability because of the need to prepare the starting reagents (especially the amide) and because of the need to prepare the two Grignard reagents.

We have now found an improved and advantageous method for the preparation of the intermediates of formula (II) which overcomes all the drawbacks of the known processes.

Therefore, object of the present invention is a process for the preparation of the intermediates of formula comprising (a) the reaction between a 6-methyl-nicotinic acid ester of formula wherein R, is a linear or branched Cl-C4 alkyl ; and (4-methylthio-phenyl)-acetonitrile in the presence of a base and in a suitable solvent to give 3-(6-methyl-pyndin-3-yl)-2-(4- methylthio-phenyl)-3-oxo-propionitrile

(b) the optional conversion of the compound (V) into a salt thereof with an organic or inorganic acid ; (c) the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof to give the compound of formula (d) the subsequent oxidation of the compound (VI) to sulfone (II).

The process object of the present invention is useful for the preparation of intermediates of the synthesis of COX-2 inhibitors.

A preferred embodiment of the process object of the present invention is represented by the synthesis of

comprising (a) the reaction between a 6-methyl-nicotinic acid ester of formula (III) and (4-methylthio- phenyl)-acetonitrile (IV) in the presence of a base and in a suitable solvent to give 3- (6- methyl-pyridin-3-yl)-2- (4-methylthio-phenyl)-3-oxo-propionitrile (b) the optional conversion of the compound (V) into a salt thereof with an organic or inorganic acid; (c) the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof A still more preferred embodiment of the present invention is represented by the synthesis of the compound of formula or of a salt thereof with an organic or inorganic acid; comprising the reaction between a 6-methyl-nicotinic acid ester of formula (III) and (4- methylthio-phenyl)-acetonitrile (IV) in the presence of a base and in a suitable solvent.

The compound 3- (6-methyl-pyridin-3-yl)-2- (4-methylthio-phenyl)-3-oxo-propionitrile (V) and the salts thereof are new and are a further object of the present invention.

The 6-methyl-nicotinic acid esters useful in the process object of the present invention are methyl, ethyl, n-propyl, isopropyl, n-butyl and sec-butyl ester.

Preferably 6-methyl-nicotinic acid methyl ester is used.

In reaction (a) between a 6-methyl-nicotinic acid ester (III) and (4-methylthio-phenyl)- acetonitrile (IV), preferred bases are alkali or alkaline-earth metal Cl-C4 alkoxide such as, for example, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide and potassium sec-butoxide, lithium or magnesium amides such as, for example, lithium or magnesium 2,2,6,6-tetramethylpiperidine and lithium or magnesium diisopropylamine, and

hydrides such as sodium hydrie.

Still more preferably sodium tert-butoxide or methoxide are used.

The base is generally used in excess with respect to the starting compounds (III) and (IV), preferably in a molar ratio from 1.2 to 1.8 with respect to (III).

Also the starting compound (IV) is used in excess with respect to the compound (III), preferably in a molar ratio from 1. 1 to 1.4 with respect to (III).

Examples of preferred solvents for reaction (a) are toluene, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, dimethylformamide, tetrahydrofuran, alcohols and mixtures thereof.

Still more preferably toluene is used.

Generally the reaction temperature ranges from the room value to the boiling temperature of the reaction mixture, more preferably from 40°C to 90°C.

The optional conversion (b) is carried out by treating compound (V) with an organic or inorganic acid according to conventional techniques.

Preferably, hydrochloric acid is used, so obtaining the hydrochloride of compound (V).

The acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof is carried out according to known methods, preferably by heating in a mixture of hydrochloric acid and acetic acid.

The starting compounds of the process object of the present invention are known compounds. In particular, (4-methylthio-phenyl)-acetonitrile can be easy prepared from the corresponding chloride according to one of the methods described in the literature, for example by reaction with sodium cyanide (Beilstein EIV, 10,563). The 6-methyl-nicotinic acid esters are commercially available or can be easy prepared from 6-methyl-nicotinic acid.

The oxidation reaction can be carried out following one of the methods already described in WO 99/15503. More preferably, the oxidation is carried out according to the method object of the co-pending Italian patent application entitled"Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyridines"filed on the same date.

In order to better illustrate the present invention the following examples are now given.

Example 1

Svnthesis of 3- (6-methyl-pyridin-3-yl)-2- (4-methvlthio-phenyl)-3-oxo-propionitrile In a 1 liter reactor, equipped with mechanic stirrer, thermometer and dropping funnel, 6- methyl-nicotinic acid methyl ester (50 g; 87.2% titer; 0.289 moles), (4-methylthio-phenyl)- acetonitrile (60.9 g; 85.4% titer; 0.319 moles), dimethylsulfoxide (20.5 g) and toluene (82 g) were charged.

The resulting mixture was heated at 70°C before adding, in 1 hour, a solution of sodium tert- butoxide (39.8 g; 97% titer; 0.402 moles) in dimethylsulfoxide (41 g) and toluene (164.2 g).

At the end of the addition, the suspension was kept at 70°C under stirring for 1 hour and then cooled at 50°C.

Then, in 20 minutes, 31% HCI (118.6 g) was added.

After 10-15 minutes from the end of the addition a plentiful precipitate formed.

The suspension was cooled at 15°C and filtered after 20 minutes at this temperature. The obtained solid was washed with toluene (2 x 126. 4 g) and then with acetone (115 g).

The product was dried in the air obtaining 3- (6-methyl-pyridin-3-yl)-2- (4-methylthio- phenyl)-3-oxo-propionitrile hydrochloride (122.1 g ; 48.5% titer as free base; 73% yield from 6-methyl-nicotinic acid methyl ester).

Example 2 Synthesis of 3- (6-methyl-pyridin-3-yl)-2-1 ; 4-methylthio-phenyl)-3-oxo-propionitrile In a 6 liter flask, equipped with mechanic stirrer, thermometer, dropping funnel, 6-methyl- nicotinic acid methyl ester (300 g; 1.99 moles) dissolved in toluene (615 g) was charged.

Then toluene (2142 g) and (4-methylthio-phenyl)-acetonitrile (319.9 g; 2.40 moles) were added.

The resulting mixture was heated at 70°C before adding sodium tert-butoxide (306.7 g ; 3.19 moles), divided into five portions.

The resulting suspension was kept at 70°C for two hours and then was cooled at 20°C.

Keeping the temperature below 35°C, acetic acid (240 g) and, subsequently, acetone (906 g) were added.

The resulting suspension was diluted with water (610 g), cooled at 15°C and, after two hours at this temperature, was filtered on Buchner. The obtained solid was washed with water (2 x

195 g) and then with acetone (3 x 150 g).

The product was dried overnight at 60°C under vacuum obtaining 3- (6-methyl-pyridin-3-yl)- 2- (4-methylthio-phenyl)-3-oxo-propionitrile (439 g).

Example 3 Synthesisof 1-(6-methvl-pvridin-3-vl)-2-(4-methylthio-phenyl)-ethanone In a 1 liter reactor, equipped with mechanic stirrer, thermometer and condenser, 3- (6-methyl- pyridin-3-yl)-2- (4-methylthio-phenyl)-3-oxo-propionitrile hydrochloride (122.1 g; 48. 5% titer as free base ; 0.21 moles), acetic acid (179.7 g) and 31% HCI (433.7 g) were added.

The suspension was heated at 70°C and kept under stirring for about 16-18 hours. At the end of the reaction, the mixture was concentrated under vacuum up to obtain a residue weighing 227 g, then toluene (227 g) and 30% NaOH (126 g) were added, bringing the pH to a value from 4 to 7.

The resulting suspension was heated at 60°C and kept under stirring for 30 minutes. The phases were separated and the aqueous phase was extracted with toluene (2 x 75.6 g).

The collected organic phases were concentrated under vacuum at 60°C up to a residue weighing 253 g. Then the mixture was slowly cooled under stirring at 0°C.

The precipitated solid was filtered and washed with toluene (2 x 30 g).

After drying under vacuum, 1- (6-methyl-pyridin-3-yl)-2- (4-methylthio-phenyl)-ethanone (35.3 g; 65.4 % yield) was obtained.

Example 4 Svnthesis of 1- (6-methyl-pyridin-3-yl)-2- (4-methylthio-phenyl)-ethanone In a 5 liter reactor, equipped with mechanic stirrer, thermometer and condenser, 3- (6-methyl- pyndin-3-yl)-2- (4-methylthio-phenyl)-3-oxo-propionitrile (439 g; 1.56 moles), acetic acid (700 g) and 31% HCI (1370 g) were added.

The suspension was heated at 80°C and kept under stirring for about 24 hours. At the end of the reaction, the mixture was concentrated under vacuum up to obtain a residual volume of about 1 liter. Then water (1350 g) was added and the pH was adjusted to 1.2-1.4 by adding 28% (w/w) ammonia (about 200 g).

Then ethyl acetate (370 g) was added and the pH of the mixture was brought to 4-4.5 by

adding 28% (w/w) ammonia (about 125 g).

This work up was carried out so that the temperature was kept between 40 and 45°C. The resulting suspension was then cooled at 0°C in two hours and, after 1 hour at this temperature, was filtered. The collected solid was washed with ethyl acetate (230 g) and water (500 g).

After drying at 60°C under vacuum up to constant weight, 1- (6-methyl-pyridin-3-yl)-2- (4- methylthio-phenyl)-ethanone (339 g; 66.4% molar yield from 6-methyl-nicotinic acid methyl ester).

Example 5 Synthesis of 6-methyl-nicotinic acid n-butyl ester In a 300 ml reactor, equipped with mechanic stirrer, condenser and thermometer, kept under nitrogen, an aqueous solution of 6-methyl-nicotinic acid potassium salt (388.4 g; 6.4% titer, 0.142 moles) was charged.

The solution was heated and concentrated under reduced pressure up to a residue weighing 212.5 g, then cooled at room temperature.

The pH was brought to 9.5 (initial value of about 11) by adding glacial acetic acid (1.5 g) and then toluene (100 ml), Aliquat 336 (1.7 g; 0.0042 moles) and n-butyl bromide (39 g; 0.284 moles) were added, in that order, under stirring.

The mixture was heated under reflux (about 86-87°C) and kept at this temperature for 15 hours. After cooling at room temperature, the phases were separated and the organic phase was washed with 50 ml of water (washing pH = 9) and with further 50 ml of water (washing pH = 7). Water (100 ml) and, dropwise, 31% HCI (22 g) were added to the organic phase up to pH 1, keeping the internal temperature at 20-25°C.

The phases were separated and the organic phase was extracted with water (100 ml). After addition of 31% HCI (2 g) up to pH 1 (initial pH = 2), the phases were separated and the acid aqueous phases were collected. Toluene (100 ml) was added to the collected aqueous phases and, after cooling at 15°C, 30% NaOH (26 g) up to pH>12 was dropwise added in 20 minutes.

The phases were separated and the aqueous phase was washed with toluene (30 ml). The

collected organic phases were washed with water at pH 7 and concentrated to residue obtaining 6-methyl-nicotinic acid n-butyl ester (26.5 g ; 98.8% HPLC titer; 95.6% yield).

Example 6 Synthesisof 3-(6-methyl-pyridin-3-yl)-2-(4-methylthio-phenyl)-3-oxo-prop ionitrile In a 300 ml reactor, equipped with mechanic stirrer and condenser, kept under nitrogen, 6- methyl-nicotinic acid n-butyl ester (25 g; 0.1285 moles), toluene (38 g) and (4-methylthio- phenyl)-acetonitrile (27.7 g) were charged.

The resulting mixture was heated at 70°C before adding portionwise, in about 50 minutes, a suspension of sodium tert-butoxide (20.8 g) in toluene (83 g) and dimethylsulfoxide (21.4 g).

The resulting suspension was kept at 70°C for two hours, cooled at 40°C and slowly poured into 31% HCI (62 g), cooled at 5°C.

At the end of the addition water (47 g) was added, the mixture was cooled at 10-15°C, kept under stirring for 30 minutes and filtered by washing with toluene (2 x 29 g), with water (2 x 29 g) and subsequently with acetone (29 g), obtaining 3- (6-methyl-pyridin-3-yl)-2- (4- methylthio-phenyl)-3-oxo-propionitrile (28.4 g; 79.7% HPLC titer; 62% yield).

Example 7 Synthesis of 1- (6-methyl-pyridin-3-yl)-2- (4-methvlthio-phenyl)-ethanone In a 300 ml reactor, equipped with mechanic stirrer, thermometer and condenser, under nitrogen, 3- (6-methyl-pyn'din-3-yl)-2- (4-methylthio-phenyl)-3-oxo-propionitn'le (25 g ; 0.0706 moles), glacial acetic acid (37.35 g) and 31% HCI (73.4 g) were charged.

The suspension was heated at 70°C and kept under stirring for about 24 hours. At the end of the reaction, the mixture was concentrated under vacuum up to a residue weighing 34.6 g.

Then water (35 g) was added and the pH was adjusted to 7 by dropwise adding 30% (w/w) NaOH (27.4 g), in 20 minutes.

Then ethyl acetate (50 g) was added and the solution was heated at 65-70°C. The phases were separated at 70°C and the aqueous phase was washed with ethyl acetate (18 g) at 70°C.

The collected organic phases were washed at 70°C with water (30 g), concentrated to a residue, which was taken up in ethyl acetate (40 g) at 70°C.

After cooling at 0°C in 4 hours and keeping this temperature overnight, the suspension was

filtered, washing with ethyl acetate (10 ml) and with cooled ethyl acetate (5 ml), obtaining 1- (6-methyl-pyridin-3-yl)-2- (4-methylthio-phenyl)-ethanone (15 g ; 51.3% molar yield from 6- methyl-nicotinic acid n-butyl ester).

Example 8 Svnthesisof 3 (6-methyl-pyridin-3-yl)-2- (4-methylthio-phenyl)-3-oxo-propionitrile In a 600 ml reactor, equipped with a reflux condenser, toluene (236 g), 6-methyl-nicotinic acid methyl ester (25.1 g; 99.5% titer; 0.1655 moles), (4-methylthio-phenyl)-acetonitrile (47.7 g; 59. 5% titer; 0.1735 moles) were charged.

The resulting mixture was kept under nitrogen and heated at about 100°C before adding, in 30 minutes, a first portion of 30% sodium methoxide (3.3 g; 7.5% of the total amount). The temperature decreased to about 98°C (internal). After 30 minutes, a further portion of 30% sodium methoxide (3.3 g; 7.5% of the total amount) was added in about 30 minutes. The temperature decreased to about 94°C and a solid formed. After further 30 minutes, a third portion of 30% sodium methoxide (6.7 g; 15% of the total amount) was added as described for the previous additions and the temperature decreased to about 92°C. After 30 minutes, in about 4 hours, the remaining portion of 30% sodium methoxide (31.4 g) was added.

At the end of the addition the temperature was about 86°C. During the additions the solvent was distilled and collected. The distillation of the solvent was continued for about 6 hours (temperature 86=87°C), then the reaction mixture cooled at about 20°C and, in about 30 minutes, glacial acetic acid (15.9 g) was added.

The addition was exothermic and the temperature was kept at 30-35°C.

Then, acetone (75.2 g) in about 15 minutes and water (76 g) were added.

The resultant suspension was kept at 30-35°C for 1 hour, then cooled at about 15°C in 1.5 hours to allow the crystallization of the product.

After 1 hour at 15°C the precipitate was filtered and washed with water (2 x 6 g) and then with acetone (2 x 5.0 g) obtaining wet 3- (6-methyl-pyridin-3-yl)-2- (4-methylthio-phenyl)-3- oxo-propionitrile (56 g) used as such in the subsequent step.

Example 9 Synthesisof 1- (6-methyl-pyridin-3-yl)-2- (4-methylthio-phenyl)-ethanone

In a 600 ml reactor, water (21. 0 g) and, keeping the temperature below 50°C, 66Be sulfuric acid (56.5 g) were added. The reactor was equipped with a Marcusson and wet 3- (6-methyl- pyridin-3-yl)-2- (4-methylthio-phenyl)-3-oxo-propionitrile (28 g) was charged at 35=40°C.

The suspension was heated at 90°C and kept at this temperature up to complete dissolution.

The solution was cooled at 40°C and further wet 3- (6-methyl-pyridin-3-yl)-2- (4-methylthio- phenyl)-3-oxo-propionitrile (28 g) was added.

The suspension was heated at about 115°C (internal). After 8 hours, the solution was cooled at about 60°C and water (47.0 g) was added.

Keeping the temperature from 40°C to 50°C, the pH of the reaction mixture was brought to 3.5-4.0 by adding 30% ammonia (60.0 g) in about 2 hours.

Ethyl acetate (55.6 g) was added to the resultant suspension and then the pH was brought up to a value from 4 to 5 by adding 30% ammonia (1.0 g) in about 30 minutes, keeping the temperature at 40 50°C.

The suspension was kept at 40°C for about 30 minutes, then cooled at about 15°C in about 1 hour.

After 1 hour at about 15°C the suspension was filtered washing with ethyl acetate (2 x 17. 6 g) and with water (2 x 45.6 g), obtaining, after drying under vacuum at 50°C, 1- (6-methyl- pyridin-3-yl)-2- (4-methylthio-phenyl)-ethanone (26 g).