Process for preparing...

Details Process for preparing... Process for preparing...

2002-03-14

2003-05-20

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S250000, C546S251000, C546S252000, C546S294000, C546S330000, C546S262000, C514S357000

Reexamination Certificate

active

06566527

ABSTRACT:

The invention encompasses a novel process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methyl-sulphonyl)phenyl]ethanone of the formula:
1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)-phenyl]ethanone is an important intermediate for preparing so-called COX-2 inhibitors, pharmaceutically active compounds having analgesic and antiinflammatory action (R. S. Friesen et al., Bioorganic & Medicinal Chemistry Letters 8 (1998) 2777-2782; WO 98/03484).
The object of the invention is to provide a technically feasible proess for preparing the intermediate for the formula I.
The object is achieved by the novel process according to the invention.
The process according to the invention is characterized by five steps, where,
in the first step a), 4-(methylthio,benzyl alcohol is converted with hydrochloric acid into 4-(methylthio)benzyl chloride,
in the second step b), 4-(methylthio)benzyl chloride is converted with an alkali metal cyanide into 4-(methyl-thio)phenylacetonitrile,
in the third step c), 4-(methylthio)phenylacetonitrile is condensed with a 6-methylnicotinic ester to give 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)-pyridine of the formula:
in the fourth step d), 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine is hydrolysed and decarboxylated under acidic conditions to give 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine of the formula:
and, in the last step e), 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine is oxidized to give the end product.
Step a:
The chlorination of 4-(methylthio)benzyl alcohol to 4-(methylthio)benzyl chloride is carried out using hydrochloric acid, advantageously using concentrated hydrochloric acid, at a temperature of from 10° C. to 40° C.
The reaction is usually carried out in an organic solvent, advantageously in a water-immiscible solvent, such as, for example, in toluene.
Typically, the chlorination takes about 1 h to 4 h. The 4-(methylthio)benzyl chloride can be obtained in a simple manner by neutralizing the organic phase and removing the solvent. Further purification can be achieved by distillation.
Step b:
The cyanidation of 4-(methylthio)benzyl chloride is carried out using an alkali metal cyanide, advantageously in the presence of a phase transfer catalyst. Suitable alkali metal cyanides are sodium cyanide or potassium cyanide. The phase transfer catalysts which can be chosen are known in the art. Suitable are tetraalkylammonium halides, such as, for example, tetra-n-butylammonium chloride or tetra-n-butylammonium bromide. In general, the reaction is carried out in the presence of a water-immiscible solvent, such as, for example, toluene; if appropriate, water can be added. The reaction temperature is advantageously from 60° C. to 100° C. After a reaction time of 1 h to 6 h, the product can be isolated in a simple manner from the organic phase by removing the solvent. Further purification of the product can be achieved by recrystallization from, for example, diisopropyl ether.
Step c:
In the third step, ((methylthio)phenyl)aceto-nitrile is condensed with a 6-methylnicotinic ester to give 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl]-(6-methyl)pyridine of the formula:
The condensation is advantageously carried out in the presence of an alkali metal alkoxide, at a temperature between 60° C. and 110° C. Suitable alkali metal alkoxides are, for example, sodium methoxide or potassium tert-butoxide. The reaction is advantageously carried out in the presence of a lower alcohol or an aromatic hydrocarbon as solvent. After the condensation, the 3-[2-(4-(methyl-thio)phenyl)-2-cyanoacetyl](6-methyl)pyridine can be obtained, for example, by adding the reaction mixture to cold water and precipitating the product from the aqueous phase by acidifying it slightly.
Step d:
Hydrolysis and decarboxylation to give 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine of the formula:
are carried out under acidic conditions. Suitable acids are hydrochloric acid, phosphoric acid or mixtures of acetic acid with a mineral acid. Advantageously, a mixture of acetic acid and a mineral acid is employed, at a temperature of from 50° C. to 115° C. Particular preference is given to mixtures of acetic acid with concentrated hydrochloric acid or mixtures of acetic acid with concentrated sulphuric acid. If appropriate, a certain amount of water can be added to the mixtures. Good results were obtained using mixtures of acetic acid/concentrated hydrochloric acid 1:3 or acetic acid/concentrated sulphuric acid/water 1:1:1. After a reaction time of about 1 h to 20 h, the mixture can be neutralized using, for example, an aqueous ammonia solution, as a result of which the product precipitates out and can be isolated in a simple manner.
Step e:
Oxidation of 3-[2-(4-(methylthio)phenyl)-acetyl](6-methyl)pyridine to the end product is advantageously carried out using hydrogen peroxide in the presence of an alkali metal tungstate, at a temperature of from 10° C. to 40° C., preferably at about 20° C. A particularly suitable alkali metal tungstate is sodium tungstate of the formula Na
4
WO 0.2H
4
O. The alkali metal tungstate is generally employed in catalytic amounts of from 0.5 mol % to 20 mol %, based on the 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine used. The reaction is advantageously carried out in the presence of a lower alcohol as solvent. After a reaction time of about 1 h to 6 h, the end product can be precipitated out by addition of water and then be isolated without any problems.


REFERENCES:
patent: 3717647 (1973-02-01), Villani
patent: 4115578 (1978-09-01), Miller et al.
patent: 4118461 (1978-10-01), Miller et al.
patent: 4380544 (1983-04-01), Dorn
patent: 0062238 (1982-03-01), None
patent: 99/15503 (1997-09-01), None
patent: 98/03484 (1998-01-01), None
patent: 98/47871 (1998-10-01), None
patent: WO-99/15503 (1999-04-01), None
Friesen, R.S., et al., Biorganic & Medical Chemistry Letters, 8, (1998), 2777-2782.
International Search Report for applicants corresponding International Patent Application.
Burger, A., and C.R. Walter, J., of American Chemical Soc., vol. 72, No. 5, (May 1950), pp. 1988-1990.

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