WO2001029004A1

WO2001029004A1 - Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyridines

Info

Publication number: WO2001029004A1
Application number: PCT/EP2000/009995
Authority: WO
Inventors: Vincenzo Cannata; Roberto Rossato
Original assignee: Zambon Group S.P.A.
Priority date: 1999-10-15
Filing date: 2000-10-11
Publication date: 2001-04-26
Also published as: ITMI992156A0; ITMI992156A1; AU7918200A; IT1315243B1

Abstract

An oxidation process for the preparation of intermediates useful in the synthesis of diarylpiridines is described. The process relates to the preparation of the compound of formula (II) by oxidation of the compound of formula (III) with an oxidant, in the presence of a catalyst and of an acid, characterized in that the oxidant is a mixture of peracetic acid and hydrogen peroxide and the acid is methanesulfonic acid.

Description

OXIDATION PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL IN THE SYNTHESIS OF DIARYLPYRIDINES

The present invention relates to an oxidation process for the preparation of intermediates useful m the synthesis of diarylpyπdines and, more particularly, it relates to an oxidation process for the preparation of intermediates useful in the synthesis of compounds of formula

wherein R is chloπne, fluorine, bromine, iodine, CN or azide. useful as cyclooxygenase-2

(COX-2) inhibitors

The compounds of formula (I) are descπbed in the patent application WO 98/03484 (Merck

Frosst Canada Inc )

An improved process for the synthesis of the compounds of formula (I), recently descπbed in the patent application WO 99/15503 (Merck & Co . Inc ), is characteπzed 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 Gngnard 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

The oxidation reaction is earned out by using different oxidation systems such as hydrogen peroxide, oxone^® (2KHS0₅ ^*KHS0₄-K₂S0₄) or hydrogen peroxide/acetic acid, preferably by usmg oxone^® or hydrogen peroxide, m the presence of a catalyst, preferably Na W0₄, under acid conditions The presence of a further oxidable function (the nitrogen atom of pyπdine) in the molecule which is oxidized leads to the formation of the N-oxide of the compound of formula II as reaction by-product

The use of softer oxidation conditions is not a valid solution to the problem because, notwithstanding the formation of the N-oxide as by-product is avoided, the oxidation of the sulfur cannot be completed with the consequent formation of sulfoxides as by-products of difficult separation

We have now found a method for the oxidation of the compound of formula III which avoids the formation of significant amounts of by-products and then allows the isolation of the intermediate II in pure form directly from the oxidation mixture

Therefore, object of the present mvention is a process for the preparation of the compound of formula

by oxidation of the compound of formula

with an oxidant, in the presence of a catalyst and of an acid, charactenzed in that the oxidant is a mixture of peracetic acid and hydrogen peroxide and the acid is methanesulfomc acid The process object of the present invention is useful for the preparation of intermediates of the synthesis of COX-2 inhibitors

The oxidant is used in excess and is a mixture of peracetic acid and hydrogen peroxide in a suitable solvent

A mixture of peracetic acid and hydrogen peroxide in acetic acid and water, already available on the market (Oxystrong^® - Ausimont) is particularly preferred Methanesulfomc acid is used in slight excess with respect to the compound III, preferably in a molar ratio from 1 1 to 1 4 Prefeπed catalyst is Na₂W0₄

The oxidation process object of the present invention allows to selectively oxidize the methylthio group to methylsulfone group with good yields and without significant amounts of N-oxide as by-product This is a remarkable advantage m compaπson with the known processes wherein the obtained amount of N-oxide is about 1%, so that one or more punfication steps are required In order to better illustrate the present invention the following examples are now given Example 1

In a 5 liter reactor, equipped with mechanic stiπer, thermometer and condenser, l-(6-methyl- pyπdιn-3-yl)-2-(4-methylthιo-phenyl)-ethanone (339 g, 1 32 moles), acetic acid (1970 g) and methanesulfomc acid (153 6 g, 1 60 moles) were added The addition of methanesulfomc acid was exothermic and the temperature was left aπse at 35°C The resulting solution was cooled at 30°C before adding Oxystrong 15^® (154 3 g, 65% titer as peracetic acid), in about 1 hour Then sodium tungstate dihydrate (1 6 g, 0 01 moles) dissolved in water (10 g) was added After heating the mixture at 35°C, further Oxystrong 15^® (158 9 g, 2 68 total moles) was added The resulting mixture was kept at 35°C for about 2 hours The excess of oxidant was removed by adding sodium thiosulfate pentahydrate and the cloudy solution was clanfied by filtration over celite Then the mixture was cooled at 20°C before adjusting the pH at 4-4 5 by adding 28% (w/w) aqueous ammonia (430 g, 7 08 moles), keeping the temperature below 25 °C The obtained suspension was kept at 20-25 °C for 1 hour before filtenng The collected solid was washed with acetic acid (100 g) and water (200 g) After drying at 60°C under vacuum up to constant weight, 319 g of l-(6-methyl- pyndιn-3-yl)-2-(4-methylsulfonyl-phenyl)-ethanone (83 7% molar yield) were obtained N-oxide content < 0 05%

Comparative example In a 100 ml reactor, equipped with mechanic stirrer, thermometer and reflux condenser, acetone (35 2 g), water (2 5 g), l-(6-methyl-pyndιn-3-yl)-2-(4-methylthιo-phenyl)-ethanone (10 g, 38 9 mmoles), acetic acid (4 5 g) and sodium tungstate dihydrate (34 g, 0 1 mmoles) were added The resulting mixture was heated at 55 °C before adding, in about 4 hours, 28 8% (w/w) hydrogen peroxide (8 9 g, 75 4 mmoles) in 10 portions The addition of hydrogen peroxide proceeded up to bring the sulfoxide content below 0 2% with respect to the startmg sulfide In total, fiirther 1 1 g (9 2 mmoles) of hydrogen peroxide were needed The formation of an amount of N-oxide coπespondmg to 1 2% with respect to the startmg sulfide was observed The reaction mixture was cooled at 15°C and, after 1 hour at this temperature, was filtered The obtained solid was washed with a mixture of acetone (7 5 g) and water (2 5 g) After drying at 55°C under vacuum 8 4 g of l-(6-methyl-pyndιn-3-yl)-2-(4-methylsulfonyl- phenyl)-ethanone containing 0 95% (w/w) of N-oxide were obtained

Claims

1) A process for the preparation of the compound of formula

by oxidation of the compound of formula

with an oxidant, in the presence of a catalyst and of an acid, charactenzed in that the oxidant is a mixture of peracetic acid and hydrogen peroxide and the acid is methanesulfomc acid

2) A process according to claim 1 wherein the oxidant is used m excess

3) A process according to claim 1 wherein the oxidant is a mixture of peracetic acid and hydrogen peroxide m a suitable solvent

4) A process according to claim 1 wherein the oxidant is a mixture of peracetic acid and hydrogen peroxide in acetic acid and water

5) A process according to claim 1 wherein methanesulfomc acid is used in a molar ratio from 1 1 to 1 4 with respect to compound III

6) A process according to claim 1 wherein the catalyst is Na₂W0₄