Patent EA-001629-B1 (EA)
Title: Process of preparing phenyl heterocycles useful as cox-2 inhibitors
Inventor: DESMOND RICHARD
IPC: C07D307/58
Filed: 1997-06-27
Abstract: 1. A method of making compounds of Formula I   wherein R<2> is mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-6-alkoxy, (4) C1-6-alkylthio, (5) CN, (6) CF3, and (7) C1-6-alkyl, R<3> and R<3>' are each independently selected from hydrogen and C1-4-alkyl, comprising: (b4) reacting in N,N-dimethylformamide a compound of Formula 2   with a phenyl acetic acid of formula   in the presence of an inorganic base to produce a compound of Formula 5a   (b5) treating in polar aprotic solvent the compound 5a with an organic base to yield a compound of Formula I. 2. A method according to Claim 1 wherein the inorganic base is sodium hydroxide. 3. A method according to Claim 1 wherein the polar aprotic solvent is N,N-dimethylformaide. 4. A method according to Claim 1 wherein step (b5) is followed by crystallization conducted at approximately 40 to 60 degree C. 5. A method according to Claim 1 wherein R<2> is mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of (1) hydrogen, (2) halo, (3) methoxy, (4) methyl, R<3> and R<3>' are both hydrogen or are both methyl. 6. A method according to Claim 1 wherein R<2> is mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of (1) hydrogen, (2) halo, R<3> and R<3>' are both hydrogen or are both methyl. 7. A method according to Claim 1 wherein the compound of Formula I is (a) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, or (b) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone. 8. A method according to Claim 1 comprising (b3) reacting in aqueous acetic acid a compound of Formula 4   with bromine to yield a compound of Formula 2   (b4) reacting in N,N-dimethylformamide a compound of Formula 2 with a phenyl acetic acid of formula   in the presence of an inorganic base to produce a compound of Formula 5a   (b5) treating in polar aprotic solvent the compound 5a with an organic base to yield a compound of Formula I. 9. A method according to Claim 8 wherein (b2) reacting in an inert solvent in the presence of a phase transfer catalyst, and an oxidizing agent, compound of Formula 3   to yield a compound of Formula 4   (b3) reacting in aqueous acetic acid a compound of Formula 4 with bromine to yield a compound of Formula 2   (b4) reacting in N,N-dimethylformamide a compound of Formula 2 with a phenyl acetic acid of formula   in the presence of an inorganic base to produce a compound of Formula 5a   (b5) treating in polar aprotic solvent the compound of Formula 5a with an organic base to yield a compound of Formula I. 10. A method according to Claim 9 wherein the phase transfer catalyst in step (2) is tricaprylylmethylammonium chloride, sodium tungstate is added in step (b2) to catalyze the oxidation and hydrogen bromide is added in step (b3) to initiate the reaction. 11. A method according to Claim 9 wherein an inert solvent is ortho di-chlorobenzene, the phase transfer catalyst is tricaprylylmethylammonium chloride, and the oxidizing agent is hydrogen peroxide. 12. A process of making a compound of Formula I according to Claim 11    wherein R<2> is reaction stable organic group such as mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-6-alkoxy, (4) C1-6-alkylthio, (5) CN, (6) CF3, and (7) C1-6-alkyl, R<3> and R<3>' are each independently selected from hydrogen and C1-4-alkyl, comprising: (b1) reacting in an inert solvent in the presence of acetyl chloride of the formula R<3>'R<3>CHC(O)Cl and aluminum chloride thioanisole   to yield a compound of Formula   (b2) reacting in an inert solvent in the presence of a phase transfer catalyst, and an oxidizing agent, compound of Formula 3 to yield a compound of Formula 4   (b3) reacting in aqueous acetic acid a compound of Formula 4 with bromine to yield a compound of Formula 2   (b4) reacting in N,N-dimethylformamide a compound of Formula 2 with an acetic acid derivative of formula   in the presence of an inorganic base to produce a compound of Formula 5a   (b5) treating in a polar aprotic solvent the compound 5a with an organic base to yield a compound of Formula I.