Patent EA-002690-B1 (EA)
Title: Process of making 3-aryloxy, 4-aryl furan-2-ones useful as inhibitors of cox-2
Inventor: CHEN CHENG Y
IPC: C07D307/60
Filed: 1998-09-21
Abstract: 1. A process for making compounds of formula I   or a pharmaceutical salt thereof wherein R<1> is selected from the group consisting of SCH3, -S(O)2CH3 and S(O)2NH2; R<2> is selected from the group consisting of OR, mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F; R is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F; R<3> is H, C1-4 alkyl optionally substituted with 1 to 3 groups of F, Cl or Br and R<4> is H, C1-4 alkyl optionally substituted with 1 to 3 groups of F, Cl or Br, with the proviso that R<3> and R<4> are not the same, the process comprising the steps of (a) reacting a compound of formula 3   wherein R<1>, R<3> and R<4> are described above; with a first ligand, a basic buffer, an oxidant and optionally a co-oxidant to yield a compound of formula 9   (b) oxidizing a compound of formula 9 with an oxidizing agent optionally in the presence of a first base to yield a compound of formula 1   wherein R<1>, R<3> and R<4> are described above; and (c) reacting a compound of formula 1 with a compound of the formula 2   wherein R<2> is defined above, an acylating agent, optionally a dehydrating agent, a suitable catalyst, and a second base to yield a compound of formula I. 2. A process according to claim 1 wherein the first ligand belongs to the group consisting of (DHQD)2PHAL, (DHQD)2DP-PHAL, (DHQD)2PYR, (DHQD)-PHN, (DHQD)2AQN, .(DHQD)2DPP and (DHQD) CLB, the basic buffer belongs to the group consisting of potassium or sodium carbonate, the oxidant is potassium osmiumate and the co-oxidant belonging to the group consisting of potassium ferrocyanide and iodine. 3. A process according to claim 2 wherein the first ligand is (HDQD)2PHAL. 4. A process according to claim 1 wherein the first base belongs to the group consisting of triethylamine, t-butylamine, and isopropylamine, the oxidizing agent is a complex of a first reagent belonging to the group consisting of dimethylsulfoxide, pyridinium chlorochromate, pyridinium dichromate, pyridinium fluorochromate and pyridinium fluorochromate and a second reagent belonging to the group consisting of oxalyl chloride, chlorine, and acetyl chloride. 5. A process according to claim 4 wherein the first base is triethylamine and the oxidizing agent is dimethylsulfoxideloxalyl chloride. 6. A process according to claim 1 wherein the molar ratio of formula 9 to first reagent is 1:4.0 or greater and the molar ratio of formula 9 to second reagent is 1:2.0 or greater. 7. A process according to claim 1 wherein the acylating agent belongs to the group consisting of 1-cyclohexyl-3-(2-morpholino- ethyl)carbodiimide metho-p-toluenesulfonate, 1,3dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and i-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, the dehydrating agent is isopropyltrifluoroacetate, the catalyst belongs to the group consisting of 4-dimethylaminopyridine and pyridine, and the second base belongs to the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine, t-butylamine, and isopropylamine. 8. A process according to claim 1 wherein the molar ratio of formula 1 to 2 is 1:1 or greater. 9. A process for making a compound of formula 3   wherein: R<1> is selected from the group consisting of-SCH3 and -S(O)2CH3; R<3> is H, C1-4 alkyl optionally substituted with 1 to 3 groups of F, Cl or Br and R<4> is H, C1-4 alkyl optionally substituted with 1 to 3 groups of F, Cl or Br, with the proviso that R<3> and R<4> are not the same, comprising (a) reacting a compound of formula 4   with a hindered base, and an anhydride or acid halide to yield a compound of formula 8   (b) reacting without purification the compound of formula 8 with a fluoride salt and metal halide, to yield a compound of formula 3. 10. A process according to claim 10 wherein the hindered base belongs to the group consisting of diisopropylethylamine, C1-10 alkyl piperidine and C1-10 alkyl pyridine and the ahydride or acid halide belongs to the group consisting of chlorodifluoroacetic anhydride, acetic anhydride, acid chloride and acid bromide. 11. A process according to claim 11 wherein the hindered base is diisopropylethylamine and the hydride is chlorodifluoroacetic anhydride. 12. A process accordng to claim 10 wherein the fluoride salt belongs to the group consisting of sodium, potassium or lithium fluoride and the metal halide is cuprous iodide. 13. A process according to claim 13 wherein the molar ratio of compound of formula 8 to metal halide is typically 1:1 to 1:1.5. 14. A process for making a compound of formula 3   wherein: R<1> is selected from the group consisting of-S(O)2CH3 and -SCH3; R<3> is H, C1-4 alkyl optionally substituted with 1 to 3 groups of F, Cl or Br and R<4> is H, C1-4 alkyl optionally substituted with 1 to 3 groups of F, Cl or Br, with the proviso that R<3> and R<4> are not the same, comprising (a) reacting a compound of formula 4   with imidazole and a halide in the presence of triphenylphosphine to yielc a compound of formula 7   (b) reacting the compound of formula 7 with an alkyl cuprate to yield a compound of formula 3. 15. A process according to claim 15 wherein the halide is iodine and the alkyl cuprate is trifluoromethylcuprate. 16. A process for making a compound formula 4   wherein: R<1> is selected from the group consisting of SCH3, -S(O)2CH3 and S(O)2NH2; and R<3> is H, C1-4 alkyl optionally substituted with 1 to 3 groups of F, Cl or Br comprising (a) reacting a compound of formula 5   R<1a> is NH2SO2, -S(O)2CH3 and CH3S; with triethyl 2-phosphonopropionate,   a Lewis acid, and amine base, to yield a compound of formula 6a   (b) reacting 6a in an C1-6 alkanol solvent, under acidic conditions, with a suitable catalyst and an oxidizing agent to yield a compound of formula 6b   (c) reacting 6b with a suitable reducing agent to yield a compound of formula 4. 17. A process according to claim 16 wherein the amine base belongs to the group consisting of triethylamine, t-butylamine, and isopropyl amine and the Lewis acid is a magnesium halide, wherein halide is bromo, chloro or iodo. 18. A process according to claim 16 wherein the C1-6 alkanol belongs to the group consisting of methanol, ethanol, propanol, isopropanol, and pentanol, the catalyst is sodium tungstate, the acid is sulfuric acid, hydrochloric acid, or fumaric acid and the oxidizing agent is hydrogen peroxide or t-butyl peroxide. 19. A process according to claim 16 wherein the reducing agent diisobutylaluminium hydride, lithium aluminum hydride, or diisopropyl aluminum. 20. A process according to claim 16 wherein the reducing agent is diisobutylaluminium hydride.