Patent EA-002975-B1 (EA)
Title: Process for synthesizing cyclooxygenase-2 inhibitors
Inventor: CORLEY EDWARD G
IPC: C12N1/00
Filed: 1999-04-20
Abstract: 1. A process for synthesizing a compound of the formula I:   wherein 0-2 R groups are present; each R, R' independently represents C1-10-alkyl, C6-10-aryl, aralkyl, halo, -S(O)mH, -S(O)mC1-6-alkyl, -S(O)m-aryl, nitro, amino, mC1-6 alkylamino, di- mC1-6 alkylamino, -S(O)mNH2, -S(O)mNH-C1-6 alkyl, -S(O)mNHC(O)CF3 and cyano, the alkyl and aryl groups, and the alkyl and aryl portions of aralkyl, -S(O)m- mC1-6-alkyl, -S(O)m aryl, mC1-6-alkylamino, di- mC1-6-alkylamino and -S(O)mNH- mC1-6-alkyl being optionally substituted with 1-3 groups selected from C1-4-alkyl, aryl, halo, hydroxyl, -S(O)mH, -S(O)mC1-6-alkyl, -CN, mC1-6-alkoxy, amino, C1-6-alkylamino, di- C1-6-alkylamino, -S(O)mNH2, -S(O)mNH-C1-6-C1-6-alkyl, -S(O)mNHC(O)CF3 and aryloxy; R" is C1-10-alkyl, halogen; Y is N; and m is 0, 1 or 2, comprising reacting a compound of formula II:   wherein R<2> through R<5> each independently represent C1-6-alkyl, aryl or aralkyl, and X represents a suitable counterion, with a compound of the formula III:   wherein R, R' and Y are as previously defined, in the presence of a base to produce a compound of formula I. 2. A process in accordance with claim 1 wherein a compound of the formula I' is produced   in which R, R' and Y are as originally defined, comprising reacting a compound of formula II   wherein R<2> through R<5> and X<-> are as originally defined, with a compound of the formula III'   in the presence of a base to produce a compound of formula I'. 3. A process in accordance with claim 1 wherein one R group is present and is C1-10-alkyl, C6-10-aryl, aralkyl, halo, -S(O)mH, -S(O)m-C1-6-alkyl, -S(O)m-aralkyl, -S(O)m-aryl, nitro or cyano. 4. A process in accordance with claim 3 wherein one R is present and represents C1-10-alkyl. 5. A process in accordance with claim 4 wherein one R is present which represents methyl. 6. A process in accordance with claim 2 wherein one R is present and represents methyl attached as follows:   7. A process in accordance with claim 1 wherein R' represents C6-10-aryl substituted with -S(O)m-C1-6-alkyl. 8. A process in accordance with claim 7 wherein R' represents phenyl substituted with methanesufonyl at the 4' position. 9. A process in accordance with claim 8 wherein R" represents halo. 10. A process in accordance with claim 9 wherein R" represents chloro. 11. A process in accordance with claim 1 wherein R<2> through R<5> represent C1-6-alkyl. 12. A process in accordance with claim 11 wherein R<2> through R<5> represent methyl. 13. A process in accordance with claim 1 wherein: X<-> represents protivonone selected from the group consisting of phosphates; sulfates; acetates; perchlorate; borates; antimonates; halides; benzoate and napsylate. 14. A process in accordance with claim 13 wherein X<-> represents a member selected from the group consisting of: hexafluorophosphate; sulfate; mesylate; tosylate; triflate; acetate; trifluoroacetate; perchlorate; tetrafluoroborate; tetraphenylborate; hexafluoroantimonate; chloride; bromide; fluoride; iodide; benzoate and napsylate. 15. A process in accordance with claim 14 wherein X<-> represents hexafluorophosphate. 16. A process in accordance with claim 14 wherein X<-> represents a halide. 17. A process in accordance with claim 16 wherein the halide is chloride. 18. A process in accordance with claim 1 wherein the base is selected from the group consisting of Na and K hydroxide; Cs carbonate; Li, Na and K C1-6-alkoxides; Li, Na and K amides, and Li, Na and K hydrides. 19. A process in accordance with claim 18 wherein the base is selected from the group consisting of: lithium isopropoxide, potassium t-butoxide, LHDMS, NaHMDS, LDA and NaH. 20. A compound having the structural formula:   wherein R<2> through R<5> each independently represent C1-6 -alkyl, aryl or aralkyl, R" independently represents C1-10-alkyl, halogen; X<-> represents a counterion selected from the group consisting of: hexafluorophosphate, tetrafluoroborate, tetraphenylborate and hexafluoroantimonate. 21. A compound in accordance with claim 20 represented by the structural formula II-a:   wherein R" independently represents C1-10-alkyl, halogen and X<-> represents hexafluorophosphate. 22. A compound in accordance with claim 21 wherein R" represents halo. 23. A compound in accordance with claim 22 wherein halo is chloro.