Patent EA-000622-B1 (EA)
Title: Process for preparation of biphenyl derivatives
Inventor: GIGUERE PIERRE
IPC: C07F3/02
Filed: 1996-06-06
Abstract: 1. A process for preparing biphenyl derivatives of the formula I:   or a salt thereof; wherein X is a protecting group and R1, R2, R3 and R4 are each independently hydrogen, C1-C6 alkyl or C1-C6 perfluoroalkyl; R5 is hydrogen or, when n is 1, R5 taken together with R3 comprises a double bond; m is 1,2 or 3; n is 0 or 1; and p is 0,1 or 2; by reacting a compound of the formula II:   or a salt thereof; wherein R1 to R5, m, n and p are each as defined above and R6 is chloro, bromo, or iodo; with a compound of the formula III   or a salt thereof; wherein X is a protecting group and R7 is a zinc halogen in the presence of a palladium or nickel catalyst 2. A process as claimed in Claim 1 wherein R7 is ZnCl-, ZnBr-. 3. A process as claimed in Claim 1 wherein the catalyst is generated from Pd(OAc)2 or PdCl2(PPh3)2NiCl2(dppe), NiCl2(PPh3)2, Ni(acac) or Pddbas and one or more reducing agents/ligands selected from die group consisting of PPh3, P(o-tolyl)3, P(2-furyl)3, P(t-butyl)3, P(OiPr)3, CuJ, CuBr, AsPh3 and diisobutylaluminum hydride (DIBAL), 1,3-bis-diphenylphosphine-propane (DPPP) or 1,3-bis-diphenylphosphine-butane (DPPB). 4. A process as claimed in any one of Claims 1 to 3 wherein the catalyst is generated in situ in the reaction vessel in which the reaction of the compounds of formulae II and III is carrdied out. 5. A process as claimed in any one of the preceding Claims wherein the reaction of the compounds of formulae II and III is carried out in the presence of a solvent species which is substantially immiscible with water. 6. A process as claimed in any one of the preceding Claims wherein die reaction of the compounds of formulae II and III is carried out in the presence of a mixture of solvents, comprising a solvent which is substantially immiscible with water and a solvent of an ester type. 7. A process as claimed in any one of the preceding Claims wherein die compound of formula III is prepared by transmetallizing a compound of formula IV   or a salt thereof; wherein X is a protecting group and R8 is MgBr or MgI; with a transmetallizing agent selected from zinc chloride, zinc bromide, tri(C1-C6 alkyl)-tin chloride or tri (C1.C6 alkyl) tin bromide. 8. A process as claimed in Claim 7 wherein zinc chloride is used as the transmetallizing agent. 9. A process as claimed in Claim 7 or 8, wherein the reaction of the compound of formula IV with the transmetallizing agent is carried out in the presence of a solvent species which is substantially immiscible with water. 10. A process as claimed in Claim 9, wherein the reaction of the compound of formula IV with the transmetallizing agent is carried out in the presence of a solvent species which is substantially immiscible with water, and a solvent of an ester type. 11. A process as claimed in any one of Claims 1 to 10, wherein die compound of formula IV is prepared by reacting a compound of formula V:   or a salt thereof, wherein X is a protecting group and R9 is Br or I; with magnesium. 12. A process as claimed in Claim 11 wherein the reaction of the compound of formula V with magnesium is carried out in the presence of a solvent in the form of an ether. 13. A process as claimed in Claim 12 wherein at least a portion of the ether solvent present during the reaction of the compound of formula V with magnesium is retained during the reaction of the compound of formula IV with the transmetallizing agent. 14. A process as claimed in Claim 13 wherein at least a portion of the ether solvent present during the reaction of the compound of formula V with magnesium is retained during the reaction of the compounds of formula II and III. 15. A process as claimed in any one of Claims 11 to 14 wherein the reactions of the compounds of formulae IV and V and in situ generation of the palladium or nickel catalyst are carried out substantially in the same reaction vessel. 16. A process as claimed in Claim 15 wherein die reactions of the compounds of formulae II, III, IV and V and in situ generation of the palladium or nickel catalyst are carried out substantially in the same reaction vessel. 17. A process as claimed in any one of the preceding Claims wherein m is 1, n is 0, p is 1, R1 and R2 axe each methyl and R3 and R4 are each hydrogen. 18. A process as claimed in any one of the preceding Claims wherein X is a C1-C6 alkyl group or a phenyl or benzyl group, in each case optionally substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy-group, nitro-, amino- group, (C1-C6)alkylamino-, di(C1-C6)alkylamino-, thio(C C1-C6)-alkyl or phenyl substituents. 19. A process as claimed in Claim 18 wherein X is a C1-C6 alkyl group optionally substituted by one or more substituents selected from C1-C6 alkoxy- group, nitro-, amino- group, (C1-C6)alkylamino-, di(C1-C6)alkylamino- or thio(C1-C6)alkyl. 20. A process as claimed in Claim 18 or 19, wherein C1-C6 alkoxy- group is selected from methoxy-, ethoxy-, propoxy-, butoxy- groups. 21. A process as claimed in Claim 20 wherein X is tert-butyl. 22. A process as claimed in any one of the preceding Claims wherein R6 is bromo. 23. A process as claimed in any one of the preceding Claims wherein R8 is MgBr. 24. A process as claimed in any one of the preceding Claims wherein R9 is bromo. 25. A process for producing 8-[2'-(2(l)-tert-butyl-2H-tetrazol-5-yl)-diphenyl-4-yl-methyl]-2,4-dimethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (or such a compound wherein a benzyl or p-methoxybenzyl group is present in place of the tert-butyl group) or a salt thereof, said process characterized in (A) reacting 2-tert-butyl-5-(2-bromo- or iodophenyl)-2H-tetrazole with magnesium to yield the bromo or iodo[2-[2-(tert-butyl)-2H-tetrazoI-5-yl]phenyl]-magnesium Grignard reagent, (B) transmetallizing said Grignard reagent with zinc chloride, zinc bromide or tributyldn chloride; and (C) reacting the transmetallized product with 8-[(4-bromo-, iodophenyl)methyl]-5,8-dihydro-2,4-dimethyl-pyrido[2,3-d]pyrimidin-7(6H)-one in (he presence of a palladium or nickel catalyst to yield the product; wherein throughout the process a benzyl or p-methoxybenzyl group may be present in place of the tert-butyl group. 26. A process according to Claim 25 wherein 2-tert-butyl-5-(2-bromophenyI)-2H-tetrazole is used in step C. 27. A process according to Claim 25 wherein the tert-butyl group is used. 28. A process according to Claim 25 wherein zinc chloride is the transmetallizing agent in step C. 29. A process according to Claim 25 wherein 8-[(4-bromophenyl)-methyl]-5,8-dihydro-2,4-dimethyl-pyrido[2,3-d]-lpyrimidin-7(6H)-one is reacted with chloro or bromo[2-[2-(tert-butyl)-2H-tetrazole-5-yl]phenyl]zinc in step C. 30. A process according to Claim 25 wherein a palladium catalyst is used in step C. 31. A process according to Claim 25 wherein the palladium catalyst is generated from Pd(OAc)2 or PdCl2(PPh3)2 and an additive selected from the group consisting of PPh3, P(o-tolyl)3, P(t-butyl)3, P(2-furyl)3, P(OiPr)3, CuI, CuBr, AsPh3 and DIBAL. 32. A process according to Claim 29 wherein the phosphinated palladium catalyst is generated in the reaction vessel containing the chloro- or bromo[2-[2-(tert-butyl)-2H-tetrazole-5-yl]phenyl]zinc. 33. A process according to Claim 25 wherein the reaction of steps B and C and the generation of the palladium or nickel catalyst, with or without an additive, are carried out in the same reaction vessel. 34. A process according to Claim 25, wherein said process characterized in (B) transinetallizing bromo[2-[2-(tert-butyl)-2H-tetrazole-5-yl]phenyl]-magnesium Grignard reagent with zinc chloride; and (C) reacting the transmetallized product with 8 [(4-bromophenyl)-methyl]-5,8-dihydro-2,4-dimethyl-pyrido[2,3-d]pyrimidin-7(6H)-one in the presence of a palladium catalyst to yield the product. 35. A process as claimed in any one of Claims 25 to 34 comprising the further step of deprotecting the product to provide 8-[2'-(lH-tetrazole-5-yl)-diphenyl-4-yl-methyI]-2,4-dimetyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one or a salt thereof.