COUPLING REACTIONS USEFUL IN THE PREPARATION OF (1H-TETRAZOL-5-YL) BIPHENYL DERIVATIVES
The present invention relates to a process for the manufacture of intermediates that may be used for the manufacture of ARBs (also called angiotension II receptor antagonists or AT 1 receptor antagonists) comprising as a common structural feature a tetrazole ring.
1 . A process for the manufacture of the compound of formula (I)
wherein Y represents a tetrazole protecting group, and R 1 and R 2 , independently of one another, represent C 1 -C 10 -alkyl, or R 1 and R 2 combined together form C 2 -C 10 -alkylene; comprising
(a) reacting a compound of formula (II a)
wherein Hal is chlorine, bromine or iodine, with an active form of magnesium in an appropriate solvent
(b) reacting a resulting aryl magnesium halide compound of formula (II b)
in the presence of a transition metal catalyst with a compound of formula (II c)
wherein X is chlorine, in the absence of a metal salt additive; and, if necessary, isolating a resulting compound of formula (I).
2 . A process according to claim 1 , wherein a transition metal catalyst is a complex of nickel(0), or a complex of nickel(II) salt with at least one organophosphorus compound containing trivalent phosphorus; or a transition metal catalyst is a nickel(II) complex with an organophosphorus ligand which contains two trivalent phosphorus atoms.
3 . A process for the manufacture of the compound of formula (I C)
wherein Y represents a tetrazole protecting group, and R 3 represents a hydroxyl protecting group; comprising reacting an aryl magnesium halide compound of formula (III b)
wherein Hal is chlorine, bromine or iodine, in the presence of a transition metal catalyst and a catalytically effective amount of a metal salt additive, with a compound of formula (II c)
wherein X is a substituent which, when bound to a phenyl ring, is not considerably replaceable at room temperature by an aryl magnesium halide reagent of formula (III b) in the absence of a catalyst; and, if necessary, isolating a resulting compound of formula (I C).
4 . A process according to claim 3 , wherein an aryl magnesium halide reagent of formula (III b) is prepared by reacting a compound of formula (III al
wherein R 3 and Hal have meanings as defined in claim 3 , with an active form of magnesium in an appropriate solvent.
5 . A process according to claim 3 , which process further comprises deprotecting a compound of formula (I C) to afford a compound of formula (I B)
6 . A process according to claim 5 , which process further comprises treating a compound of formula (I B) with an oxidizing agent in the presence of a suitable solvent to afford a compound of formula (I A)
7 . A process according to claim 3 , wherein variable Y is selected from the group consisting of 1-butoxyethyl, 1-ethoxyethyl, 2-tetrahydropyranyl and 2-tetrahydrofuranyl.
8 . A process according to claim 3 , wherein a transition metal catalyst is a complex of a transition metal or a transition metal salt and one, two or up to four coordinating ligands selected from the group consisting of triphenylphosphine, tri(ortho-tolyl)phosphine, tri(para-tolyl)phosphine, trimethylphosphine, triethylphosphine, tributylphosphine, tri(1,1-dimethylethyl)phosphine, tricyclopentylphosphine, tricyclohexylphosphine, trimethylphosphite, triethylphosphite, tri(1-methylethyl)phosphite, tricyclopentylphosphite, tricyclohexylphosphite, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,1′-bis(diphenylphosphino)ferrocene, 1,1′-bis(di-[2-propyl]-phosphino)ferrocene, 1,1′-bis(di-tert-butylphosphino)ferrocene, 1,2-bis(diphenylphosphino)benzene, 2,2′-bis(diphenylphosphino)-1,1′-biphenyl, 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl, bis(2-diphenylphosphinophenyl)ether and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
9 . A process according to claim 8 , wherein a transition metal salt is selected from the group consisting of nickel(II) chloride, nickel(II) bromide and nickel(II) acetylacetonate.
10 . A process according to claim 8 , wherein a transition metal catalyst is selected from the group consisting of dichlorobis(triphenylphosphine)nickel(II), dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II) and dichloro[1,3-bis(diphenylphosphino)propane]-nickel(II).
11 . A process according to claim 8 , wherein a transition metal salt is selected from the group consisting of palladium(II) chloride, palladium(II) bromide and palladium(II) acetate.
12 . A process according to claim 8 , wherein a transition metal catalyst is selected from the group consisting of dichlorobis(triphenylphosphine)palladium(II), dichloro[1,3-bis(diphenylphosphino)propane]palladium(II) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II), or a dichloromethane adduct thereof.
13 . A process according to claim 3 wherein a metal salt additive is selected from the group consisting of a copper(I), copper(II), zinc(II), silver(I), cadmium(II), mercury(II), aluminum(III), gallium(III), indium(III), tin(IV), titanium(IV) and zirconium(IV) salt.
14 . A process according to claim 13 , wherein the amount of metal salt additive used is between 0.1 and 8 molar % relative to a compound of formula (II c).
15 . A process according to claim 3 , wherein X is chlorine; and a transition metal catalyst is a complex of nickel(0), or a complex of nickel(II) salt with at least one organophosphorus compound containing trivalent phosphorus; or a transition metal catalyst is a nickel(II) complex with an organophosphorus ligand which contains two trivalent phosphorus atoms.
16 . A process according to claim 15 , wherein a transition metal catalyst is dichloro[1,2-bis(diphenylphosphino)ethane]nickel(II); and a metal salt additive is ZnCl 2 or ZnBr 2 .
17 . A process according to claim 3 , wherein X is bromine; and a transition metal catalyst is a complex of palladium(0), or a complex of a palladium(II) salt with at least one organophosphorus compound containing trivalent phosphorus; or a transition metal catalyst is a palladium(II) complex with an organophosphorus ligand which contains two trivalent phosphorus atoms.
18 . A process according to claim 17 , wherein a transition metal catalyst is dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II), or a dichloromethane adduct thereof; and a metal salt additive is ZnCl 2 or ZnBr 2 .
19 . A process according to claim 3 , wherein a transition metal catalyst is an uncomplexed transition metal which is selected from the group consisting of nickel, palladium, platinum, cobalt, manganese or copper; or wherein a transition metal catalyst is an uncomplexed transition metal salt which is selected from the group consisting of nickel(II), palladium(II), platinum(II), cobalt(II), manganese(II), copper(I) or copper (II) chloride, bromide, iodide, hydroxide, oxide, acetate, hydroxyacetate, propionate, succinate, trifluoroacetate, acetylacetonate, nitrate, cyanide, sulfate, trifluoromethanesulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate thereof.
20 . A process for the manufacture of the compound of formula (I)
wherein Y represents a tetrazole protecting group, and R 3 represents a hydroxyl protecting group; comprising
(a′) reacting a compound of formula (III a)
wherein Hal is chlorine, bromine or iodine, with an active form of magnesium in an appropriate solvent;
(b′) reacting a resulting aryl magnesium halide compound of formula (III b)
in the presence of a transition metal catalyst with a compound of formula (II c)
wherein X is chlorine, in the absence of a metal salt additive; and, if necessary, isolating a resulting compound of formula (I C).
21 . A process according to claim 20 , wherein a transition metal catalyst is a complex of nickel(0), or a complex of nickel(II) salt with at least one organophosphorus compound containing trivalent phosphorus; or a transition metal catalyst is a nickel(II) complex with an organophosphorus ligand which contains two trivalent phosphorus atoms.
22 . A compound of formula (I C)
wherein Y represents a tetrazole protecting group, and R 3 represents a hydroxyl protecting group.
23 . A compound according to claim 22 , wherein Y and R 3 , independently of one another, are 1-butoxyethyl, 1-ethoxyethyl, 2-tetrahydropyranyl or 2-tetrahydrofuranyl.