Process for preparing biphenyltetrazole compounds
AssigneesE. I. Du Pont de Nemours and Company, Merck & Co., Inc.
InventorsYoung S. Lo, Lucius T. Rossano, Robert D. Larsen, Anthony O. King
Life of this patent
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Abstract
Method for the preparing biphenyltetrazole compounds which are angiotensin II receptor antagonists or which are useful intermediates to prepare angiotensin II receptor antagonists. An illustrative biphenyl tetrazole compound is 2-n-butyl-4-chloro-1-[(2'-(tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-im idazole-5-methanol, potassium salt.
Claims29
A process for preparing a compound of formula II ##STR28## which comprises the following steps:
- (a) mixing a compound of formula I ##STR29## wherein:
- P is triphenylmethyl, tertiary-butyl, C.sub.1 -C.sub.4 alkoxymethyl, methylthiomethyl, phenyl C.sub.1 -C.sub.4 alkoxymethyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, 2-(trimethylsilyl)ethyl, tetrahydropyranyl, piperonyl, or benzenesulfonyl;
- and
- R.sup.1a and R.sup.1b are each independently chlorine, bromine, C.sub.1 -C.sub.4 alkoxy, hydroxy, or
- R.sup.1a and R.sup.1b can be taken together with B to form a structure:
- ##STR30## A is phenyl, or (CH.sub.2)n, n is 2-4,
- with coupling solvent(s), wherein the coupling solvent(s) is(are) selected from the group consisting of benzene, toluene, ethyl ether, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethanol, methanol, propanol, water, 2-methyl-tetrahydrofuran or diethoxymethane;
- (b) mixing into the reaction mixture of step (a), a base, wherein the base is selected from:
- (i) an organic tertiary non-nucleophilic base, wherein the organic tertiary non-nucleophilic base is selected from the group consisting of triethylamine or diisopropylethylamine,
- (ii) an inorganic base, wherein the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, thallium hydroxide, potassium alkoxide or sodium alkoxide, and
- (iii) an organic solvent soluble base, wherein the organic solvent soluble base is selected from the group consisting of tetra-n-butylammonium carbonate, tetra-n-butylammonium hydroxide, benzyltrimethylammonium carbonate, benzyltrimethylammonium methyl carbonate, benzyltrimethylammonium methoxide, or benzyltrimethylammonium hydroxide;
- and a compound having the formula:
- ##STR31## X is bromine, iodine, methanesulfonyloxy, toluenesulfonyloxy, fluorosulfonyloxy, or trifluoromethanesulfonyloxy;
- and
- Q is hydrogen, methyl, C.sub.1 -C.sub.4 alkyl, hydroxymethyl, triorganosilyloxymethyl, hydroxy C.sub.1 -C.sub.4 alkyl, formyl, C.sub.1 -C.sub.4 acyl, C.sub.1 -C.sub.4 alkoxycarbonyl, or W-L--;
- L is a single bond, --(CH.sub.2).sub.t --, --(CH.sub.2).sub.r O(CH.sub.2).sub.r --, or --(CH.sub.2).sub.r S(O).sub.r (CH.sub.2).sub.r --,
- t is 1 to 4;
- r is 0 to 2;
- and
- W is a mono-, bi-, or multi-cyclic heteroaromatic group, which may be partially or completely hydrogenated, in which each ring member of said group includes at least 1 carbon atom and from 1 to 5 heteroatoms;
- (c) charging the reaction mixture of step (b) with a metal catalyst, wherein the metal catalyst is selected from the group consisting of nickel complex, palladium complex or platinium complex, for one to thirty hours at a temperature ranging from room temperature to 150.degree. C.;
- (d) purifying the reaction mixture (c) containing the compound of formula II to give the purified compound of formula II;
- and
- (e) recrystallizing the purified compound of formula II with a recrystallizing solvent.
The process of clam 2 wherein the palladium complex is a phosphinated palladium II complex selected from the group consisting of bis(triphenylphosphine)palladium chloride, bis(triphenylphosphine)palladium bromide, bis(triphenylphosphine)palladium acetate, bis(triisopropylphosphite)palladium chloride, bis(triisopropylphosphite)palladium bromide, bis(triisopropylphosphite)palladium acetate, [1,2-bis(diphenylphosphino)ethane]palladium chloride, [1,2-bis(diphenylphosphino)ethane]palladium bromide, [1,2-bis(diphenylphosphino)ethane]palladium acetate, [1,3-bis(diphenylphosphino)propane]palladium chloride, [1,3-bis(diphenylphosphino)propane]palladium bromide, [1,3-bis(diphenylphosphino)propane]palladium acetate, [1,4-bis(diphenylphosphino)butane]palladium chloride, [1,4-bis(diphenylphosphino)butane]palladium bromide and [1,4-bis(diphenylphosphino)butane]palladium acetate.
A process for preparing 2-n-butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphen yl-4-yl)methyl]-1H-imidazole-5-methanol, the compound of Formula B ##STR47## which comprises the following steps:
- (a) mixing a compound of formula A ##STR48## with coupling solvents, wherein the coupling solvents are water, tetrahydrofuran, and diethoxymethane, for 30 minutes;
- (b) adding to the mixture a base, wherein the base is potassium carbonate, and a compound having the formula:
- ##STR49## and mixing for 30 minutes;
- (c) charging the mixture of step (b) with a metal catalyst, bis(triphenylphosphine)palladium acetate, which is generated in the reaction mixture by contacting palladium acetate and triphenylphosphine in tetrahydrofuran from room temperature up to 60.degree. C. for 30 minutes, and heating to reflux at a temperature range of 76.degree.-79.degree. C. for 2-6 hours to produce the compound of formula B;
- (d) purifying the reaction mixture containing the compound of formula B which comprises:
- (i) diluting the reaction mixture with tetrahydrofuran and water;
- (ii) isolating the organic solvent soluble layer containing the compound of formula B,
- iii) treating the organic solvent soluble layer containing the compound of formula B with tributylphosphine;
- (iv) distilling off the tetrahydrofuran from the organic solvent soluble layer containing the compound of formula B and tributylphosphine;
- and
- (v) diluting with diethoxymethane and distilling off the diethoxymethane to produce the residue of the compound of formula B.
Dependencies are inferred from the claim text.