Novel synthesis of irbesartan

Abstract

Provided are a method of making irbesartan via a Suzuki coupling reaction and a novel intermediate, 2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one, for such process. The novel process includes the step of reacting such intermediate with a protected imidazolephenylboronic acid.

1 - 39 . (canceled) 
   
   
       40 . A process for making irbesartan, comprising the steps of:
 a) reacting 5-phenyl-1-trityl-1H-tetrazole with a borate in the presence of a solvent and a base;   b) recovering 2-(5-tetrazoyl)phenylboronic acid; and   c) converting the product of step b) to irbesartan.   
   
   
       41 . A process for making irbesartan, comprising the steps of:
 b) reacting 5-phenyl-1-trityl-1H-tetrazole with a borate in the presence of THF and butyllithium;   c) recovering 2-(5-tetrazoyl)phenylboronic acid;   d) reacting a 2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one acid addition salt with a bromobenzyl bromide in a two-phase solvent system, wherein the second phase comprises the 2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one acid addition salt, water, and KOH, and wherein the first phase comprises the bromobenzyl bromide, toluene, and a first phase transfer catalyst selected from the group consisting of quaternary ammonium compounds and phosphonium compounds;   e) separating the two phases from step d);   f) recovering 2-butyl-3-(4′bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one;   g) reacting the product recovered in step c) with the product recovered in step f) in a two-phase solvent system in the presence of a second phase transfer catalyst, wherein the first phase comprises a solvent selected from the group consisting of ethers, formals, hydrocarbons, tetralins and mixtures thereof, wherein the second phase comprises water and potassium carbonate, and wherein the second phase transfer catalyst comprises a palladium complex or a nickel complex;   h) separating the two phases from step g);   i) recovering 2-butyl-3-[2′-(triphenylmethyltetrazol-5-yl)-biphenyl-4-yl methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one;   j) dissolving the product of step i) in acetone;   k) acidifying the solution;   l) neutralizing the solution and separating the trityl alcohol, whereby a second solution is obtained;   m) acidifying the second solution;   n) cooling the acidified second solution; and   o) recovering irbesartan.   
   
   
       42 . A process for making irbesartan comprising the steps of:
 a) reacting an acid addition salt of 2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one with 4-bromobenzyl bromide in the presence of a catalyst in a two-phase solvent system having a first, organic phase and a second, aqueous phase, whereby 2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one is obtained;   b) reacting the 2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one from step a) with 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid, whereby 2-butyl-3-[2′-(triphenylmethyltetrazol-5-yl)-biphenyl-4-yl methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one is obtained; and   c) cleaving the trityl group from the tetrazole ring in the 2-butyl-3-[2′-(triphenylmethyltetrazol-5-yl)-biphenyl-4-yl methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one to obtain irbesartan.   
   
   
       43 . The process of  claim 41 , wherein the product of step a) is isolated prior to step b). 
   
   
       44 . The process of  claim 41 , wherein the borate in step b) is triisopropyl borate. 
   
   
       45 . The process of  claim 41 , wherein in step b) the reacting is at a temperature not higher than about −20° C. 
   
   
       46 . The process of  claim 41 , wherein step c) comprises evaporating the solvent to recover 2-(5-tetrazoyl)phenylboronic acid. 
   
   
       47 . The process of  claim 41 , wherein the 2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one acid addition salt is 2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one hydrochloride. 
   
   
       48 . The process of  claim 41 , wherein the bromobenzyl bromide is 4-bromobenzyl bromide. 
   
   
       49 . The process of  claim 41 , wherein the first phase transfer catalyst is tetrabutylammonium hydrogensulfate. 
   
   
       50 . The process of  claim 41 , wherein step f) comprises evaporating the toluene to recover 2-butyl-3-[2′-(triphenylmethyltetrazol-5-yl)-biphenyl-4-yl methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one. 
   
   
       51 . The process of  claim 41 , wherein the second phase transfer catalyst comprises Pd(OAc) 2 . 
   
   
       52 . The process of  claim 41 , wherein the second phase transfer catalyst further comprises a triaryl phosphine. 
   
   
       53 . The process of  claim 41 , wherein the first phase in step g) comprises a solvent selected from the group consisting of 1,2-dimethoxyethane, diethoxymethane, tetrahydrofuran, toluene, m-xylene, o-xylene, tetralin, and mixtures thereof. 
   
   
       54 . The process of  claim 41 , wherein the first phase in step g) comprises 1,2-dimethoxyethane. 
   
   
       55 . The process of  claim 54 , wherein the first phase in step g) further comprises THF. 
   
   
       56 . The process of  claim 41 , wherein step i) comprises evaporating the solvent to recover the 2-butyl-3-[2′-(triphenylmethyltetrazol-5-yl)-biphenyl-4-yl methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one. 
   
   
       57 . The process of  claim 41 , further comprising crystallizing 2-butyl-3-[2′-(triphenylmethyltetrazol-5-yl)-biphenyl-4-yl methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one from step i) in isopropyl alcohol prior to step j). 
   
   
       58 . The process of  claim 41 , wherein step o) comprises recovering irbesartan by filtration.