Process for the preparation of adapalene and related compounds

Abstract

The invention provides an improved process for the preparation of a benzonaphthalene derivative including, in particular, the manufacture of high purity adapalene. The invention further includes a method for assessing the color of adapalene by means of a quantitative colorimetric measurement of the produced adapalene.

1 .- 27 . (canceled) 
     
     
         28 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process comprising the steps of:
 (a) providing adapalene, or a salt thereof;   (b) assessing the purity of said adapalene, or a salt thereof, by using 3,3′-diadamantyl-4,4′-dimethoxybiphenyl as a reference marker to determine the level of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl impurity; and   (c) subjecting the adapalene, or a salt thereof, to one or more purification steps until the content of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl in said adapalene is not more than 0.2% with respect to adapalene.   
     
     
         29 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 28 , wherein step (c) is carried out until the amount of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl is not more than 0.1% with respect to adapalene. 
     
     
         30 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 28 , wherein step (c) is carried out until the 3,3′-diadamantyl-4,4′-dimethoxybiphenyl is not detected. 
     
     
         31 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 28 , wherein step (c) is carried out until the adapalene is more than 99.8% pure. 
     
     
         32 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 28 , wherein step (c) is carried out until the adapalene is more than 99.9% pure. 
     
     
         33 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 28 , wherein the purification step of step (c) comprises at least one of the steps of (i) suspending or recrystallizing solid adapalene, or salt thereof, in an organic solvent; and (ii) dissolving the 3,3′-diadamantyl-4,4′-dimethoxybiphenyl impurity in an aromatic apolar solvent. 
     
     
         34 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 33 , wherein the aromatic apolar solvent is toluene. 
     
     
         35 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 33 , wherein the organic solvent is at least one of an aromatic hydrocarbon solvent, a ketone solvent, an ether solvent, an alcohol solvent, an ester solvent, water, and mixtures thereof. 
     
     
         36 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 28 , wherein the adapalene salt is the sodium salt, potassium salt, lithium salt, or cesium salt. 
     
     
         37 . Adapalene, or a salt thereof, suitable for pharmaceutical use, obtained according to a process as defined in  claim 28 , wherein the use of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl as a reference marker comprises providing a standard solution of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl and using the solution as a reference marker to determine the level of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl impurity.