Process for the preparation of aromatic derivatives of 1-adamantane

Abstract

Process for the obtaining of 1-adamantane (tricycle[3.3.1.1 (3,7)]decane) derivatives, or of a pharmaceutically acceptable salt thereof, based on a carboxylation reaction, via metallation, of a precursor compound with an adequate leaving group. It also comprises the preparation of the precursor compound by means of a selective coupling of the corresponding boron, magnesium or zinc derivative with the corresponding disubstitute aromatic derivative. It is especially useful for the obtaining of Adapalene at industrial scale with good yield and high purity.

1 . A preparation process of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 
     
       
         
         
             
             
         
       
       wherein: 
       W is a biradical selected from the group consisting of: —CH 2 —, —O—, and —SO 2 —; 
       R 1  and R 2  are radicals, the same or different, independently selected from the group consisting of H, halogen, and a (C 1 -C 6 )-alkyl; 
       R 3  is a radical selected from the group consisting of hydroxyl, acyl, amide, halogen; (C 1 -C 6 ) alkyl optionally substituted by one or more hydroxyl or acyl groups, and (C 1 -C 4 )-alkoxyl optionally substituted by one or more hydroxyl, (C 1 -C 4 )-alkoxyl groups or amide, and/or optionally interrupted by one or more oxygen atoms; 
       R 4  is a radical selected from the group consisting of H, hydroxyl, (C 1 -C 6 )-alkyl, and (C 1 -C 4 )-alkoxyl; 
       or R 3  and R 4  form together a biradical —OCH 2 O—; 
       R 5  is a radical selected from the group consisting of H, (C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxyl, and an halogen; 
       S is a radical selected from the following formulae: 
     
     
       
         
         
             
             
         
       
       wherein: 
       R 6  is a radical selected from H, (C 1 -C 6 )-alkyl, and halogen; 
       R 7  is a radical selected from H, hydroxyl, and halogen; 
       V is a biradical —CH— and V′ is an O atom; or V is a N atom and V′ is a biradical —NH—; 
       said process comprises submitting a compound of formula (II) 
     
     
       
         
         
             
             
         
       
       wherein: 
       U is a radical selected from the following formulae: 
     
     
       
         
         
             
             
         
       
       wherein: 
       X is a leaving group adequate to carry out a metallation/carboxylation; and 
       W, V, V′, R 1 , R 2 ; R 3 , R 4 , R 5 , R 6 , and R 7  have the same meaning as defined before for the compound of formula (I); 
       to a carboxylation reaction which comprises the metallation of said compound of formula (II) using a metallation agent, followed by treatment with carbon dioxide, and optionally carrying out a treatment with an acid, and optionally, converting the compound obtained after the acid treatment into a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . The preparation process, according to  claim 1 , where the compound of formula (I) is the compound of formula (Ia) and the compound of formula (II) is the compound of formula (IIa) wherein X is a leaving group adequate to carry out a metallation/carboxylation. 
     
       
         
         
             
             
         
       
     
   
   
       3 . The preparation process, according to  claim 1 , wherein X is an halogen selected from the group consisting of by Cl, Br and I. 
   
   
       4 . The preparation process, according to  claim 3 , where the halogen is Br. 
   
   
       5 . The preparation process, according to  claim 1 , where the metallation agent is a (C 1 -C 4 )-alkyl-lithium or magnesium. 
   
   
       6 . The preparation process, according to  claim 5 , where the metallation agent is a (C 4 )-alkyl-lithium. 
   
   
       7 . The preparation process of a compound of formula (II) as defined in  claim 1 , which comprises a coupling reaction between a compound of formula (III) and, either, the 2,4,6-tris[3-(1-adamantyl)-4-methoxyphenyl]-1,3,5,2,4,6-trioxatribohnane, or a compound of formula (IV); 
     
       
         
         
             
             
         
       
       wherein: 
       U, W, R 1 , R 2 ; R 3 , R 4 , R 5 , have the same meaning as defined in  claim 1 ; 
       Y is a leaving group adequate to carry out a coupling and R 8  is a radical selected from MgZ, ZnZ and a radical of formula 
     
     
       
         
         
             
             
         
       
       wherein Z is an halogen selected from Cl and Br, and T 1  and T 2  are each independently selected from the group consisting of hydroxyl, (C 1 -C 4 )-alkoxyl and phenoxyl, the last optionally substituted by a (C 1 -C 4 )-alkoxyl group, (C 1 -C 4 )-alkyl group or an halogen; or alternatively T 1  and T 2  are taken together with the boron atom to form a cyclic structure selected from the following, 
     
     
       
         
         
             
             
         
       
       wherein M is selected from the group consisting of (CH 2 ) n , (CH 2 ) r CR u R v (CH 2 ) s  and CR u R v (CH 2 ) t CR u R v ; n is an integer from 2 to 4; r and s are integers from 0 to 4 with the condition that r and s are not both 0; t is an integer from 0 to 1, and R u  and R v  are each independently selected from the group consisting of H, (C 1 -C 4 )-alkyl, phenyl, and mono- or di-substituted phenyl, being the substituents halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxyl. 
     
   
   
       8 . The preparation process according to  claim 7 , where the compound of formula (II) is the compound of formula (IIa), and the coupling reaction is carried out between a compound of formula (IIIa) and, either, the 2,4,6-tris[3-(1-adamantyl)-4-methoxyphenyl]-1,3,5,2,4,6-trioxatriborinane or a compound of formula (IVa) wherein R 8  has the same meaning as in  claim 7 . 
     
       
         
         
             
             
         
       
     
   
   
       9 . The preparation process, according to  claim 7 , where Y is selected from an halogen selected from Cl, Br, I, a sulphonate of formula —OSO 2 R 9 , wherein R 9  is a radical selected from CF 3 , (C 1 -C 4 )-alkyl, phenyl and phenyl mono- or di-substituted by a radical selected from (C 1 -C 4 )-alkyl, halogen and nitro. 
   
   
       10 . The preparation process, according to  claim 9 , where the halogen is Br. 
   
   
       11 . The preparation process, according to  claim 9 , where the sulphonate is the trifluoromethanesulphonate of formula OSO 2 CF 3 . 
   
   
       12 . The preparation process, according to  claim 8 , where the compound of formula (IIIa) is coupled with the 2,4,6-tris[3-(1-adamantyl)-4-methoxyphenyl]-1,3,5,2,4,6-trioxatriborinane, or with a compound of formula (IVa) selected from 3-(1-adamantyl)-4-methoxyphenylboronic acid, [3-(1-adamantyl)-4-methoxyphenyl]-5,5-dimethyl-1,3,2-dioxaborinane and zinc chloride of 3-(1-adamantyl)-4-methoxybenzene. 
   
   
       13 . The preparation process, according to  claim 7 , where the coupling is carried out is presence of a transition metal compound. 
   
   
       14 . The preparation process, according to  claim 13 , where the metallic compound is selected from palladium and nickel compounds. 
   
   
       15 . The preparation process, according to  claim 14 , where the transition metal compound is the tetrakis(triphenylphosphine)palladium (0). 
   
   
       16 . The preparation process, according to  claim 15 , where, when the coupling is carried out with the 2,4,6-tris[3-(1-adamantyl)-4-methoxyphenyl]-1,3,5,2,4,6-trioxatriborinane, or a compound of formula (IV) being R 8  the radical of formula 
     
       
         
         
             
             
         
       
       wherein T 1  and T 2  have the same meaning as defined above, said coupling is carried out in presence of a base which is selected from the group formed by a alkaline metal carbonate and a alkaline metal phosphate. 
     
   
   
       17 . The preparation process, according to  claim 7 , which additionally comprises the transformation of the compound of formula (II) into the compound of formula (I) and, optionally, into a pharmaceutically acceptable salt thereof. 
   
   
       18 . (canceled) 
   
   
       19 . (canceled) 
   
   
       20 . (canceled)