Process for the preparation and purification of etravirine and intermediates thereof

Abstract

In one embodiment the present invention encompasses 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (“ETHER”), 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethyl-benzonitrile (“ETHER C-2 isomer”), mixtures and salts thereof of. The present invention encompasses the use of ETHER and salts thereof to prepare Etravirine and Etravirine intermediates, and salts thereof. In another embodiment the present invention encompasses the use of ETHER and salts thereof to prepare debrometravirine (“DEBETV”) and salts thereof. In yet another embodiment the present invention encompasses the use of ETHER and salts thereof to prepare 4-(6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (“ARCPBN”) and salts thereof.

1 . The compound, 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (“ETHER”), or a salt thereof, of the following formula: 
       
         
           
           
               
               
           
         
         wherein n is either 0 or 1 and HA is an acid. 
       
     
     
         2 . The compound according to  claim 1 , wherein said compound is characterized by data selected from: a  1 H NMR pattern (600.1 MHz, DMSO-d 6 ,), δ/ppm, having peaks at about 7.69 (2H, br), 7.52 (1H, s), and 2.12 (6H, s); a  1 H NMR pattern substantially as depicted in  FIG. 1 ; a  13 C NMR pattern (150.9 MHz, DMSO-d 6 ,), δ/ppm, having peaks at about 169.9 (C, s), 162.7 (C, s), 159.1 (C, s), 152.6 (C, s), 133.3 (CH, d), 132.8 (C, s), 118.7 (C, s), 109.9 (C, s), 107.1 (CH, d), and 16.1 (CH 3 , q); a  13 C NMR pattern substantially as depicted in  FIG. 2 ; and combinations thereof. 
     
     
         3 . The compound according to  claim 1 , wherein said compound is isolated. 
     
     
         4 . The compound according to  claim 1 , wherein said compound is crystalline. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The compound 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile (“ETHER C-2 isomer”), or a salt thereof, of the following formula: 
       
         
           
           
               
               
           
         
         wherein n is either 0 or 1 and HA is an acid. 
       
     
     
         9 . The compound according to  claim 8 , wherein said compound is characterized by data selected from: a  1 H NMR pattern (600.1 MHz, DMSO-d 6 ,), δ/ppm, having peaks at about 7.75 (1H, s), 7.69 (2H, br), and 2.12 (6H, s); a  1 H NMR pattern substantially as depicted in  FIG. 1 ; a  13 C NMR pattern (150.9 MHz, DMSO-d 6 ,), δ/ppm, having peaks at about 169.9 (C, s), 163.6 (2C, s), 152.6 (C, s), 133.2 (C, d), 132.7 (C, s), 118.7 (C, s), 117.3 (CH, d), 109.9 (C, s), and 16.1 (CH 3 , q); a  13 C NMR pattern substantially as depicted in  FIG. 2 ; and combinations thereof. 
     
     
         10 . The compound according to  claim 8 , wherein said compound is isolated. 
     
     
         11 . The compound according to  claim 8 , wherein said compound is crystalline. 
     
     
         12 . A crystalline form of a mixture of the compounds, 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile and 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile, characterized by data selected from: a PXRD pattern having peaks at about 8.0, 11.2, 13.1, 13.8 and 24.2±0.2 degrees two-theta; a PXRD pattern substantially as depicted in  FIG. 3 ; and combinations thereof. 
     
     
         13 . The crystalline form of  claim 12 , further characterized by a PXRD pattern having additional peaks at about 11.9, 17.4, 19.6, 26.7 and 30.4±0.2 degrees two-theta. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A process for preparing the compound 4-(2,6-dichloro-pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile, its mixture with 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile, or salts thereof, said process comprising reacting 2,4,6-trihalopyrimidine (ThalP) of the following structure: 
       
         
           
           
               
               
           
         
         and 4-hydroxy-3,5-dimethylbenzonitrile (DMHB); wherein each A is independently a halogen. 
       
     
     
         18 . The process of  claim 17 , wherein said process is carried out in the presence of a solvent. 
     
     
         19 . The process of  claim 18 , wherein the solvent is a mixture of water and a water miscible organic solvent comprising a C 1 -C 3  ketone. 
     
     
         20 . The process of  claim 18 , wherein the water miscible organic solvent is acetone. 
     
     
         21 . The process of  claim 17 , wherein said process is carried out in the presence of a base. 
     
     
         22 . The process of  claim 21  wherein the base is an inorganic base. 
     
     
         23 . The process of  claim 22 , wherein the inorganic base is an alkali metal base. 
     
     
         24 . The process of  claim 24 , wherein the alkali metal base is sodium hydroxide. 
     
     
         25 . The process of  claim 17 , further comprising recovering the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile or its mixture with 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile or salts thereof. 
     
     
         26 . The process of  claim 17 , further comprising converting the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile, or its mixture with 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile or salts thereof to Etravirine, or Etravirine intermediates or salts thereof. 
     
     
         27 . The process of  claim 17 , further comprising converting the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile or its mixture with 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile or salts thereof to 4-(6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (“ARCPBN”) of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         28 . A process for preparing the compound 4-(6 chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (ARCPBN): 
       
         
           
           
               
               
           
         
         comprising reacting the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile or its mixture with 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile or a salt thereof and 4-aminobenzonitrile (ABN). 
       
     
     
         29 . The process of  claim 28 , wherein said process is carried out in the presence of a solvent. 
     
     
         30 . The process of  claim 29 , wherein the solvent is a polar aprotic organic solvent. 
     
     
         31 . The process of  claim 30  wherein the polar aprotic solvent is dimethylacetamide. 
     
     
         32 . The process of  claim 28 , wherein said process is carried out in the presence of a base. 
     
     
         33 . The process of  claim 32 , wherein the base is an inorganic base. 
     
     
         34 . The process of  claim 33 , wherein the inorganic base is a metal hydride base. 
     
     
         35 . The process of  claim 34 , wherein the metal hydride base is sodium hydride. 
     
     
         36 . The process of  claim 28 , further comprising recovering the compound ARCPBN 4-(6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile. 
     
     
         37 . The process of  claim 28 , further comprising converting the compound 4-(6 chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile to the compound 4-(6-amino-2-(4-cyanophenyl-amino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (DEBETV) or a salt thereof. 
     
     
         38 . The process of  claim 28 , further comprising converting the compound 4-(6 chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile to Etravirine or a salt thereof. 
     
     
         39 . A process for preparing Etravirine and salts thereof by converting the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile or its mixture with 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile or their salt to 4-(6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (ARCPBN) and subsequently converting the ARCPBN to 4-(6-amino-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (DEBETV) and then converting the compound DEBETV to Etravirine or a salt thereof. 
     
     
         40 . A process according to  claim 39  wherein the conversion of the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile to the compound 4-(6 chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile is done by reacting the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile or a salt thereof and 4-aminobenzonitrile (ABN). 
     
     
         41 . A process according to  claim 39  wherein the reaction is carried out in the presence of a solvent. 
     
     
         42 . A process according to  claim 41  wherein the solvent is a polar aprotic organic solvent. 
     
     
         43 . A process according to  claim 42  wherein the solvent is dimethylacetamide. 
     
     
         44 . A process according to  claim 39  wherein the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile and the base are suspended in the solvent to form a suspension, and the obtained suspension is combined with a solution of ABN in a polar aprotic organic solvent to obtain a reaction mixture comprising 4-(6 chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile. 
     
     
         45 . A process according to  claim 44  wherein the base is an inorganic base. 
     
     
         46 . A process according to  claim 45  wherein the base is an alkali metal hydride. 
     
     
         47 . A process according to  claim 46  wherein the base is sodium hydride. 
     
     
         48 . A process according to  claim 39 , wherein the compound ETHER 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile or its mixture with the compound C-2 ETHER isomer is prepared by a process according to any one of  claims 17 - 25 . 
     
     
         49 . A process for preparing the compound 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile, its mixture with 4-(4,6-dichloropyrimidin-2-yloxy)-3,5-dimethylbenzonitrile, or salts thereof, said process comprising reacting 2,4,6-trisubstituted-pyrimidine (TsubP) of the following structure: 
       
         
           
           
               
               
           
         
         and  4 -hydroxy-3,5-dimethylbenzonitrile (DMHB); 
         wherein each L is independently a leaving group. 
       
     
     
         50 . The process of  claim 49 , wherein the leaving group is selected from halogens and sulfonyl esters. 
     
     
         51 . The process of  claim 50 , wherein the leaving group is selected from Br, Cl, I, mesylate, tosylate and triflate.