Process for the preparation of aripiprazole lauroxil

Abstract

It is provided a process for the preparation of aripiprazole lauroxil that comprises reacting 1-(hydroxymethyl) aripiprazole with lauric acid in the presence of a suitable solvent and a carboxyl activating agent in the presence of a suitable solvent and, optionally, in the presence of an appropriate base. -(Hydroxymethyl) aripiprazole can be prepared by reacting aripiprazole or an hydrate thereof with paraformaldehyde in the presence of a suitable organic 10 solvent and a suitable base, wherein the reaction is carried out without the addition of water as a solvent to the reaction mixture. Additionally, (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydro-2-oxoquinolin-1(2H)-yl)methyl formate is provided as a reference standard.

1 . A process for the preparation of a compound of formula (I), which is aripiprazole lauroxil, 
       
         
           
           
               
               
           
         
         which comprises the steps of: 
         a) preparation a compound of formula (II) 
       
       
         
           
           
               
               
           
         
         by reacting a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         which is aripiprazole, or a hydrate thereof, with paraformaldehyde in the presence of a suitable organic solvent and a suitable base, wherein the reaction is carried out either in the absence of water or in the presence of a content of water which comes from either the use of a non-anhydrous organic solvent, non-anhydrous reactants, or the use of a hydrated form of aripiprazole, without addition of further water; and 
         b) subsequently converting the compound of formula (II) into aripiprazole lauroxil. 
       
     
     
         2 . The process according to  claim 1 , wherein the organic solvent in step a) is selected from the group consisting of toluene, ethyl acetate, dimethylsulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, acetonitrile, and mixtures thereof. 
     
     
         3 . The process according to  claim 1 , wherein the base in step a) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, potassium carbonate, sodium carbonate, cesium carbonate, potassium tertbutoxide, and diisopropylethylamine. 
     
     
         4 . The process according to  claim 1 , wherein, if present, the amount of water in the reaction mixture comprising aripiprazole and paraformaldehyde is equal to or lower than 1 wt %. 
     
     
         5 . The process according to  claim 1 , wherein aripiprazole, or a hydrate thereof, and paraformaldehyde are in a molar ratio of from 1:1 to 1:3. 
     
     
         6 . The process according to  claim 1 , wherein step b) is carried out by reacting the compound of formula (II) with lauric acid and a carboxyl activating agent in the presence of a suitable solvent and, optionally, in the presence of a suitable base. 
     
     
         7 . The process according to  claim 6 , wherein the solvent in step b) is selected from the group consisting of toluene, dimethylsulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, acetonitrile, and mixtures thereof. 
     
     
         8 . The process according to  claim 6 , wherein the carboxyl activating agents is selected from the group consisting of dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide, and a combination of one of the previous with a compound selected from the group consisting of N-hydroxysuccinimide or N-hydroxyphthalimide; 1′-carbonyldiimidazole, 1,1′-carbonyl-di-(1,2,4-triazol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate, bromo-tripyrrolidino-phosphonium hexafluoro-phosphate, benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluoro-phosphate, 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminium hexafluorophosphate, 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-aminium hexafluorophosphate, and 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminium tetrafluoroborate. 
     
     
         9 . The process according to  claim 6 , wherein the base in step b) is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylmorpholine, and dimethylaminopiridine. 
     
     
         10 . A process for the preparation of a compound of formula (I), which is aripiprazole lauroxil, 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula (II) 
       
       
         
           
           
               
               
           
         
         with lauric acid and a carboxyl activating agent in the presence of a suitable solvent and, optionally, in the presence of an appropriate base. 
       
     
     
         11 . The process according to  claim 10 , wherein the solvent is selected from the group consisting of toluene, dimethylsulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, acetonitrile, and mixtures thereof. 
     
     
         12 . The process according to  claim 10 , wherein the carboxyl activating agent is selected from the group consisting of dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide, and a combination of one of the previous with a compound selected from the group consisting of N-hydroxysuccinimide or N-hydroxyphthalimide; 1′-carbonyldiimidazole, 1,1′-carbonyl-di-(1,2,4-triazol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate, bromo-tripyrrolidino-phosphonium hexafluoro-phosphate, benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluoro-phosphate, 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminium hexafluorophosphate, 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-aminium hexafluorophosphate, and 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminium tetrafluoroborate. 
     
     
         13 . The process according to  claim 10 , wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylmorpholine, and dimethylaminopiridine. 
     
     
         14 . An isolated compound of formula (IV) 
       
         
           
           
               
               
           
         
       
     
     
         15 . Use of the compound of formula (IV) as defined in  claim 14  as a reference standard. 
     
     
         16 . A method for determining the content of an impurity in aripiprazole lauroxil sample by high-performance liquid chromatography analysis, wherein the compound of formula (IV) as defined in  claim 14  is used as a reference compound. 
     
     
         17 . The process according to  claim 2 , wherein the base in step a) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, potassium carbonate, sodium carbonate, cesium carbonate, potassium tertbutoxide, and diisopropylethylamine. 
     
     
         18 . The process according to  claim 2 , wherein, if present, the amount of water in the reaction mixture comprising aripiprazole and paraformaldehyde is equal to or lower than 1 wt %. 
     
     
         19 . The process according to  claim 3 , wherein, if present, the amount of water in the reaction mixture comprising aripiprazole and paraformaldehyde is equal to or lower than 1 wt %. 
     
     
         20 . The process according to  claim 2 , wherein aripiprazole, or a hydrate thereof, and paraformaldehyde are in a molar ratio of from 1:1 to 1:3.