Process for the Synthesis of Quaternary Amine Compounds

Abstract

The invention relates to a process for the synthesis of quaternized compounds of formula:

1 . A process for the synthesis of a compound of Formula IIA by quaternization of a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein, 
         s is 0, 1, 2 or 3; 
         Y— is a pharmaceutically acceptable counterion; 
         each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is independently selected from absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; alternatively, two or more of R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  together with the atoms they are attached to form two, three or four additional optionally substituted ring(s); 
         alternatively R 2  and R 3  together with the carbon they are attached to form a C═X group; 
         wherein each R 20  and R 21  is independently selected from absent, hydrogen, halogen, —OH, —SH, —NH 2 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OH, —C(O)NH 2 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; 
         X is S, O or C(R 20 )(R 21 ); and, 
         Q is aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; 
         wherein the quaternization process comprises the step of reacting a compound of Formula II with Q-LG in the presence of a base and a solvent, wherein LG is a leaving group; 
         wherein said solvent is a biphasic solvent, or at least said compound of Formula IIA is insoluble in said solvent. 
       
     
     
         2 . The process according to  claim 1 , wherein said compound of Formula II is a compound of Formula III and said compound of Formula IIA is a compound of Formula IIIA: 
       
         
           
           
               
               
           
         
         wherein, s, Y—, R 1 , R 2 , R 3 , R 4 , R 8 , R 20 , and R 21  are as defined above; 
         t is 0, 1, 2, 3, 4, 5, 6, or 7; 
         each R 10  and R 11  is independently selected from absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; 
         alternatively two R 10  groups together with the carbon they are attached to form a C═X group; 
         alternatively two R 10  groups together with the atoms they are attached to, form an additional ring with optional substitution; 
         R 7  and R 9  together with the atoms they are attached to, form an additional ring. 
       
     
     
         3 . The process according to  claim 1 , wherein said compound of Formula II is a compound of Formula IV and said compound of Formula IIA is a compound of Formula IVA: 
       
         
           
           
               
               
           
         
         wherein, s, t, Y—, R 1 , R 2 , R 3 , R 4 , R 8 , R 10 , R 11 , R 20 , and R 21  are as defined above. 
       
     
     
         4 . The process according to  claim 1 , wherein said compound of Formula II is a compound of Formula V and said compound of Formula IIA is a compound of Formula VA: 
       
         
           
           
               
               
           
         
         wherein, s, t, Y—, R 1 , R 2 , R 3 , R 4 , R 8 , R 10 , R 11 , R 20 , and R 21  are as defined above; 
         R 14  and R 15  are independently selected from alkyl, substituted alkyl, aryl and substituted aryl. 
       
     
     
         5 . The process according to  claim 1 , wherein said quaternization process is selected from methylation of a tertiary amine from Processes below:
 Process 2:   
       
         
           
           
               
               
           
         
         Process 3: 
       
       
         
           
           
               
               
           
         
         Process 4: 
       
       
         
           
           
               
               
           
         
         Process 5: 
       
       
         
           
           
               
               
           
         
         Process 8: 
       
       
         
           
           
               
               
           
         
         Process 9: 
       
       
         
           
           
               
               
           
         
         Process 10: 
       
       
         
           
           
               
               
           
         
         Process 19: 
       
       
         
           
           
               
               
           
         
         Process 20: 
       
       
         
           
           
               
               
           
         
         wherein R 13  is selected from H, cyclopropyl, cyclobutyl, phenyl, —CH═CH 2 , —CH═C(CH 3 ) 2 . 
       
     
     
         6 . The process according to  claim 1 , wherein said base is selected from: triethyl amine, dimethyl amine, tert-butyl amine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. 
     
     
         7 . The process according to  claim 1 , wherein Q-LG is an alkyl halide. 
     
     
         8 . The process according to  claim 1 , wherein Q-LG is CH 3 -LG, and LG is selected from bromide, chloride, iodide, alkyl sulfonate or aryl sulfonate, preferably mesylate or tosylate. 
     
     
         9 . The process according to  claim 1 , wherein Q-LG is CH 3 CH 2 -LG, and LG is selected from bromide, chloride, iodide, alkyl sulfonate or aryl sulfonate, preferably mesylate or tosylate. 
     
     
         10 . The process according to  claim 1 , wherein Y is a halogen, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl. 
     
     
         11 . The process according to  claim 1  wherein said solvent is a polar aprotic solvent or a non-polar solvent. 
     
     
         12 . The process according to  claim 11 , wherein said polar aprotic solvent is selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile, sulfolane, dimethylacetamide, N-methylpyrrolidine-2-one, isopropyl acetate, dimethylsulfoxide, nitromethane and mixtures thereof. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . A method of treating opioid induced constipation in a patient comprising the step of administering a composition comprising a compound of Formula IIA and a compound of Formula II wherein the molar ratio of Formula IIA to Formula II is more than 100:1 wherein said compound of Formula IIA is synthesized by the process according to  claim 2 . 
     
     
         16 . (canceled) 
     
     
         17 . The method according to  claim 15 , wherein said molar ratio of Formula IIA to Formula II is more than 500:1. 
     
     
         18 . The method according to  claim 17 , wherein said compound of Formula II is: 
       
         
           
           
               
               
           
         
         and, said compound of Formula IIA is: 
       
       
         
           
           
               
               
           
         
       
     
     
         19 . (canceled) 
     
     
         20 . A unit dosage form of a compound of Formula IIA comprising about 10 to about 100 mg of a compound of a compound Formula IIA and about 0 to about 0.25 mg of a compound of a compound Formula II. 
     
     
         21 . A method of treating opioid induced constipation in a patient comprising the step of administering a composition comprising a unit dosage form according to  claim 20 . 
     
     
         22 . A method of treating opioid induced constipation in a patient comprising the step of administering a unit dosage form according to  claim 21 . 
     
     
         23 . A method of treating a disease or disorder selected from a group consisting of constipation, post-operative ileus, immune suppression, inhibition of gastrointestinal motility, inhibition of gastric emptying, nausea, emesis, incomplete evacuation, bloating, abdominal distension, increased gastroesophageal reflux, hypotension, bradycardia, gastrointestinal dysfunction, pruritus, dysphoria, or urinary retention, comprising the step of administering a compound of Formula IIA or a composition comprising a compound of Formula IIA wherein said compound of Formula IIA is synthesized by the process according to  claim 1 . 
     
     
         24 . The method according to  claim 23 , wherein said disease or disorder is selected from opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, opioid- or nonopioid-induced inhibition of gastric emptying by enteric feeding, and opioid- or nonopioid-induced constipation. 
     
     
         25 . The method according to  claim 23 , wherein said disease or disorder is post-operative ileus. 
     
     
         26 - 28 . (canceled)