Process of a quaternary ammonium salt using phosphate

Abstract

The present invention relates to a novel process for preparing quaternary ammonium salt derivatives.

1 - 17 . (canceled) 
     
     
         18 . A composition containing a compound of formula (8): 
       
         
           
           
               
               
           
         
       
       or an acid addition salt thereof and by-product (R) 
       wherein
 B is carbonyl group or sulfonyl group, 
 R 5a , R 5b , R 5c , and R 5d  are independently hydrogen atom or C 1-4  alkyl group, alternatively R 5a  and R 5b , or R 5a  and R 5c  may be taken together to form a hydrocarbon ring, or R 5a  and R 5c  may be taken together to form an aromatic hydrocarbon ring, wherein the hydrocarbon ring may be bridged with C 1-4  alkylene or oxygen atom wherein the C 1-4  alkylene and the hydrocarbon ring may be substituted with at least one C 1-4  alkyl, 
 q is 0 or 1, and 
 Y is a substituent of the following formula (3a) or (3b): 
 
       
         
           
           
               
               
           
         
         wherein R 3  is independently methylene or oxygen atom; R 4  is independently C 1-6  alkyl group, C 1-6  alkoxy group, or hydroxy group; m and n are independently 0, 1, 2, or 3; and p is 1 or 2, and 
         Z is ═N—R 1  or ═CH—R 2  wherein R 1  is C 1-6  alkyl group, C 3-7  cycloalkyl group, C 5-7  cycloalkenyl group, C 6-10  aryl group, or 5- to 10-membered monocyclic or bicyclic heteroaryl group; R 2  is C 1-6  alkyl group, C 1-6  alkoxy group, C 1-6  alkylthio group, C 3-7  cycloalkyl group, C 3-7  cycloalkyloxy group, C 3-7  cycloalkylthio group, C 5-7  cycloalkenyl group, C 5-7  cycloalkenyloxy group, C 5-7  cycloalkenylthio group, C 6-10  aryl group, C 6-10  aryloxy group, C 6-10  arylthio group, 5- to 10-membered monocyclic or bicyclic heteroaryl group, 5- to 10-membered monocyclic or bicyclic heteroaryloxy group, or 5- to 10-membered monocyclic or bicyclic heteroarylthio group, 
         prepared by a process comprising the following steps (i) and (ii): 
       
       step (i) 
       a process for preparing a quaternary ammonium salt of formula (4): 
       
         
           
           
               
               
           
         
       
       wherein X is halogen atom, C 1-6  alkylsulfonyloxy group, or C 6-10  arylsulfonyloxy group, and Y and Z are as defined above,
 comprising reacting a compound of formula (1): 
 
       
         
           
           
               
               
           
         
       
       wherein Z is as defined above
 with 1 to 2 mole of a compound of formula (2): 
 
       
         
           
           
               
               
           
         
       
       wherein X and Y are as defined above, per one mole of the compound of formula (1)
 in the presence of 1 to 5 mole of a phosphate per one mole of the compound of formula (1) and 0.01 to 0.1 part by weight of water per one part by weight of the phosphate; and 
 
       step (ii) 
       a process for preparing the compound of formula (8)
 comprising reacting the quaternary ammonium salt (4) prepared in step (i) with a compound of formula (7): 
 
       
         
           
           
               
               
           
         
       
       wherein B, R 5a , R 5b , R 5c , R 5d  and q are as defined above, 
       in the presence of a solid inorganic base selected from an alkali metal carbonate, an alkali earth metal carbonate and/or an alkali metal bicarbonate
 wherein the production rate of the by-product (R) in step (ii) is about 3% or less, wherein the by-product (R) is produced by the reaction of the unreacted compounds of formula (1) and formula (2) with the potassium carbonate in step (ii), and the by product (R) has a carbonate part therein. 
 
     
     
         19 . The composition of  claim 18 , wherein the production rate is about 0.019% or less. 
     
     
         20 . The composition of  claim 18 , wherein X is independently C 1-6  alkylsulfonyloxy group, or C 6-10  arylsulfonyloxy group. 
     
     
         21 . The composition of  claim 18 , wherein X is methanesulfonyloxy group. 
     
     
         22 . The composition of  claim 18 , wherein Y is the substituent of formula (3a). 
     
     
         23 . The composition of  claim 18 , wherein m is 2 and n is 0. 
     
     
         24 . The composition of  claim 18 , wherein Z is ═N—R 1 . 
     
     
         25 . The composition of  claim 18 , wherein R 1  is 5- to 10-membered monocyclic or bicyclic heteroaryl group. 
     
     
         26 . The composition of  claim 18 , wherein R 1  is 1,2-benzisothiazol-3-yl. 
     
     
         27 . The composition of  claim 18 , wherein the phosphate is dibasic potassium phosphate. 
     
     
         28 . The composition of  claim 18 , wherein the phosphate is 1 to 3 mole per one mole of the compound of formula (1). 
     
     
         29 . The composition of  claim 18 , wherein the amount of water is 0.01 to 0.05 part by weight per one part by weight of the phosphate. 
     
     
         30 . The composition of  claim 18 , which further comprises the following step (iii) after the reaction of step (ii): 
       step (iii) 
       adding a solvent to the product in step (ii) to obtain the compound of formula (8) as a crystal, 
       wherein the solvent is an aliphatic hydrocarbon solvent and/or an alcohol solvent. 
     
     
         31 . The composition of  claim 30 , wherein the solvent in step (iii) is an alcohol solvent. 
     
     
         32 . The composition of  claim 31 , wherein the alcohol solvent is methanol, ethanol and/or isopropanol. 
     
     
         33 . The composition of  claim 18 , wherein the solid inorganic base in step (ii) is a potassium carbonate. 
     
     
         34 . The composition of  claim 18 , wherein B is carbonyl group. 
     
     
         35 . The composition of  claim 18 , wherein R 5a  and R 5c  are taken together to form a hydrocarbon ring which may be bridged with C 1-4  alkylene, and R 5b  and R 5d  are hydrogen atom. 
     
     
         36 . The composition of  claim 18 , wherein formula (1) is the following formula (1a): 
       
         
           
           
               
               
           
         
       
     
     
         37 . The composition of  claim 18 , wherein formula (2) is the following formula (2a): 
       
         
           
           
               
               
           
         
       
     
     
         38 . The composition of  claim 18 , wherein formula (4) is the following formula (4a): 
       
         
           
           
               
               
           
         
       
     
     
         39 . The composition of  claim 18 , wherein formula (7) is the following formula (7b): 
       
         
           
           
               
               
           
         
       
     
     
         40 . The composition of  claim 18 , wherein formula (2) is the following: 
       
         
           
           
               
               
           
         
       
     
     
         41 . The composition of  claim 18 , wherein formula (7) is the following: 
       
         
           
           
               
               
           
         
       
     
     
         42 . The composition of  claim 18 , wherein the compound of formula (8) is (3aR,4S,7R,7aS)-2-{[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-ylmethyl]cyclohexyl-methyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione. 
     
     
         43 . A process for preparing the composition of  claim 18 . 
     
     
         44 . A process for preparing a compound of formula (8): 
       
         
           
           
               
               
           
         
       
       or an acid addition salt thereof 
       wherein
 B is carbonyl group or sulfonyl group, 
 R 5a , R 5b , R 5c , and R 5d  are independently hydrogen atom or C 1-4  alkyl group, alternatively R 5a  and R 5b , or R 5a  and R 5c  may be taken together to form a hydrocarbon ring, or R 5a  and R 5c  may be taken together to form an aromatic hydrocarbon ring, wherein the hydrocarbon ring may be bridged with C 1-4  alkylene or oxygen atom wherein the C 1-4  alkylene and the hydrocarbon ring may be substituted with at least one C 1-4  alkyl, 
 q is 0 or 1, and 
 Y is a substituent of the following formula (3a) or (3b): 
 
       
         
           
           
               
               
           
         
         wherein R 3  is independently methylene or oxygen atom; R 4  is independently C 1-6  alkyl group, C 1-6  alkoxy group, or hydroxy group; m and n are independently 0, 1, 2, or 3; and p is 1 or 2, and 
         Z is ═N—R 1  or ═CH—R 2  wherein R 1  is C 1-6  alkyl group, C 3-7  cycloalkyl group, C 5-7  cycloalkenyl group, C 6-10  aryl group, or 5- to 10-membered monocyclic or bicyclic heteroaryl group; R 2  is C 1-6  alkyl group, C 1-6  alkoxy group, C 1-6  alkylthio group, C 3-7  cycloalkyl group, C 3-7  cycloalkyloxy group, C 3-7  cycloalkylthio group, C 5-7  cycloalkenyl group, C 5-7  cycloalkenyloxy group, C 5-7  cycloalkenylthio group, C 6-10  aryl group, C 6-10  aryloxy group, C 6-10  arylthio group, 5- to 10-membered monocyclic or bicyclic heteroaryl group, 5- to 10-membered monocyclic or bicyclic heteroaryloxy group, or 5- to 10-membered monocyclic or bicyclic heteroarylthio group, 
         comprising reacting the quaternary ammonium salt (4) prepared according to claim  1  with a compound of formula (7): 
       
       
         
           
           
               
               
           
         
       
       wherein B, R 5a , R 5b , R 5c , R 5d , and q are as defined above, 
       in the presence of a solid inorganic base. 
     
     
         45 . The process of  claim 44 , wherein B is carbonyl group. 
     
     
         46 . The process of  claim 44 , wherein R 5a  and R 5c  are taken together to form a hydrocarbon ring which may be bridged with C 1-4  alkylene, and R 5b  and R 5d  are hydrogen atom. 
     
     
         47 . The process of  claim 44 , wherein formula (7) is the following formula (7b): 
       
         
           
           
               
               
           
         
       
     
     
         48 . The process of  claim 44 , wherein the compound of formula (8) is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione. 
     
     
         49 . The process of  claim 44 , wherein formula (7) is the following: