Process for preparation of citalopram and enantiomers

Abstract

The present invention provides a process for preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran car-bonitrile comprising reacting a compound of formula IVa, in the presence of a base with a compound of formula RX, wherein R is selected from alkyl, alkenyl, aryl and heteroaryl which may be optionally substituted with electron withdrawing groups and X is selected from F, Cl, Br, I, CN, OTf and OR 1 , wherein Tf represents trifluoromethanesulfonyl group, and R 1 is optionally substituted alkyl, Z is a cyano group or a group that may be converted to a cyano group; further wherein RX is selected such that an intermediate ether derivative, a compound of formula Va formed from said reaction cyclizes to a compound of formula VI, and where Z is not a cyano group, conversion of the group Z in the compound of formula VI to a cyano group to form 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile. The present invention also provides novel ether compound, a compound of formula Va and a process for preparation thereof.

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram with HPLC purity greater than 99.5% and a chiral purity greater than 99.5% obtained without chiral chromatographic separation of (±)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile, in more than 50% yield based on the S-enantiomer of the compound of formula IVa, 
       
         
           
           
               
               
           
         
       
       wherein Z is a cyano group or a group that may be converted to a cyano group selected from the group consisting of halogen, —OH, —CHO, —CH 2 OH, —CH 2 NH 2 , —CH 2 NO 2 , —CH 3 , —CH 2 Cl, —CH 2 Br, —NHR 2 , —COOR 3 , —CONR 3 R 4  and CF 3 —(CF 2 ) n —SO 2 —O— wherein n is 0-8, R 2  is hydrogen or C1 to C6 alkylcarbonyl and R 2  and R 3  are selected from hydrogen, optionally substituted C1 to C6 alkyl or aryl and, a group of formula VII: 
       
         
           
           
               
               
           
         
       
       wherein Y is O or S; R 5  and R 6  are each independently selected from hydrogen and C1 to C6 alkyl or R 5  and R 6  together form a C2 to C5 alkylene chain thereby forming a spiro ring; R 7  is selected from hydrogen, C1 to C6 alkyl, R 8  is selected from hydrogen, C1 to C6 alkyl, a carboxy group or a precursor group thereof, or R 7  and R 8  together form a C2 to C5 alkylene chain thereby forming a spiro ring. 
     
     
         5 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 4 , wherein the escitalopram has a chiral purity greater than 99.7%. 
     
     
         6 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 4 , wherein the escitalopram has a HPLC purity greater than 99.7%. 
     
     
         7 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 4 , wherein the escitalopram has a chiral purity greater than 99.7% and an HPLC purity greater than 99.7%. 
     
     
         8 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile as claimed in  claim 4 , wherein the yield represents a quantity greater than 10 kg escitalopram. 
     
     
         9 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile as claimed in  claim 4 , wherein the yield represents a quantity greater than 30 kg escitalopram. 
     
     
         10 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram with an HPLC purity greater than 99.2% and chiral purity greater than 99.8% obtained without chiral chromatographic separation of (±)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile, in more than 50% yield based on the S-enantiomer of the compound of formula IVa, 
       
         
           
           
               
               
           
         
       
       wherein Z is a cyano group or a group that may be converted to a cyano group selected from the group consisting of halogen, —OH, —CHO, —CH 2 OH, —CH 2 NH 2 , —CH 2 NO 2 , —CH 3 , —CH 2 Cl, —CH 2 Br, —NHR 2 , —COOR 3 , —CONR 3 R 4  and CF 3 —(CF 2 ) n —SO 2 —O— wherein n is 0-8, R 2  is hydrogen or C1 to C6 alkylcarbonyl and R 2  and R 3  are selected from hydrogen, optionally substituted C1 to C6 alkyl or aryl and, a group of formula VII: 
       
         
           
           
               
               
           
         
       
       wherein Y is O or S; R 5  and R 6  are each independently selected from hydrogen and C1 to C6 alkyl or R 5  and R 6  together form a C2 to C5 alkylene chain thereby forming a Spiro ring; R 7  is selected from hydrogen, C1 to C6 alkyl, R 8  is selected from hydrogen, C1 to C6 alkyl, a carboxy group or a precursor group thereof, or R 7  and R 8  together form a C2 to C5 alkylene chain thereby forming a spiro ring. 
     
     
         11 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile as claimed in  claim 10 , wherein the yield represents a quantity greater than 10 kg escitalopram. 
     
     
         12 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile as claimed in  claim 10 , wherein the yield represents a quantity greater than 30 kg escitalopram. 
     
     
         13 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 10 , wherein the escitalopram has a HPLC purity greater than 99.5%. 
     
     
         14 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 10 , wherein the escitalopram has a HPLC purity greater than 99.7%. 
     
     
         15 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 11 , wherein the escitalopram has a HPLC purity greater than 99.5%. 
     
     
         16 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 11 , wherein the escitalopram has a HPLC purity greater than 99.7%. 
     
     
         17 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 12 , wherein the escitalopram has a HPLC purity greater than 99.5%. 
     
     
         18 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram according to  claim 12 , wherein the escitalopram has a HPLC purity greater than 99.7%. 
     
     
         19 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile or Escitalopram with a sum of chiral impurity and HPLC impurity no greater than 0.8% obtained without chiral chromatographic separation of (±)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile, in more than 50% yield based on the S-enantiomer of the compound of formula IVa, 
       
         
           
           
               
               
           
         
       
       wherein Z is a cyano group or a group that may be converted to a cyano group selected from a group consisting of halogen, —OH, —CHO, —CH 2 OH, —CH 2 NH 2 , —CH 2 NO 2 , —CH 3 , —CH 2 Cl, CH 2 Br, —NHR 2 , —COOR 3 , —CONR 3 R 4  and CF 3 —(CF 2 ) n —SO 2 —O— wherein n is 0-8, R 2  is hydrogen or C1 to C6 alkylcarbonyl and R 2  and R 3  are selected from hydrogen, optionally substituted C1 to C6 alkyl or aryl and, a group of formula VII: 
       
         
           
           
               
               
           
         
       
       wherein Y is O or S; R 5  and R 6  are each independently selected from hydrogen and C1 to C6 alkyl or R 5  and R 6  together form a C2 to C5 alkylene chain thereby forming a spiro ring; R 7  is selected from hydrogen, C1 to C6 alkyl, R 8  is selected from hydrogen, C1 to C6 alkyl, a carboxy group or a precursor group thereof, or R 7  and R 8  together form a C2 to C5 alkylene chain thereby forming a Spiro ring. 
     
     
         20 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile as claimed in  claim 19 , wherein the yield represents a quantity greater than 10 kg escitalopram. 
     
     
         21 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile as claimed in  claim 19 , wherein the yield represents a quantity greater than 30 kg escitalopram. 
     
     
         22 . (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile as claimed in any of the  claims 19  to  21 , wherein the sum of chiral impurity and HPLC impurity is not greater than 0.5%.