Process for the preparation of citalopram

Abstract

The present invention provides, inter alia, a novel process for the preparation of Citalopram, a known antidepressant.

1 . A method for preparing a compound of Formula IV having the following structure:  
     
       
         
         
             
             
         
       
     
     said method comprising: 
 (a) contacting a salt of the compound of Formula III having the following structure:  
                     
 with about 2 to about 10 equivalents of phosphoric acid to form a reaction mixture;  
 (b) adding an organic solvent to said reaction mixture; and  
 (c) quenching said reaction mixture with base to form a product mixture comprising said compound of Formula IV.  
 
   
   
       2 . The method of  claim 1 , wherein said salt of the compound of Formula III is a HCl salt.  
   
   
       3 . The method of  claim 1 , wherein said phosphoric acid is 20% phosphoric acid.  
   
   
       4 . The method of  claim 1 , wherein said compound of Formula III is contacted with about 6 to about 9 equivalents of 20% phosphoric acid.  
   
   
       5 . The method of  claim 1 , wherein said compound of Formula III is contacted with about 9 equivalents of 20% phosphoric acid.  
   
   
       6 . The method of  claim 1 , wherein said organic solvent in step (b) is a member selected from the group consisting of toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.  
   
   
       7 . The method of  claim 1 , wherein said organic solvent in step (b) is toluene.  
   
   
       8 . The method of  claim 1 , wherein said base is a member selected from the group consisting of ammonium hydroxide, sodium hydroxide and potassium hydroxide.  
   
   
       9 . The method of  claim 1 , wherein said base is aqueous ammonium hydroxide.  
   
   
       10 . The method of  claim 1 , further comprising: 
 (c) isolating said compound of Formula IV from said product mixture.    
   
   
       11 . The method of  claim 10 , wherein step (c) comprises: 
 (i) separating the organic phase and the aqueous phase;    (ii) re-extracting the aqueous phase with toluene;    (iii) combining the organic phases to form a combined organic phase and washing said combined organic phase with water; and    (iv) distilling said washed organic phase to obtain the compound of Formula IV.    
   
   
       12 . A method for preparing a compound of Formula V having the following structure:  
     
       
         
         
             
             
         
       
     
     said method comprising: 
 (a) contacting a compound of Formula IV having the following structure:  
                     
 with a mixture of cuprous cyanide and sodium cyanide to form a reaction mixture;  
 (b) heating said reaction mixture until the reaction is complete; and  
 (c) quenching said reaction mixture to form a product mixture comprising said compound of Formula V.  
 
   
   
       13 . The method of  claim 12 , wherein said compound of Formula IV is in a first organic solvent.  
   
   
       14 . The method of  claim 13 , wherein said first organic solvent is a member selected from the group consisting of toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.  
   
   
       15 . The method of  claim 14 , wherein said first organic solvent is toluene.  
   
   
       16 . The method of  claim 12 , wherein said mixture of cuprous cyanide and sodium cyanide is in a second organic solvent.  
   
   
       17 . The method of  claim 16 , wherein said second organic solvent is a member selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidione, quinoline, collidine, xylene, dimethylsulfone, hexamethylphosphoramide and trifluoromethylchlorobenzene.  
   
   
       18 . The method of  claim 16 , wherein said second organic solvent is N,N-dimethylformamide.  
   
   
       19 . The method of  claim 12 , wherein the ratio of cuprous cyanide:sodium cyanide in said mixture of cuprous cyanide and sodium cyanide is about 2.5:1.0 to about 1:2.5.  
   
   
       20 . The method of  claim 12 , wherein the ratio of cuprous cyanide:sodium cyanide in said mixture of cuprous cyanide and sodium cyanide is about 0.50:1.0 to about 2.5:1.  
   
   
       21 . The method of  claim 12 , wherein the ratio of cuprous cyanide:sodium cyanide in said mixture of cuprous cyanide and sodium cyanide is about 0.75:1.0 to about 1.0:1.0.  
   
   
       22 . The method of  claim 13 , wherein said first organic solvent is removed from said reaction mixture prior to step (b).  
   
   
       23 . The method of  claim 12 , wherein said reaction mixture is quenched with a member selected from the group consisting of aqueous sodium cyanide and aqueous potassium cyanide.  
   
   
       24 . The method of  claim 20 , wherein said reaction mixture is quenched with 10% aqueous sodium cyanide.  
   
   
       25 . The method of  claim 12 , further comprising: 
 (d) isolating said compound of Formula V from said product mixture.    
   
   
       26 . The method of  claim 21 , wherein step (d) comprises: 
 (i) adding ethylenediamine and a first organic solvent to said reaction mixture and separating the organic phase and the aqueous phase;    (ii) re-extracting the aqueous phase with said first organic solvent;    (iii) combining the organic phases to form a combined organic phase and back-extracting the combined organic phase with an acid to form an acid extract;    (iv) neutralizing said acid extract with a base to a pH of about 8.5 to about 11 to form a neutralized extract;    (v) extracting said neutralized extract with a second organic solvent to form a second organic solvent extract;    (vi) treating said second organic solvent extract with charcoal and removing said second organic solvent to generate the compound of Formula V.    
   
   
       27 . The method of  claim 26 , wherein said first and second organic solvents are independently selected from the group consisting of toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.  
   
   
       28 . The method of  claim 27 , wherein said first and second organic solvents are both toluene.  
   
   
       29 . The method of  claim 26 , wherein said acid in step (iii) is a member selected from the group consisting of HCl, HBr, H 2 SO 4 , H 3 PO 4 , trifluoroacetic acid and acetic acid.  
   
   
       30 . The method of  claim 29 , wherein said acid in step (iii) is 20% aqueous acetic acid.  
   
   
       31 . The method of  claim 26 , wherein said base in step (iv) is a member selected from the group consisting of sodium hydroxide, potassium hydroxide and sodium carbonate.  
   
   
       32 . The method of  claim 26 , wherein said base in step (iv) is sodium hydroxide.  
   
   
       33 . The method of  claim 26 , wherein in step (iv) said acid extract is neutralized with said base to a pH of about 9 to about 10.  
   
   
       34 . The method of  claim 26 , wherein said compound of Formula V is further purified using simulated moving bed chromatography having a stationary phase and a mobile phase.  
   
   
       35 . The method of  claim 34 , wherein the stationary phase is a reverse phase silica gel and the mobile phase is an organic solvent/water mixture.  
   
   
       36 . The method of  claim 35 , wherein said reverse phase silica gel is a C 18 -derivatized silica gel.  
   
   
       37 . The method of  claim 35 , wherein the pH of the mobile phase is about 1.5 to about 4.0.  
   
   
       38 . The method of  claim 37 , wherein the pH of the mobile phase is about 2.5.  
   
   
       39 . The method of  claim 37 , wherein the pH of the mobile phase is maintained by the addition of 0.1 to 2% trifluoroacetic acid.  
   
   
       40 . The method of  claim 35 , wherein said organic solvent in the mobile phase is methanol.  
   
   
       41 . The method of  claim 35 , wherein said organic solvent in the mobile phase is ethanol.  
   
   
       42 . The method of  claim 35 , wherein said organic solvent in the mobile phase is acetonitrile.  
   
   
       43 . The method of  claim 34 , wherein the stationary phase is a normal phase silica gel and the mobile phase is an organic solvent mixture.  
   
   
       44 . The method of  claim 42 , wherein said organic solvent mixture is a mixture of an alcohol, a hydrocarbon and an organic base.  
   
   
       45 . The method of  claim 43 , wherein said alcohol is a member selected from the group consisting of methanol, ethanol, n-propanol and isopropanol.  
   
   
       46 . The method of  claim 43 , wherein said hydrocarbon is a member selected from the group consisting of heptane, n-heptane, hexane, isohexane, toluene, cyclohexane, benzene and combinations thereof.  
   
   
       47 . The method of  claim 43 , wherein said organic base is a member selected from the group consisting of triethylamine, diethylamine, trimethylamine, dimethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine and diethylisopropylamine.  
   
   
       48 . The method of  claim 43 , wherein said organic base is present in said organic solvent mixture at about 0.05 to about 5%.  
   
   
       49 . The method of  claim 48 , wherein said organic base is present in said organic solvent mixture at about 0.1 to about 0.5%.  
   
   
       50 . The method of  claim 48 , wherein said organic base is present in said organic solvent mixture at about 0.2 to about 0.4%.  
   
   
       51 . The method of  claim 43 , wherein said organic solvent mixture is a mixture of ethanol, heptane and triethylamine.  
   
   
       52 . The method of  claim 34 , wherein the stationary phase is a chiral phase silica gel and the mobile phase is an organic solvent mixture.  
   
   
       53 . The method of  claim 52 , wherein said organic solvent mixture is a mixture of an alcohol, a hydrocarbon and an organic base.  
   
   
       54 . The method of  claim 53 , wherein said alcohol is a member selected from the group consisting of methanol, ethanol, n-propanol and isopropanol.  
   
   
       55 . The method of  claim 53 , wherein said hydrocarbon is a member selected from the group consisting of heptane, n-heptane, hexane, isohexane, toluene, cyclohexane, benzene and combinations thereof.  
   
   
       56 . The method of  claim 53 , wherein said organic base is a member selected from the group consisting of triethylamine, diethylamine, trimethylamine, dimethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine and diethylisopropylamine.  
   
   
       57 . The method of  claim 53 , wherein said organic base is present in said organic solvent mixture at about 0.05 to about 5%.  
   
   
       58 . The method of  claim 57 , wherein said organic base is present in said organic solvent mixture at about 0.1 to about 0.5%.  
   
   
       59 . The method of  claim 57 , wherein said organic base is present in said organic solvent mixture at about 0.2 to about 0.4%.  
   
   
       60 . The method of  claim 26 , wherein said compound of Formula V is further purified using single column chromatography having a stationary phase and a mobile phase.  
   
   
       61 . A method for preparing a compound of Formula VI having the following structure:  
     
       
         
         
             
             
         
       
     
     said method comprising: 
 (a) dissolving a compound of Formula V having the following structure:  
                     
 in an organic solvent to form a reaction mixture; and  
 (b) contacting said reaction mixture with HBr to form a product mixture comprising said compound of Formula VI.  
 
   
   
       62 . The method of  claim 50 , wherein said organic solvent in step (a) is a member selected from the group consisting of acetone, methylethylketone, ethylacetate, toluene, benzene, xylene, diethylether, t-butylmethylether, dioxane, and mixtures thereof.  
   
   
       63 . The method of  claim 51 , wherein said organic solvent in step (a) is diethylether.  
   
   
       64 . The method of  claim 51 , wherein said organic solvent in step (a) is acetone.  
   
   
       65 . The method of  claim 51 , wherein said HBr is gaseous HBr.  
   
   
       66 . The method of  claim 51 , wherein said HBr is aqueous HBr.  
   
   
       67 . The method of  claim 50 , further comprising: 
 (c) isolating said compound of Formula VI from said product mixture.    
   
   
       68 . The method of  claim 50 , wherein step (c) comprises: 
 (i) cooling the product mixture and filtering said product mixture to obtain the compound of Formula VI as a precipitated solid;    (ii) washing said precipitated solid with an organic solvent; and    (iii) drying said precipitated solid to obtain the compound of Formula VI.    
   
   
       69 . The method of  claim 55 , further comprising (iv) recrystallizing the compound of Formula VI.  
   
   
       70 . The method of  claim 56 , wherein said compound of Formula VI is recrystallized from a solvent mixture of toluene and methanol.  
   
   
       71 . The method of  claim 56 , wherein step (iv) comprises: 
 (i′) combining said precipitated solid with toluene and methanol to form a mixture and heating said mixture;    (ii′) filtering said mixture through Celite and slowly cooling said mixture;    (iii′) filtering said mixture to obtain the crystallized solid, washing the crystallized solid with toluene, and drying said crystallized solid to obtain the compound of Formula VI.    
   
   
       72 . The method of  claim 58 , wherein in step (ii′) said mixture is cooled to about ambient temperature.  
   
   
       73 . The method of  claim 58 , wherein in step (ii′) said mixture is cooled to about 0° C. to about 5° C.  
   
   
       74 . The method of  claim 56 , wherein step (iv) comprises: 
 (i′) combining said precipitated solid with methanol and isopropylalcohol to form a mixture and heating said mixture;    (ii′) filtering said mixture through Celite and slowly cooling said mixture;    (iii′) filtering said mixture to obtain the crystallized solid, washing the crystallized solid with isopropylalcohol, and drying said crystallized solid to obtain the compound of Formula VI.    
   
   
       75 . A method for removing demethyl- and/or didemethyl-impurities from a mixture of Citalopram containing demethyl- and/or didemethyl impurities in a solvent, said method comprising: 
 (a) contacting said mixture of Citalopram with a scavenger resin having a functional group that is reactive with a primary or secondary amine to form resin-bound demethyl- and/or didemethyl impurities, wherein said scavenger resin is insoluble in said solvent; and    (b) filtering said resin-bound demethyl- and/or didemethyl-impurities, thereby removing said demethyl and/or didemethyl-impurities from said mixture of Citalopram.    
   
   
       76 . The method of  claim 75 , wherein said functional group is a member selected from the group consisting of isocyanates, isothiocyanates, acid chlorides, esters and anhydrides.  
   
   
       77 . The method of  claim 75 , wherein said scavenger resin is a polystene-based resin.  
   
   
       78 . The method of  claim 75 , wherein said scavenger resin is a silica gel-based resin.  
   
   
       79 . The method of  claim 77 , wherein said polystene-based resin has the following structure:  
     
       
         
         
             
             
         
       
     
     wherein R is a member selected from the group consisting of isocyanates, isothiocyanates, acid chlorides, esters and anhydrides.