Process for preparing anyhdrous and hydrate forms of antihistaminic piperidine derivatives, polymorphs and pseudomorphs thereof

Abstract

The present invention is related to novel processes for preparing anhydrous and hydrated forms of piperidine derivatives, polymorphs and pseudomorphs thereof of the formulas which are useful as antihistamines, antiallergic agents and bronchodilators.

What is claimed is:  
     
         1 . A process for preparing a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  represents hydrogen or hydroxy;  
 R 2  represents hydrogen; or  
 R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 ;  
 n is an integer of from 1 to 5;  
 R 3  is —CH 2 OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;  
 W is —CH(OH)— or —C(═O)—;  
 A is hydrogen or hydroxy;  
 Y is a pharmaceutically acceptable acid; and the individual optical isomers thereof,  
 comprising subjecting a compound of the formula  
                     
 and the individual optical isomers thereof, wherein R 1 , R 2 , R 3 , n, W, A and Y are defined above and X is a number ranging essentially from 0.10 to 5 to an azeotropic distillation.  
 
     
     
         2 . A process for preparing a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  represents hydrogen or hydroxy;  
 R 2  represents hydrogen; or  
 R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 ;  
 n is an integer of from 1 to 5;  
 R 3  is —CH 2 OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;  
 W is —CH(OH)— or —C(═O)—;  
 A is hydrogen or hydroxy;  
 Y is a pharmaceutically acceptable acid; and the individual optical isomers thereof,  
 comprising subjecting a compound of the formula  
                     
 and the individual optical isomers thereof, wherein R 1 , R 2 , R 3 , n, W, A and Y are defined above and X is a number ranging essentially from 0.10 to 5 to a water-minimizing recrystallization.  
 
     
     
         3 . A process for preparing a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  represents hydrogen or hydroxy;  
 R 2  represents hydrogen; or  
 R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 ;  
 n is an integer of from 1 to 5;  
 R 3  is —CH 2 OH, —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;  
 W is —CH(OH)— or —C(═O)—;  
 A is hydrogen or hydroxy;  
 Y is a pharmaceutically acceptable acid;  
 X is a number ranging essentially from 0.1 to 5; and the individual optical isomers thereof,  
 comprising subjecting a compound of the formula  
                     
 and the individual optical isomers thereof wherein R 1 , R 2 , R 3 , n, A, W and Y are as defined above, to an aqueous recrystallization.  
 
     
     
         4 . A process for preparing a compound of the formula  
       
         
           
           
               
               
           
         
       
       and the individual optical isomers thereof, wherein Y is a pharmaceutically acceptable acid, comprising subjecting a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein Y is as defined above and X is a number ranging essentially from 0.10 to 5 to a azeotropic distillation.  
     
     
         5 . A process for preparing a compound of the formula  
       
         
           
           
               
               
           
         
       
       and the individual optical isomers thereof, wherein Y is a pharmaceutically acceptable acid, comprising subjecting a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein Y is as defined above and X is a number ranging essentially from 0.10 to 5 to a water-minimizing recrystallization.  
     
     
         6 . A process for preparing a compound of the formula  
       
         
           
           
               
               
           
         
       
       and the individual optical isomers thereof, wherein Y is a pharmaceutically acceptable acid and X is a number ranging essentially from 0.10 to 5, comprising subjecting a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein Y is as defined above to an aqueous recrystallization.  
     
     
         7 . A process according to  claim 4 ,  claim 5  or  claim 6  wherein Y is HCl.  
     
     
         8 . A process according to  claim 7  wherein x is a number ranging from 1 to 4.  
     
     
         9 . A process according to  claim 8  wherein x is a number ranging from 2 to 3.  
     
     
         10 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       and the individual optical isomers thereof, formed by the process comprising the steps of: 
 a) treating a compound of the formula  
                     
  wherein X is a number ranging from 0.1 to 5 and the individual optical isomers thereof, with a suitable solvent or solvent mixture;  
 b) heating the mixture to a suitable temperature; and  
 c) cooling the mixture to complete crystallization.  
 
     
     
         11 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       and the individual optical isomers thereof, formed by the process comprising the steps of: 
 a) treating a compound of the formula  
                     
  wherein X is a number ranging from 0.1 to 5 and the individual optical isomers thereof, with a suitable anhydrous solvent or solvent mixture in an amount sufficient to cause dissolution;  
 b) heating the mixture to a suitable temperature.  
 c) adding an additional volume of a suitable anhydrous solvent or solvent mixture in a quantity sufficient to initiate crystallization; and  
 d) cooling the reaction mixture to complete crystallization.  
 
     
     
         12 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein X is a number from 0.1 to 5 and the individual optical isomers thereof, formed by the process comprising the steps of: 
 a) treating a compound of the formula  
                     
  and the individual optical isomers thereof with a suitable solvent;  
 b) heating the mixture to a suitable temperature; and  
 c) cooling the mixture to initiate crystallization.  
 
     
     
         13 . Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride.  
     
     
         14 . Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride.  
     
     
         15 . Form III anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride.  
     
     
         16 . Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride.  
     
     
         17 . A pharmaceutical composition comprising an effective antiallergic amount of a compound of  claim 13  in admixture or otherwise in association with an inert carrier.  
     
     
         18 . A pharmaceutical composition comprising an effective antiallergic amount of compound of  claim 14  in admixture or otherwise in association with an inert carrier.  
     
     
         19 . A pharmaceutical composition comprising an effective antiallergic amount of a compound of  claim 15  in admixture or otherwise in association with an inert carrier.  
     
     
         20 . A pharmaceutical composition comprising an effective antiallergic amount of a compound of  claim 16  in admixture or otherwise in association with an inert carrier.  
     
     
         21 . A method of treating allergic reactions in a patient in need thereof which comprises administering to said patient an anti-allergically effective amount of a compound off  claim 13 .  
     
     
         22 . A method of treating allergic reactions in a patient in need thereof which comprises administering to said patient an anti-allergically effective amount of a compound of  claim 14 .  
     
     
         23 . A method of treating allergic reactions in a patient in need therof which comprises administering to said patient an anti-allergically effective amount of a compound of  claim 15 .  
     
     
         24 . A method of treating allergic reactions,in a patient in need thereof which comprises administering to said patient an anti-allergically effective amount of a compound of  claim 16 .  
     
     
         25 . A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to a water-minimizing recrystallization.  
     
     
         26 . A process according to  claim 25  wherein suitable anhydrous solvents or solvent mixtures which are sufficient to cause dissolution are acetone and water and a suitable anhydrous antisolvent is ethyl acetate.  
     
     
         27 . A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to an azeotropic distillation.  
     
     
         28 . A process according to  claim 27  wherein suitable solvents or solvent mixtures which are sufficient to cause dissolution are methanol, acteone/water and methyl ethyl ketone/water and a suitable anhydrous antisolvent is methyl ethyl ketone.  
     
     
         29 . A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethy)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form III anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to a crystal digestion.  
     
     
         30 . A process for preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to a water-minimizing recrystallization.  
     
     
         31 . A process according to  claim 30  wherein suitable anhydrous solvents or solvent mixtures which are sufficient to cause dissolution are acetone and water and a suitable anhydrous antisolvent is ethyl acetate.  
     
     
         32 . A process for Preparing the Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to an azeotropic distillation.  
     
     
         33 . A process according to  claim 32  wherein suitable solvents or solvent mixtures which are sufficient to cause dissolution are methanol, acteone/water and methyl ethyl ketone/water and a suitable anhydrous antisolvent is methyl ethyl ketone.  
     
     
         34 . A process for preparing the Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises: 
 a) reacting ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride with an appropriate reducing agent in a suitable solvent;  
 b) acidifying with hydrochloric acid; and  
 c) adding water over a period of tide ranging from 1 minute to 45 minutes at a temperature range of about −20° C. to 50° C.  
 
     
     
         35 . A process according to  claim 34  wherein the water is added over a period of time ranging from 10 minutes to 30 minutes at a temperature range of about 0° C. to 40° C.  
     
     
         36 . A process according to  claim 35  wherein the water is added over a period of time ranging from 10 minutes to 30 minutes at a temperature range of about 20° C. to 40° C.  
     
     
         37 . A process for preparing the Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises: 
 a) reacting ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate with an appropriate reducing agent in a suitable solvent;  
 b) acidifying with hydrochloric acid; and  
 c) adding water over a period of time ranging from 1 minute to 45 minutes at a temperature range of about −20° C. to 50° C.  
 
     
     
         38 . A process according to  claim 37  wherein the water is added over a period of time ranging from 10 minutes to 30 minutes at a temperature range of about O° C. to 40° C.  
     
     
         39 . A process according to  claim 38  wherein the water is added over a period of time ranging from 10 minutes to 30minutes a temperature range of about 20° C. to 40° C.  
     
     
         40 . A process for preparing the Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form I anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to an aqueous recrystallization.  
     
     
         41 . A process for preparing the Form III anhydrous 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises subjecting Form II hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride to a water-minimizing recrystallization.  
     
     
         42 . A process for preparing the Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises: 
 a) reacting ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride with an appropriate reducing agent in a suitable solvent;  
 b) acidifying with hydrochloric acid; and  
 c) adding water over period of time ranging from 30 minutes to 24 hours at a temperature range of about 0° C. to 50° C.  
 
     
     
         43 . A process according to  claim 42  wherein the water is added over a period of time ranging from 1 hour to 12 hours at a temperature range of about 10° C. to 40° C.  
     
     
         44 . A process according to  claim 43  wherein the water is added over a period of time ranging from 2 hours to 8 hours at a temperature range of about 20° C. to 40° C.  
     
     
         45 . A process for preparing thee Form IV hydrated 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride which comprises: 
 a) reacting ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate with an appropriate reducing agent in a suitable solvent;  
 b) acidifying with hydrochloric acid; and  
 c) adding water over a period of time ranging from 30 minutes to 24 hours at a temperature range of about 0° C. to 50° C.  
 
     
     
         46 . A process according to  claim 45  wherein the water is added over a period of time ranging from 1 hour to 12 hours at a temperature range of about 10° C. to 40° C.  
     
     
         47 . A process according to  claim 46  wherein the water is added over a period of time ranging from 2 hours to 8 hours at a temperature range of about 20° C. to 40° C.