Process for the Preparation of Esomeprazole Magnesium Dihydrate

Abstract

A process for preparing Form A of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium dihydrate, processes for preparing various intermediates useful in the preparation of Form A of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium dihydrate and a novel polymorphic Form II of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole.

What is claimed is: 
     
         1 . Form II of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole having an XRPD pattern with ° 2θ values at 20.7, 20.9 and 25.6±0.2° 2θ. 
     
     
         2 . Form II of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole according to  claim 1 , having the XRPD pattern as shown in  FIG. 2 . 
     
     
         3 . A process for preparing Form II of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole comprising crystallising or recrystallising crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole from ethyl acetate at a temperature ranging from 50 to 60° C., cooling and isolating the Form II of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole. 
     
     
         4 . The process according to  claim 3 , wherein the cooling is to a temperature ranging from −10 to −5° C. 
     
     
         5 . The process according to  claim 3 , wherein the isolation comprises filtration followed by washing with ethyl acetate. 
     
     
         6 . The process according to  claim 3 , wherein the crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is extracted with methylene dichloride before recrystallisation. 
     
     
         7 . The process according to  claim 6 , wherein the washed Form II of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is dried at a temperature ranging from 30 to 35° C. 
     
     
         8 . The process according to  claim 3 , wherein the crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is prepared by condensing 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride and 2-mercapto-5-methoxy benzimidazole. 
     
     
         9 . The process according to  claim 8 , wherein the 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride is prepared by converting 2-hydroxymethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride to 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine. 
     
     
         10 . A process for preparing (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole comprising oxidising 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole in the absence of a base, the oxidising comprising the steps of preparing a chiral titanium complex, reacting the chiral titanium complex with 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole and adding an oxidising agent to the reaction mixture at a temperature ranging from 10 to 15° C., wherein the 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is polymorphic Form II. 
     
     
         11 . The process according to  claim 10 , wherein Form II of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is prepared by crystallising or recrystallising crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole from ethyl acetate at a temperature ranging from 50 to 60° C., cooling and isolating the Form II of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole. 
     
     
         12 . The process according to  claim 10 , wherein the (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole is converted to a salt thereof. 
     
     
         13 . The process according to  claim 12 , wherein the salt is an alkali metal salt, preferably the potassium salt. 
     
     
         14 . The process according to  claim 13 , wherein the (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole is converted to the potassium salt in the presence of a potassium source. 
     
     
         15 . The process according to  claim 14 , wherein the potassium source is methanolic potassium hydroxide, methanolic potassium methoxide or ethanolic potassium hydroxide, preferably methanolic potassium hydroxide. 
     
     
         16 . The process according to  claim 12 , wherein the salt of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole is converted to (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium dihydrate in the presence of a magnesium source. 
     
     
         17 . The process according to  claim 5 , wherein the crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is extracted with methylene dichloride before recrystallisation. 
     
     
         18 . The process according to  claim 5 , wherein the crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is prepared by condensing 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride and 2-mercapto-5-methoxy benzimidazole. 
     
     
         19 . The process according to  claim 6 , wherein the crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is prepared by condensing 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride and 2-mercapto-5-methoxy benzimidazole. 
     
     
         20 . The process according to  claim 17 , wherein the crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is prepared by condensing 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride and 2-mercapto-5-methoxy benzimidazole. 
     
     
         21 . The process according to  claim 11 , wherein the (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole is converted to a salt thereof.