Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole

Abstract

The present invention provides a process comprising admixing a thioether with about 1.05 to about 1.6 molar equivalents of an active chlorine-containing oxidant, preferably sodium hypochlorite, and about 2.5 to about 5.0 molar equivalents of an alkali metal base; and recovering a sulfoxide that is preferably pantoprazole, lansoprazole, omeprazole, or rabeprazole. The process may further comprise contacting the sulfoxide with a source of sodium ions, preferably sodium hydroxide, to produce the sodium salt of the sulfoxide. The invention also relates to novel chlorinated derivatives of pantoprazole including 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole and 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole and processes for making them. The invention also relates to processes of quantifying and identifying a compound other than pantoprazole in a mixture of pantoprazole and at least one other compound.

1 - 75 . (canceled)  
   
   
       76 . A mixture comprising 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)chloromethyl]sulfinyl]-1H-benzimidazole in an amount of about 0.1% or greater as determined by HPLC.  
   
   
       77 . The mixture of  claim 76 , wherein the 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole is present in an amount of 20% or greater as determined by HPLC.  
   
   
       78 . The mixture of  claim 77 , further comprising pantoprazole.  
   
   
       79 . The mixture of  claim 78 , wherein the 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole is present in an amount of 50% or greater as determined by HPLC.  
   
   
       80 . The mixture of  claim 76 , wherein the 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole is characterized by  1 H NMR (600 MHz, CD 3 CN) δ (ppm): 3.888 (s, 3H), 3.894 (s, 3H), 6.76 (t, 1H, JH-F=75 Hz, JC-F=256.5 Hz), 7.06 (d, 1H, J=5.4 Hz), 7.07 (dd, 1H, J=2.4 and 9.0 Hz), 7.43 (dd, 1H, J=0.6 and 2.4 Hz), 7.67 (dd, 1H, J=0.6 and 2.9 Hz) and 8.03 (d, 1H, J=5.4 Hz).  
   
   
       81 . The mixture of  claim 76 , wherein the 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole is characterized by  13 C NMR (150 MHz, CD 3 CN) δ (ppm): 56.88, 62.33, 69.72, 107.80, 110.52, 117.73, 118.03, 145.60, 146.86, 146.94, 147.67, 148.96, 149.07, 154.33, and 160.11.  
   
   
       82 . The mixture of  claim 76 , wherein the 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole is characterized by an NMR spectrum substantially as depicted in  FIG. 2  or  FIG. 3 .  
   
   
       83 . 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole.  
   
   
       84 . The compound of  claim 84 , characterized by  1 H NMR (600 MHz, CD 3 CN) δ (ppm): 3.888 (s, 3H), 3.894 (s, 3H), 6.76 (t, 1H, JH-F=75 Hz, JC-F=256.5 Hz), 7.06 (d, 1H, J=5.4 Hz), 7.07 (dd, 1H, J=2.4 and 9.0 Hz), 7.43 (dd, 1H, J=0.6 and 2.4 Hz), 7.67 (dd, 1H, J=0.6 and 2.9 Hz) and 8.03 (d, 1H, J=5.4 Hz).  
   
   
       85 . The compound of  claim 84 , characterized by  13 C NMR (150 MHz, CD 3 CN) δ (ppm): 57.11, 61.60, 98.07, 108.65, 111.83, 117.25, 118.11, 120.27, 141.54, 143.50, 143.81, 146.34, 146.51, 148.61, 150.66 and 161.37.  
   
   
       86 . The compound of  claim 84 , characterized by an NMR spectrum substantially as depicted in  FIG. 5  or  FIG. 6 .  
   
   
       87 . A pharmaceutical composition comprising pantoprazole and the compound of  claim 84 .  
   
   
       88 . A process for preparing 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)chloromethyl]sulfinyl]-1H-benzimidazole and/or 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole comprising: 
 a) mixing 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1 H-benzimidazole with about 3 to about 5 molar equivalents of NaOCl and about 1.5 to about 2.5 molar equivalents of NaOH in a water miscible protic solvent or water miscible aprotic solvent to form a mixture, and    b) recovering 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)chloromethyl]sulfinyl]-1H-benzimidazole and/or 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole from the mixture.    
   
   
       89 . The process of  claim 91 , wherein the water miscible protic solvent is selected from the group consisting of methanol, ethanol, and propan-2-ol.  
   
   
       90 . The process of  claim 91 , wherein the water miscible aprotic solvent is selected from the group consisting of acetonitrile and tetrahydrofuran.  
   
   
       91 . The process of  claim 91 , wherein the 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)chloromethyl]sulfinyl]-1H-benzimidazole and/or 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole is recovered by flash column chromatography through a silicon dioxide column using ethyl acetate as an eluent.  
   
   
       92 . The process of  claim 91 , wherein 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole is recovered from the mixture.  
   
   
       93 . The process of  claim 91 , 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole is recovered from the mixture.  
   
   
       94 . A method of quantifying the amount of a compound selected from the group consisting of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole and 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole in a mixture comprising the compound and pantoprazole, the method comprising: 
 a) determining by chromatography the area under a peak corresponding to the compound in a sample of the mixture,    b) determining by chromatography the area under a peak corresponding to the compound in a reference solution comprising a known quantity of the compound, and    c) determining the quantity of the compound in the mixture by comparing the area under the peak corresponding to the compound in the mixture with that in the reference solution.    
   
   
       95 . A method of identifying a compound selected from the group consisting of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole and 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole in a mixture comprising the compound and pantoprazole comprising: 
 a) determining by chromatography the relative retention time corresponding to the compound in a sample of the mixture,    b) determining by chromatography the relative retention time corresponding to a reference marker selected from the group consisting of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H-benzimidazole and 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chlorohydroxymethyl]sulfinyl]-1H-benzimidazole, and    c) identifying the compound by comparing the relative retention time of the compound to the relative retention time of the reference marker.