Patent Application
20070287839
The preparation of 3 is typically achieved by the enantioselective oxidation of sulfide 2 by any known method in the art, such as the procedure described in U.S. Pat. No. 5,948,789, followed by reaction with an alkyl, aryl or aralkyl chloroformate in the presence of a base, such as triethylamine to form crystalline compounds 3. Surprisingly, it was discovered that derivatives of 3 were readily isolable and purifiable, making the process efficient and practical for industrial scale.
The reaction of the sulfoxide intermediate with the alkyl, aryl or aralkyl chloroformate is achieved in a suitable organic solvent, most preferably a C1 to C3 chlorinated hydrocarbon such as dichloromethane or a C3 to C6 dialkyl ketone such as methyl isobutyl ketone. This reaction is performed at about −5 to about 30° C. and in the presence of an alkylamine base such as triethylamine. The stoichiometry of both the base and the chloroformate reagent is about 1.0 to 3.0 equivalents per equivalent of 2. The products 3 are extracted into a suitable organic solvent, such as ethyl acetate or another C3 to C6 alkyl ester, and precipitated by concentration of the organic solvent and/or addition of an anti-solvent. Examples of suitable anti-solvents include C6 to C9 hydrocarbons such as hexane or heptane. The most preferred anti-solvent is heptane.
Preferred chloroformates for use in the formation of 3 would be comprised of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C6-C9 aryl groups, or unsubstituted C7-C10 aralkyl groups. More preferred chloroformates would be comprised of benzyl or tert-butyl groups.
In another aspect of the invention, it has been found that when compounds 3 are treated with a C1 to C4 alkyl alcohol such as methanol, surprisingly, the N-protecting group is easily removed. After concentrating the alcoholic solution and/or addition of an anti-solvent, pure esomeprazole is precipitated and isolated by filtration.
It has been also found that the above process is also suitable for preparing alkali or alkaline earth salts of esomeprazole. Thus, the N-protected compounds 3 are treated with a solution of alkali or alkaline earth metal alkoxide in a C1 to C4 alkyl alcohol. The most preferred alcohol is methanol. The esomeprazole salt is isolated by concentration of the solution followed by the optional addition of an anti-solvent and/or by spray drying.
The esomeprazole salts prepared by this process can be any pharmaceutically acceptable alkali or alkaline earth metal salts. Preferably, the counter-ion would be an alkali or alkaline earth metal, selected from one of Li, Na, K, Ca or Mg. Most preferably the alkali or alkaline earth metal would be selected from sodium or magnesium, with the most preferable amount of the alkali or alkaline earth metal alkoxide being about 1 or 0.5 equivalents, respectively, relative to esomeprazole. The reaction temperature is from about −20° C. to refluxing temperature, preferably 0 to 25° C. Preferred C1 to C4 alkyl alcohols include methanol, ethanol, iso-propanol, n-propanol, and n-butanol, with the most preferred alcohol being methanol.
If a desired polymorph or amorphous form needs to be prepared, a person skilled in the art could make it accordingly. For example, if an amorphous form of the salt is required, an anti-solvent or anti-solvents could be added into the reaction mixture to precipitate the product in its amorphous form. The anti-solvents are organic solvents such as C4 to C8 alkyl ethers and C1 to C3 alkyl acetates, but not limited as such, in which the product has limited solubility. Similarly, other polymorphs known in the prior art can be prepared accordingly.
The following non-limiting examples further illustrate the manner of carrying out the inventive process described herein.
To a solution of 2-[2-(3,5-dimethyl-4-methoxypyridyl)methylthio]-5-methoxy-benzimidazole 2 (10 g) in 50.0 mL toluene under an inert atmosphere, was added (D)-diethyl tartrate (2.75 g). The mixture was heated to 50-55° C. and stirred for 30 minutes. Titanium (IV) isopropoxide (1.73 g) was added and the temperature was maintained at 50-55° C. for an additional 60 minutes. The reaction mixture was cooled to 0-5° C. whereupon diisopropylethylamine (1.33 g) and 80% cumene hydroperoxide (6.93 g) were added while keeping the temperature below 10° C. The reaction mixture was stirred at 0-10° C. for 2-4 hours until the reaction was complete. The reaction mixture was warmed to room temperature, filtered through Celite and extracted with 12-14% ammonium hydroxide. The aqueous and methyl isobutyl ketone (MIBK, 30 mL) phases were cooled to 0-5° C. The pH was adjusted to 7.3 to 7.8 with acetic acid and phases were separated. The aqueous phase was extracted with MIBK. The combined organic phases were washed with brine and vacuum distilled to 40 mL to give a solution of (S)-(−)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole in MIBK. The sulfoxide solution was diluted with dichloromethane (30 mL) and triethylamine (4.61 g). The mixture was cooled to 0-10° C. and 95% benzyl chloroformate (6.0 g) was added while keeping the temperature below 10° C. After stirring for 1-4 hours, water (30 mL) and ethyl acetate (30 mL) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases was washed with brine and saturated sodium bicarbonate, vacuum distilled to 30 mL and filtered through Celite™. The filtrate was stirred while 80 mL of heptanes was added dropwise whereupon the suspension was cooled to 0-5° C. and maintained at this temperature for 1-2 hours. The suspension was filtered, washed with heptanes/ethyl acetate (4/1) and dried under vacuum at room temperature to afford (S)-5/6-methoxy-3-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole. Weight: 11.5 g. Purity: 99% by HPLC. Chiral purity: 99.5% (S-form) by HPLC. Ratio of 5- and 6-methoxy products: ˜1:1. The analytical data were consistent with the assigned structure.
H-NMR (400 MHz, CDCl3):
5-Methoxy isomer: δ/ppm=2.18 (3H, s), 2.32 (3H, s), 3.73 (3H, s), 3.76 (3H, s), 4.67 (2H, dd, J=13, 38 Hz), 5.54 (2H, s), 6.95-7.01 (1H, m), 7.38 (1H, d, J=2 Hz), 7.40-7.43 (2H, m), 7.47-7.59 (2H, m), 7.68 (1H, d, J=9 Hz), 8.05 (1H, s);
6-Methoxy isomer: 6/ppm=2.18 (3H, s), 2.32 (3H, s), 3.73 (3H, s), 3.83 (3H, s), 4.67 (2H, dd, J=13, 38 Hz), 5.53 (2H, s), 6.95-7.01 (1H, m), 7.29 (1H, d, J=2 Hz), 7.40-7.43 (2H, m), 7.47-7.59 (2H, m), 7.75 (1H, d, J=9 Hz), 8.05 (1H, s).
Magnesium metal (0.26 g) was added to methanol (60 mL) and stirred at room temperature for 3-4 hours. To the mixture was added (S)-5/6-methoxy-3-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole (10 g ˜1:1 of 5- and 6-methoxy compounds) in portions. After stirring for 20-30 minutes the methanol was evaporated to a small volume and ethyl acetate was added, which caused precipitation. The damp cake obtained by filtration was pulped in ethyl acetate for 2-3 hours. The cake obtained by filtration was vacuum-dried to afford optically pure esomeprazole magnesium salt. X-ray powder diffraction pattern demonstrated the amorphous nature of the product. Weight: 7.1 g (75% overall yield). Purity: 99.3% by HPLC. Chiral purity: 99.2% (S-form) by HPLC. Mg content: 3.4%. Analytical data were consistent with that from the prior art.
To a solution of 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole (30 g) in dichloromethane (165 mL) at 0-5° C., under an inert atmosphere, was added meta-chloroperbenzoic acid (0.95 eq) over 10 minutes. The mixture was stirred for 10-15 minutes. To the reaction was added 12% ammonium hydroxide (180 mL). The layers were separated. The organic layer was extracted with 12% ammonium hydroxide (2×180 mL). The combined aqueous layers were washed with toluene (90 mL). To the aqueous layer was added dichloromethane (120 mL) and the mixture was cooled to 0-5° C. The pH was adjusted to pH=8.5-9.5 using 50% aqueous acetic acid. The layers were separated. The aqueous layer was extracted with dichloromethane (2×90 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered through celite and vacuum distilled to 150 mL to give a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphinyl]1H-benzimidazole in dichloromethane.
The sulfoxide solution was treated with triethylamine (25.4 mL). The mixture was cooled to 0-10° C. and 95% benzyl chloroformate (13.5 g) in dichloromethane (30 mL) was added while keeping the temperature below 10° C. After stirring for 2-3 hours, water (90 mL) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (60 mL). The combined organic phases were washed with brine (60 mL) and saturated sodium bicarbonate (30 mL) and vacuum distilled to 90 mL. Ethyl acetate (180 mL) was added to the solution and vacuumed distilled to 90 mL. The solution was stirred while 150 mL of heptanes was added at 20-25° C. The suspension was cooled to 0-5° C. and maintained at this temperature for 2-3 hours. The suspension was filtered and the damp cake was pulped in ethyl acetate (30 mL) and heptanes (120 mL) for 1-2 hours. The suspension was filtered, washed with heptanes/ethyl acetate (4/1) (2×30 mL) and dried under vacuum at room temperature to afford 5/6-methoxy-1-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole. Weight: 25.91 g. Yield: 59%. Ratio of 5- and 6-methoxy products: 3:2. The analytical data was consistent with the assigned structure.
1H-NMR (300 MHz, CDCl3):
5-Methoxy isomer: δ/ppm=2.19 (3H, s), 2.33 (3H, s), 3.74 (3H, s), 3.77 (3H, s), 4.68 (2H, dd, J=13, 29 Hz), 5.54 (2H, s), 6.96-7.03 (1H, m), 7.39 (1H, m). 7.40-7.42 (2H, m), 7.51-7.56 (2H, m), 7.70 (1H, d, J=9 Hz), 8.05 (1H, s);
6-Methoxy isomer: δ/ppm=2.19 (3H, s), 2.33 (3H, s), 3.74 (3H, s), 3.84 (3H, s), 4.68 (2H, dd, J=13, 29 Hz), 5.53 (2H, s), 6.96-7.03 (1H, m), 7.30 (1H, d, J=2 Hz), 7.40-7.42 (2H, m), 7.51-7.56 (2H, m), 7.76 (1H, d, J=9 Hz), 8.05 (1H, s).
Magnesium metal (0.26 g) was added to methanol (60 mL) and stirred at room temperature for 3-4 hours. To the mixture was added 5/6-methoxy-3-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(10 g) in portions. After stirring for 20-30 minutes the methanol was evaporated to s small volume and ethyl acetate was added, which caused precipitation. The damp cake obtained by filtration was pulped in ethyl acetate for 2-3 hours. The suspension was filtered and cake was vacuum-dried to afford omeprazole magnesium salt. Weight:7.0 g. Purity: 99.5% by HPLC.
As many changes can be made to the preferred embodiments of the invention without departing from the scope thereof, it is intended that all matter contained herein be considered illustrative of the invention and not in a limiting sense.
This application is a continuation-in-part of application Ser. No. 11/449,707 filed on Jun. 9, 2006.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11449707 | Jun 2006 | US |
| Child | 11797921 | US |
