A kind of preparation method of esomeprazole

Abstract

The invention discloses a preparation method of esomeprazole: in a solvent, omeprazole sulfide is used as a starting raw material, D-diethyl tartrate and 2-ethyl-1-hexyl titanium are used as inducing agents, and phthaloyl peroxide is asymmetric oxidized to obtain high-yield esomeprazole, wherein the ee% is above 99.6%, the peroxide impurity "sulfone" is less than 0.032%, no titanium residue is present, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical synthesis, and particularly relates to a method for preparing esomeprazole. Background Art

[0002] Esomeprazole sodium, chemically known as S-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-benzimidazole sodium, is the sodium salt of S-(-)-omeprazole, a single enantiomer of omeprazole, developed by AstraZeneca. It was the first optically pure proton pump inhibitor to be marketed in Europe in 2003. The drug is mainly used for the treatment of gastric ulcers, duodenal ulcers, peptic esophagitis and gastritis. It is currently the first choice for the treatment of gastric acid-related diseases. The structural formula is as follows:

[0003]

[0004] Esomeprazole is the single enantiomer of omeprazole, S-(-)-omeprazole. The literature reports that there are three main methods for synthesizing S-(-)-omeprazole:

[0005] Patents WO2002098423A1, WO2006094904A1, and WO2007013743A1 disclose the technology of using different chiral resolving agents to resolve the omeprazole racemate to obtain the inner inclusion complex of esomeprazole, and then dissociate to obtain esomeprazole. Such resolution technology wastes 50% of omeprazole, and the resolution and dissociation steps are complicated, which is not suitable for large-scale production.

[0006] Patents WO96 / 17076A1 and WO96 / 17077A1 use biological enzymes to oxidize omeprazole sulfide or reduce omeprazole sulfone to obtain single enantiomer S-(-)-omeprazole of omeprazole. This technology requires special production equipment, strict and complicated process control, and high cost.

[0007] Patent WO96 / 02535A1 adopts asymmetric oxidation technology and uses a chiral catalyst to prepare esomeprazole. Compared with the first two technologies, this technology is convenient and easy to operate, and the product has high optical purity, but the yield is low, less than 50%.

[0008] CN1157614A and WO2010148314A3, using 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole, i.e. omeprazole sulfide, as the starting material, using diethyl D-tartrate and tetraisopropyl titanate as inducing agents, isopropylbenzene hydroperoxide is asymmetric oxidized to esomeprazole, with a calculated yield of more than 85%. This process route does not control the impurity "sulfone" in the oxidation product, and the impurity is similar to the product structure and is difficult to remove in the subsequent refining process.

[0009] The technology disclosed in patent CN106366070A also adopts an asymmetric oxidation method, with omeprazole sulfide as the starting material, diethyl D-tartrate and tetraisopropyl titanate as inducing agents, and asymmetric oxidation of cumene hydroperoxide to esomeprazole. The reaction process is detected by HPLC, and the residual content of omeprazole sulfide during the asymmetric oxidation reaction is controlled to be ≤14%, and the content of the peroxide impurity "sulfone" is ≤3%, and the reaction is stopped to achieve the purpose of controlling the peroxide impurity "sulfone" to meet the requirements of standard raw materials. It is relatively cumbersome.

[0010] At present, the methods for synthesizing S-(-)-omeprazole reported in the literature all use titanate as an inducer, resulting in a high level of titanium residue in the raw material, which poses certain safety risks.

[0011] Therefore, it is urgent to find a new method to increase the enantiomeric percentage of the chiral compound esomeprazole while reducing the impurity content, especially reducing the titanium residue. Summary of the invention

[0012] The present invention aims to provide a method for preparing esomeprazole with low specific impurity content, no titanium residue and high enantiomer percentage.

[0013] The inventors of the present invention unexpectedly discovered that esomeprazole, which originally did not have the characteristics of asymmetric oxidized thioether, exhibited good characteristics of asymmetric oxidized thioether under a specific reaction system, increased the percentage of enantiomers, reduced the content of impurities, and also solved the problem of high titanium residue in the raw material drug.

[0014] The invention provides a method for preparing esomeprazole, which comprises the following technical scheme: in the presence of D-(-)-diethyl tartaric acid, an organic base and 2-ethyl-1-hexyl titanium, omeprazole sulfide and phthalyl peroxide react at 25-35° C. to generate esomeprazole.

[0015] Specifically, proceed as follows:

[0016] D-(-)-diethyl tartrate, 2-ethyl-1-hexyl titanium and omeprazole sulfide are mixed at 35-45°C, and stirred at the temperature; then the temperature is lowered to 15-25°C, an organic base and phthaloyl peroxide are added, and the temperature is stirred at the temperature; after the reaction is completed, esomeprazole is obtained by extraction.

[0017] The first heat preservation and stirring time is 0.1-2 hours, preferably 0.5-1.5 hours; the second heat preservation and stirring time is 0.5-3 hours, preferably 1-2.5 hours.

[0018] Preferably, the organic solvent is at least one of ethyl acetate, propyl acetate, butyl acetate or isopropyl acetate; more preferably ethyl acetate.

[0019] The mass volume ratio of the omeprazole thioether to the organic solvent is 1:3-20; in some embodiments, the ratio is 1:8-10.

[0020] The molar ratio of omeprazole thioether to D-(-)-diethyl tartarate is 1:0.6-0.8, preferably 1:0.7.

[0021] The molar ratio of the omeprazole sulfide to 2-ethyl-1-hexyl titanium is 1:0.3-0.5, preferably 1:0.4. The molar ratio of the omeprazole sulfide to the organic base is 1:1-1.2, preferably 1:1.1.

[0022] The molar ratio of omeprazole sulfide to phthaloyl peroxide is 1:1.0-1.3, preferably 1:1.2.

[0023] Preferably, the temperature of the reaction system is 15-25° C. when the organic base is added. In some embodiments, the organic base is one or more of trimethylamine, triethylamine, pyridine, 2,6-lutidine, N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.

[0024] The above preparation process is specifically described as follows: omeprazole sulfide is added to an organic solvent, the temperature is raised to 35-45°C, and after stirring until dissolved, D-(-)-diethyl tartaric acid and 2-ethyl-1-hexyl titanium are added in sequence, and the mixture is stirred at the temperature; then the temperature is lowered to 15-25°C, an organic base and phthaloyl peroxide are added in sequence and stirred for reaction; after the reaction is completed, an ammonia solution is added for extraction twice, the aqueous phases are combined, activated carbon is added, the mixture is stirred at room temperature for decolorization, filtered, the aqueous phase is taken and an organic solvent is added, the filtrate is temperature controlled at 5-10°C, the pH value is adjusted to 7.0-8.0 with an organic acid, extracted, the organic phases are combined, the mixture is washed with a saturated sodium chloride aqueous solution, and the filtrate is concentrated under reduced pressure to obtain a viscous oily substance, which is esomeprazole.

[0025] Preferably, the ammonia solution is a 15±5% ammonia solution, and the mass volume ratio of omeprazole sulfide to the ammonia solution is 1:24-27; preferably 1:25.

[0026] Preferably, the temperature is 5-10°C when adjusting the pH.

[0027] Compared with the prior art, the present invention has the following significant advantages:

[0028] Innovative use of asymmetric oxidation reaction system, with D-diethyl tartrate and 2-ethyl-1-hexyl titanium as induction agents, phthalyl peroxide participates in asymmetric oxidation of omeprazole sulfide to obtain high optical purity esomeprazole, ee% above 99.6%, titanium residue is not detected, and peroxide impurity "sulfone" ≤ 0.032%. The reaction conditions are mild, energy consumption is low, and it is suitable for large-scale production. DETAILED DESCRIPTION

[0029] The beneficial effects of the present invention are now further described by the following examples. It should be understood that these examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention.

[0030] Example 1

[0031] In a 1000mL three-necked round-bottom flask, add 329mL of ethyl acetate, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat in a water bath to 35-45°C, add 14.43g (0.07mol) of D-(-)-diethyl tartarate and 22.59g (0.04mol) of 2-ethyl-1-hexyl titanium, stir for 1 hour, cool to 18-22°C, add 14.22g (0.11mol) of N, N-diisopropylethylamine, add 19.68g (0.12mol) of phthaloyl peroxide, and react for 2-3 hours. After the reaction is completed, add Add 274.2mL of 15% ammonia water, stir for 20min, extract and separate, extract the organic layer twice with 15% ammonia water, 274.2mL each time, combine the ammonia water layers, add 4g of activated carbon, stir at room temperature for 2 hours to decolorize, filter, add 800mL of ethyl acetate to the ammonia water layer, cool to 5-10℃ in an ice bath, add glacial acetic acid to adjust the pH to 7.0-8.0, complete the separation, add 450mL of ethyl acetate to the water layer for the second extraction, combine the ethyl acetate layers, wash twice with saturated brine, dry with anhydrous sodium sulfate for 4 hours, filter, and control the temperature of the filtrate at 35-45℃ to vacuum concentrate to dryness to obtain 30.95g of viscous oil, with a yield of 89.7%. The purity is 99.68%, the peroxide impurity "sulfone": 0.006%, no titanium residue is detected, and the ee% is 99.9%.

[0032] Example 2

[0033] In a 1000mL three-necked round-bottom flask, add 263.2mL of ethyl acetate, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat in a water bath to 35-45°C, add 12.37g (0.06mol) of D-(-)-diethyl tartarate and 16.94g (0.03mol) of 2-ethyl-1-hexyl titanium, stir for 1 hour, cool to 18-22°C, add 12.93g (0.1mol) of N, N-diisopropylethylamine, add 16.4g (0.1mol) of phthaloyl peroxide, react for 2-3 hours, and add 20% ethanol (0.1mol) of 1 ... 263.2mL of 15% ammonia water, stirred for 20min, extracted and separated, the organic layer was extracted twice with 15% ammonia water, 263.2mL each time, the ammonia water layer was combined, 4g of activated carbon was added to stir at room temperature for 2 hours for decolorization, filtered, 800mL of ethyl acetate was added to the ammonia water layer, cooled to 5-10℃ in an ice bath, glacial acetic acid was added dropwise to adjust the pH to 7.0-8.0, the water layer was separated after dripping, 450mL of ethyl acetate was added to the water layer for the second extraction, the ethyl acetate layer was combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was concentrated to dryness under vacuum at 35-45℃ to obtain 30.46g of viscous oil, with a yield of 88.3%. The purity was 99.61%, the content of peroxide impurity "sulfone" was 0.018%, no titanium residue was detected, and the ee% was 99.7%.

[0034] Example 3

[0035] In a 1000mL three-necked round-bottom flask, add 329mL of butyl acetate, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat in a water bath to 35-45°C, add 14.43g (0.07mol) of D-(-)-diethyl tartarate and 22.59g (0.04mol) of 2-ethyl-1-hexyl titanium, stir for 1 hour, cool to 18-22°C, add 14.22g (0.11mol) of N, N-diisopropylethylamine, add 21.34g (0.13mol) of phthaloyl peroxide, and react for 2-3 hours. After the reaction is completed, add Add 274.2mL of 15% ammonia water, stir for 20min, extract and separate, extract the organic layer twice with 15% ammonia water, 274.2mL each time, combine the ammonia water layers, add 4g of activated carbon, stir at room temperature for 2 hours to decolorize, filter, add 800mL of ethyl acetate to the ammonia water layer, cool to 5-10℃ in an ice bath, add glacial acetic acid to adjust the pH to 7.0-8.0, add 450mL of ethyl acetate to the water layer for the second extraction, combine the ethyl acetate layers, wash twice with saturated brine, dry with anhydrous sodium sulfate for 4 hours, filter, and control the temperature of the filtrate at 35-45℃ and vacuum concentrate to dryness to obtain 28.95g of viscous oil, with a yield of 83.9%. The purity is 98.93%, the content of peroxide impurity "sulfone" is 0.021%, no titanium residue is detected, and the ee% is 99.6%.

[0036] Example 4

[0037] In a 1000mL three-necked round-bottom flask, add 296.1mL of ethyl acetate, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat in a water bath to 35-45°C, add 16.50g (0.08mol) of D-(-)-diethyl tartarate and 28.24g (0.05mol) of 2-ethyl-1-hexyl titanium, stir for 1 hour, cool to 15-18°C, add 15.51g (0.12mol) of N, N-diisopropylethylamine, add 21.34g (0.13mol) of phthaloyl peroxide, and react for 2-3 hours. After the reaction is completed, add 2% chlorinated ether to the reaction solution. Add 296.1mL of 15% ammonia water, stir for 20min, extract and separate, extract the organic layer with 15% ammonia water twice, 296.1mL each time, combine the ammonia water layers, add 4g of activated carbon, stir at room temperature for 2 hours to decolorize, filter, add 800mL of ethyl acetate to the ammonia water layer, cool to 5-10℃ in an ice bath, add glacial acetic acid to adjust the pH to 7.0-8.0, complete the separation, add 450mL of ethyl acetate to the water layer for the second extraction, combine the ethyl acetate layers, wash twice with saturated brine, dry with anhydrous sodium sulfate for 4 hours, filter, and control the temperature of the filtrate at 35-45℃ to vacuum concentrate to dryness to obtain 28.39g of viscous oil, with a yield of 82.3%. The purity is 98.27%, the content of peroxide impurity "sulfone" is 0.032%, no titanium residue is detected, and the ee% is 99.6%.

[0038] Comparative Example 1

[0039] In a 1000mL three-necked round-bottom flask, add 329mL toluene, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat in a water bath to 35-45°C, add 14.43g (0.07mol) of D-(-)-diethyl tartarate and 11.37g (0.04mol) of tetraisopropyl titanate, keep warm and stir for 1 hour, cool to 28-32°C, add 14.22g (0.11mol) of N, N-diisopropylethylamine, add 18.24g (0.12mol) of cumene hydroperoxide, keep warm and react for 2-3 hours, and after the reaction, add 15% 274.2mL of ammonia water, stirred for 20min, extracted and separated, the organic layer was extracted twice with 15% ammonia water 2, 74.2mL each time, the ammonia water layer was combined, 4g of activated carbon was added to stir at room temperature for decolorization for 2 hours, filtered, 800mL of ethyl acetate was added to the ammonia water layer, cooled to 5-10℃ in an ice bath, glacial acetic acid was added dropwise to adjust the pH to 7.0-8.0, the separation was completed, 450mL of ethyl acetate was added to the water layer for the second extraction, the ethyl acetate layer was combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was concentrated to dryness under vacuum at 35-45℃ to obtain 26.67g of viscous oil, with a yield of 77.3%. The purity was 95.31%, the content of peroxide impurity "sulfone" was 2.21%, titanium residue was 480ppm, and ee% was 97.2%.

[0040] Comparative Example 2

[0041] In a 1000mL three-necked round-bottom flask, add 329mL toluene, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat to 35-45°C in a water bath, add 14.43g (0.07mol) of D-(-)-diethyl tartarate and 22.59g (0.04mol) of 2-ethyl-1-hexyl titanium, stir for 1 hour, cool to 22-25°C, add 14.22g (0.11mol) of N, N-diisopropylethylamine, add 18.24g (0.12mol) of cumene hydroperoxide, and react for 2-3 hours. After the reaction is completed, add 1 274.2mL of 5% ammonia water, stirred for 20min, extracted and separated, the organic layer was extracted twice with 15% ammonia water, 274.2mL each time, the ammonia water layers were combined, 4g of activated carbon was added to the room temperature for decolorization for 2 hours, filtered, 800mL of ethyl acetate was added to the ammonia water layer, cooled to 5-10°C in an ice bath, glacial acetic acid was added dropwise to adjust the pH to 7.0-8.0, the separation was completed, 450mL of ethyl acetate was added to the water layer for the second extraction, the ethyl acetate layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was concentrated to dryness under vacuum at a temperature of 35-45°C to obtain 26.91g of viscous oil, with a yield of 78.0%. The purity was 96.03%, the content of the oxidized impurity "sulfone" was 2.19%, the titanium residue was 350ppm, and the ee% was 97.5%

[0042] Comparative Example 3

[0043] In a 1000mL three-necked round-bottom flask, add 329mL of ethyl acetate, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat in a water bath to 35-45°C, add 14.43g (0.07mol) of D-(-)-diethyl tartarate and 11.37g (0.04mol) of tetraisopropyl titanate, stir for 1 hour, cool to 18-22°C, add 14.22g (0.11mol) of N, N-diisopropylethylamine, add 19.68g (0.12mol) of phthaloyl peroxide, and react for 2-3 hours. After the reaction is completed, add 1 74.2mL of 5% ammonia water, stirred for 20min, extracted and separated, the organic layer was extracted twice with 15% ammonia water, 274.2mL each time, the ammonia water layer was combined, 4g of activated carbon was added to decolorize at room temperature for 2 hours, filtered, 800mL of ethyl acetate was added to the ammonia water layer, cooled to 5-10℃ in an ice bath, glacial acetic acid was added dropwise to adjust the pH to 7.0-8.0, the water layer was separated after the dropwise separation, 450mL of ethyl acetate was added to the water layer for the second extraction, the ethyl acetate layer was combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was concentrated to dryness under vacuum at 35-45℃ to obtain 27.32g of viscous oil, with a yield of 79.2%. The purity was 96.80%, the content of peroxide impurity "sulfone" was 1.05%, titanium residue was 340ppm, and ee% was 97.9%.

[0044] Comparative Example 4

[0045] In a 1000mL three-necked round-bottom flask, add 329mL of ethyl acetate, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat in a water bath to 35-45°C, add 14.43g (0.07mol) of D-(-)-diethyl tartarate and 22.59g (0.04mol) of 2-ethyl-1-hexyl titanium, stir for 1 hour, cool to 18-22°C, add 14.22g (0.11mol) of N, N-diisopropylethylamine, add 15.36g (0.12mol) of cyclopropanediyl peroxide, and react for 2-3 hours. After the reaction is completed, add Add 274.2mL of 15% ammonia water, stir for 20min, extract and separate, extract the organic layer twice with 15% ammonia water, 274.2mL each time, combine the ammonia water layers, add 4g of activated carbon, stir at room temperature for 2 hours to decolorize, filter, add 800mL of ethyl acetate to the ammonia water layer, cool to 5-10℃ in an ice bath, add glacial acetic acid to adjust the pH to 7.0-8.0, separate after dropping, add 450mL of ethyl acetate to the water layer for the second extraction, combine the ethyl acetate layers, wash twice with saturated brine, dry with anhydrous sodium sulfate for 4 hours, filter, control the temperature of the filtrate at 35-45℃ and vacuum concentrate to dryness to obtain 27.01g of viscous oil, with a yield of 78.3%. The purity is 96.47%, the content of peroxide impurity "sulfone" is 1.94%, the titanium residue is 310ppm, and the ee% is 97.8%.

[0046] Comparative Example 5

[0047] In a 1000mL three-necked round-bottom flask, add 329mL of ethyl acetate, add 32.9g (0.1mol) of omeprazole sulfide under stirring, heat in a water bath to 35-45°C, add 14.43g (0.07mol) of D-(-)-diethyl tartarate and 22.59g (0.04mol) of 2-ethyl-1-hexyl titanium, stir for 1 hour, cool to 22-25°C, add 14.22g (0.11mol) of N, N-diisopropylethylamine, add 10.81g (0.12mol) of tert-butyl hydroperoxide, and react for 2-3 hours. After the reaction is completed, add 274.2mL of 15% ammonia water, stirred for 20min, extracted and separated, the organic layer was extracted twice with 15% ammonia water, 274.2mL each time, the ammonia water layer was combined, 4g of activated carbon was added to decolorize at room temperature for 2 hours, filtered, 800mL of ethyl acetate was added to the ammonia water layer, cooled to 5-10°C in an ice bath, glacial acetic acid was added dropwise to adjust the pH to 7.0-8.0, the separation was completed, 450mL of ethyl acetate was added to the water layer for the second extraction, the ethyl acetate layer was combined, washed twice with saturated brine, dried over anhydrous sodium sulfate for 4 hours, filtered, and the filtrate was concentrated to dryness under vacuum at 35-45°C to obtain 27.08g of viscous oil, with a yield of 78.5%. The purity was 96.29%, the content of peroxide impurity "sulfone" was 2.05%, titanium residue was 320ppm, and ee% was 97.6%.

Claims

1. A method for preparing esomeprazole, characterized in that: The method comprises the following steps: mixing D-(-)-diethyl tartrate, 2-ethyl-1-hexyl titanium and omeprazole sulfide at 35-45° C., and stirring while keeping warm; then cooling to 15-25° C., adding an organic base and phthalyl peroxide, and stirring while keeping warm; after the reaction is completed, extracting and treating to obtain esomeprazole; the organic base is one or more of trimethylamine, triethylamine, pyridine, 2.6-lutidine, and N,N-diisopropylethylamine.

2. The method for preparing esomeprazole according to claim 1, characterized in that: The first heat preservation and stirring time is 0.1-2 hours; the second heat preservation and stirring time is 0.5-3 hours.

3. The method for preparing esomeprazole according to claim 1, characterized in that: The reaction is carried out in an organic solvent, which is one or more of ethyl acetate, propyl acetate, butyl acetate and isopropyl acetate.

4. The method for preparing esomeprazole as claimed in claim 3, characterized in that: The feed mass volume ratio of the omeprazole thioether to the organic solvent is 1:3-20.

5. The method for preparing esomeprazole according to claim 1, characterized in that: The molar ratio of omeprazole thioether to D-(-)-diethyl tartrate is 1:0.6-0.

8.

6. The method for preparing esomeprazole according to claim 1, characterized in that: The molar ratio of omeprazole sulfide to 2-ethyl-1-hexyl titanium is 1:0.3-0.

5.

7. The method for preparing esomeprazole according to claim 1, characterized in that: The molar ratio of omeprazole sulfide to phthaloyl peroxide is 1:1-1.

3.

8. The method for preparing esomeprazole according to claim 1, characterized in that: The specific steps are as follows: adding an organic solvent to a reaction bottle, adding omeprazole sulfide under stirring, heating to 35-45°C, stirring until dissolved, adding D-(-)-diethyl tartaric acid and 2-ethyl-1-hexyl titanium in sequence, stirring for reaction, cooling to 15-25°C, adding an organic base and phthaloyl peroxide in sequence, stirring for reaction, adding an ammonia solution for extraction, combining the aqueous phases, adding activated carbon, stirring for decolorization at room temperature, filtering, adding ethyl acetate to the aqueous phase, controlling the temperature to 5-10°C, adjusting the pH value to 7.0-8.0 with an organic acid, extracting with ethyl acetate, combining the organic phases, washing with a saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering with suction, and concentrating the filtrate under reduced pressure to obtain esomeprazole.

9. The method for preparing esomeprazole according to claim 8, characterized in that: The ammonia solution is 15±5% ammonia solution, and the mass volume ratio of omeprazole sulfide to the ammonia solution is 1:24-27.

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