Methods for stabilizing proton pump inhibitors

Abstract

The present invention relates to a method for stabilizing proton pump inhibitors. On the one hand, the present invention provides a 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfinyl}-1H-benzimidazole sodium salt, which has a melting point of about 171°C and a powder X-ray diffraction pattern with diffraction peaks at 9.46° and 14.50°. A method for preparing the compound is also provided, as well as the following pharmaceutical uses of the compound: peptic ulcer bleeding, anastomotic ulcer bleeding; acute gastric mucosal damage complicated by stress state, acute gastric mucosal damage caused by non-steroidal anti-inflammatory drugs; prevention of upper gastrointestinal bleeding caused by stress state of severe diseases (such as cerebral hemorrhage, severe trauma, etc.) and gastric surgery; as an alternative therapy for the following diseases when oral therapy is not applicable: duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome. The compounds of the present invention have excellent properties such as excellent stability.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a proton pump inhibitor, in particular to a method for stabilizing the proton pump inhibitor. The proton pump inhibitor is preferably the sodium salt of omeprazole. Background Art

[0002] The advent of proton pump inhibitors (PPIs) opened up a new way of action for anti-peptic ulcer drugs. It rose in the 1980s. The first generation of product, omeprazole, was synthesized in 1979 and launched in Switzerland in 1988. Its acid-suppressing effect does not lie in blocking various receptors, but in entering the high-acid environment of the secretory tubules of gastric parietal cells to interact with H + Combined with H + / K + -ATPase sulfhydryl dehydration coupling, resulting in H + / K + -ATPase activity is permanently inhibited. The drug is highly selective and can inhibit the final step of gastric acid formation, so it can effectively inhibit both basic gastric acid secretion and various forms of stress gastric acid secretion. The drug has complete acid suppression, strong effect, and long duration. It has a higher efficacy for peptic ulcers, a shorter course of treatment, and the ulcer healing time is shorter than H 2 Receptor antagonists are fast.

[0003] Omeprazole sodium is the first proton pump inhibitor to be marketed. It was successfully developed by Swedish Astra Pharmaceuticals (the predecessor of AstraZeneca Pharmaceuticals) and was first marketed in Switzerland in 1988 under the trade name "Antra". It entered the US market in 1989 and is used to treat duodenal ulcers, gastric ulcers, reflux esophagitis and Zollinger-Ellison syndrome under the trade name "Losec". Since then, Losec has become popular all over the world and has become one of the most prescribed drugs in the United States. From 1998 to 2000, it ranked first in the world's best-selling drugs for three consecutive years. In 2000, the global sales of Losec were US$6.26 billion, which can be called a "blockbuster" at the end of the 20th century.

[0004] The chemical name of omeprazole sodium is: 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfinyl}-1H-benzimidazole sodium monohydrate, English name: Omeprazole Sodium, molecular weight: 385.4, molecular formula: C 17 H 18 N 3 NaO 3 S.H. 2 O, the structural formula is as follows:

[0005]

[0006] Omeprazole sodium can highly selectively bind to H + / K + -ATPase binds to it, making it inactive, thereby controlling and blocking the final link of gastric acid secretion, making H in the gastric wall cells + It cannot be transported to the stomach and is a strong inhibitor of gastric acid secretion. It has significant therapeutic effects on duodenal ulcer, gastric ulcer, reflux esophagitis, Zollinger-Ellison syndrome, etc.

[0007] Omeprazole for injection is usually administered in its sodium salt, such as omeprazole sodium and lyophilized powder injection included in the 2020 edition of the Chinese Pharmacopoeia. The omeprazole sodium included in the Pharmacopoeia and commercially available is a monohydrate of the sodium salt. However, it has been found that the existing omeprazole sodium still needs to be improved. For example, those skilled in the art expect to provide a method for stabilizing proton pump inhibitors. Summary of the invention

[0008] The present invention aims to provide a method for stabilizing proton pump inhibitors, for example, the method is used to improve the quality of existing omeprazole sodium. Another object of the present invention is to provide an omeprazole sodium, which is expected to present one or more advantages. Another object of the present invention is to provide a method for preparing the omeprazole sodium, and a further object of the present invention is to provide pharmaceutical uses of the prepared omeprazole sodium. It has been unexpectedly found that the use of the method of the present invention to prepare omeprazole sodium can present one or more advantages, and the present invention is completed based on this discovery.

[0009] To this end, the first aspect of the present invention provides a compound shown in the following formula I:

[0010]

[0011] The compound according to the first aspect of the present invention is omeprazole sodium, that is, 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfinyl}-1H-benzimidazole sodium salt.

[0012] According to the compound described in the first aspect of the present invention, its melting point is 169.0-172.0°C, for example, 169.5-172.0°C, preferably 170.0-171.5°C, as determined by "0612 Melting Point Determination Method" "A. Temperature Transfer Liquid Heating Method" of Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

[0013] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 26.02°±0.20°, and 26.88°±0.20° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0014] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 26.02°±0.10°, and 26.88°±0.10° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0015] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 26.02° and 26.88° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0016] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 24.68°±0.20°, 26.02°±0.20°, 26.88°±0.20°, 27.44°±0.20°, and 31.72°±0.20° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0017] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 24.68°±0.10°, 26.02°±0.10°, 26.88°±0.10°, 27.44°±0.10°, and 31.72°±0.10° in a powder X-ray diffraction pattern expressed in 2θ angles.

[0018] The compound according to the first aspect of the present invention uses Cu-Kα radiation and has diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 24.68°, 26.02°, 26.88°, 27.44°, and 31.72° in the powder X-ray diffraction pattern expressed in 2θ angles.

[0019] According to the first aspect of the present invention, the compound, using Cu-Kα radiation, has Figure 1 Powder X-ray diffraction pattern shown.

[0020] The compound according to the first aspect of the present invention is prepared using a method comprising the following steps:

[0021] (a) adding sodium hydroxide to glycerol to dissolve it;

[0022] (b) adding omeprazole and acetone-glycerol mixed solvent into a reaction vessel under heating conditions, stirring, adding sodium hydroxide solution and continuing stirring, filtering, washing the filter with acetone, and combining the filtrate and the washings to obtain a mixed solution;

[0023] (c) Cooling the mixed solution to 25-30°C, for example, and then standing for 3-5 hours, for example, 4 hours, followed by stirring for 2-10 minutes, for example, 5 minutes, and then standing at -8-5°C for 20-30 hours, filtering, washing with cold acetone, and drying to obtain the target compound.

[0024] According to the compound of the first aspect of the present invention, in step (a), the ratio of sodium hydroxide to glycerol is 0.37 mol: 50-70 ml.

[0025] According to the compound of the first aspect of the present invention, in step (a), sodium hydroxide and glycerol are dissolved at a temperature of 32-38°C, for example, 35°C.

[0026] According to the compound described in the first aspect of the present invention, in step (b), the acetone-glycerol mixed solvent is a mixed solvent with a volume ratio of 3.5 to 4.5:1, such as 3.8 to 4.2:1.

[0027] According to the compound of the first aspect of the present invention, in step (b), the ratio of omeprazole to the mixed solvent is 0.35 mol:400-500 ml, for example, 0.35 mol:450 ml.

[0028] According to the compound of the first aspect of the present invention, in step (a) and step (b), the ratio of omeprazole to sodium hydroxide is 0.35 mol:0.37 mol.

[0029] According to the compound of the first aspect of the present invention, in step (b), omeprazole and the mixed solvent are first stirred at 42-45° C. for 25-40 min, for example, for 30 min.

[0030] According to the compound of the first aspect of the present invention, in step (b), sodium hydroxide solution is added under heat preservation and stirring conditions and then stirred for 2 hours. Optionally, 5-7 g (for example, 3A) molecular sieve is added and stirred for 1 hour, and then filtered.

[0031] According to the compound described in the first aspect of the present invention, the operation of step (b) is: add 0.35 mol of omeprazole and 450 ml of acetone-glycerol (3.8-4.2:1, v / v) mixed solvent into a three-necked reaction bottle, stir at 42-45°C for 25-40 min, then add sodium hydroxide solution under insulation and stirring conditions and stir for 2 hours, add 5-7 g of 3A molecular sieve and stir for 1 hour, filter, wash the filter with 20 ml of acetone, combine the filtrate and the washing liquid to obtain a mixed solution.

[0032] According to the compound described in the first aspect of the present invention, the operation of step (c) is: the reaction mixture of the previous step is cooled to 26-28°C and then allowed to stand for 3-5 hours, then stirred for 5 minutes, and then allowed to stand at -8--5°C for 22-28 hours, filtered, washed twice with 50 ml of cold acetone (-5°C), and dried at 50°C for 3-6 hours to obtain the target compound.

[0033] Furthermore, the second aspect of the present invention provides a method for preparing the compound shown in the following formula I:

[0034]

[0035] The method comprises the following steps:

[0036] (a) adding sodium hydroxide to glycerol to dissolve it;

[0037] (b) adding omeprazole and acetone-glycerol mixed solvent into a reaction vessel under heating conditions, stirring, adding sodium hydroxide solution and continuing stirring, filtering, washing the filter with acetone, and combining the filtrate and the washings to obtain a mixed solution;

[0038] (c) Cooling the mixed solution to 25-30°C, for example, and then standing for 3-5 hours, for example, 4 hours, followed by stirring for 2-10 minutes, for example, 5 minutes, and then standing at -8-5°C for 20-30 hours, filtering, washing with cold acetone, and drying to obtain the target compound.

[0039] According to the method of the second aspect of the present invention, in step (a), the ratio of sodium hydroxide to glycerol is 0.37 mol: 50-70 ml.

[0040] According to the method of the second aspect of the present invention, in step (a), sodium hydroxide and glycerol are dissolved at a temperature of 32-38°C, for example, 35°C.

[0041] According to the method of the second aspect of the present invention, in step (b), the acetone-glycerol mixed solvent is a mixed solvent with a volume ratio of 3.5 to 4.5:1, such as 3.8 to 4.2:1.

[0042] According to the method of the second aspect of the present invention, in step (b), the ratio of omeprazole to mixed solvent is 0.35 mol:400-500 ml, for example, 0.35 mol:450 ml.

[0043] According to the method described in the second aspect of the present invention, in step (a) and step (b), the ratio of omeprazole to sodium hydroxide is 0.35 mol:0.37 mol.

[0044] According to the method of the second aspect of the present invention, in step (b), omeprazole and the mixed solvent are first stirred at 42-45° C. for 25-40 min, for example, for 30 min.

[0045] According to the method of the second aspect of the present invention, in step (b), sodium hydroxide solution is added under heat preservation and stirring conditions and then stirred for 2 hours. Optionally, 5-7 g of molecular sieve (such as 3A) is added and stirred for 1 hour, and then filtered.

[0046] According to the method described in the second aspect of the present invention, the operation of step (b) is as follows: 0.35 mol of omeprazole and 450 ml of a mixed solvent of acetone-glycerol (3.8-4.2:1, v / v) are added to a three-necked reaction flask, and stirred at 42-45° C. for 25-40 min, followed by adding a sodium hydroxide solution and stirring for 2 hours under heat preservation and stirring conditions, adding 5-7 g of 3A molecular sieve and stirring for 1 hour, filtering, washing the filter with 20 ml of acetone, and combining the filtrate and the washing liquid to obtain a mixed solution.

[0047] According to the method described in the second aspect of the present invention, the operation of step (c) is as follows: the reaction mixture of the previous step is cooled to 26-28°C and then allowed to stand for 3-5 hours, then stirred for 5 minutes, and then allowed to stand at -8--5°C for 22-28 hours, filtered, washed twice with 50 ml of cold acetone (-5°C), and dried at 50°C for 3-6 hours to obtain the target compound.

[0048] According to the method of the second aspect of the present invention, the compound is omeprazole sodium, that is, 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfinyl}-1H-benzimidazole sodium salt.

[0049] According to the method described in the second aspect of the present invention, the compound obtained has a melting point of 169.0-172.0°C, for example, 169.5-172.0°C, preferably 170.0-171.5°C, as determined by "0612 Melting Point Determination Method" "A. Temperature Transfer Liquid Heating Method" in Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

[0050] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 26.02°±0.20°, and 26.88°±0.20°.

[0051] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 26.02°±0.10°, and 26.88°±0.10°.

[0052] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 26.02°, and 26.88°.

[0053] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 24.68°±0.20°, 26.02°±0.20°, 26.88°±0.20°, 27.44°±0.20°, and 31.72°±0.20°.

[0054] According to the method described in the second aspect of the present invention, the compound prepared therefrom uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 24.68°±0.10°, 26.02°±0.10°, 26.88°±0.10°, 27.44°±0.10°, and 31.72°±0.10°.

[0055] According to the method described in the second aspect of the present invention, the compound prepared uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 24.68°, 26.02°, 26.88°, 27.44°, and 31.72°.

[0056] According to the method of the second aspect of the present invention, the compound prepared by the method uses Cu-Kα radiation, and has Figure 1 Powder X-ray diffraction pattern shown.

[0057] Furthermore, the third aspect of the present invention provides the use of any one of the compounds of the first aspect of the present invention in the preparation of a medicament for the following diseases or conditions:

[0058] Bleeding from peptic ulcer and anastomotic ulcer;

[0059] Acute gastric mucosal damage during stress and acute gastric mucosal damage caused by nonsteroidal anti-inflammatory drugs;

[0060] Preventing stress caused by severe diseases (such as cerebral hemorrhage, severe trauma, etc.) and upper gastrointestinal bleeding caused by gastric surgery, etc.;

[0061] As an alternative treatment for the following conditions when oral therapy is not appropriate: duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome.

[0062] According to any aspect of the present invention, the omeprazole sodium is measured according to the moisture determination method of Method 1, Part 0832, General Rules of Part 4 of the 2020 edition of the Chinese Pharmacopoeia, and its moisture content is less than 2%, preferably less than 1.5%, preferably less than 1%, and preferably less than 0.5%.

[0063] In the steps of the above-mentioned preparation method of the present invention, although the specific steps described therein are different from the steps described in the preparation examples in the specific implementation mode part below in some details or language descriptions, those skilled in the art can fully summarize the above-mentioned method steps based on the detailed disclosure of the full text of the present invention.

[0064] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical features in other embodiments, as long as they do not conflict.

[0065] The present invention is further described below.

[0066] All documents cited in the present invention are incorporated herein by reference in their entirety, and if the meanings expressed in these documents are inconsistent with the present invention, the description of the present invention shall prevail. In addition, the various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0067] As described in the context of the present invention, the omeprazole sodium obtained by the present invention has excellent properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 :X-ray powder diffraction (XRPD) pattern of omeprazole sodium DETAILED DESCRIPTION

[0069] The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. The present invention provides general and / or specific descriptions of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described in as much detail as possible at this point.

[0070] Example 1: Preparation of Omeprazole Sodium

[0071] (a) 14.8 g (0.37 mol) of sodium hydroxide was added to 60 ml of glycerol (35° C.) and dissolved;

[0072] (b) 120.9 g (0.35 mol) of omeprazole and 450 ml of a mixed solvent of acetone-glycerol (4:1, v / v) were added to a three-necked reaction flask, and the mixture was stirred at 42-45° C. for 30 min. Then, sodium hydroxide solution was added under heat preservation and stirring conditions, and the mixture was stirred for 2 hours. 6 g of 3A molecular sieve was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter was washed with 20 ml of acetone. The filtrate and the washing solution were combined to obtain a mixed solution.

[0073] (c) The mixed solution was cooled to 26-28°C and allowed to stand for 4 hours. The mixture was then stirred for 5 minutes and allowed to stand at -8-5°C for 24 hours. The mixture was filtered and washed twice with 50 ml of cold acetone (-5°C). The mixture was dried at 50°C for 4 hours to obtain 103.6 g of a white crystalline powder with a yield of 80.6% and a melting point of 170.2-170.9°C.

[0074] Example 2: Preparation of Omeprazole Sodium

[0075] (a) 14.8 g (0.37 mol) of sodium hydroxide was added to 70 ml of glycerol (32° C.) and dissolved;

[0076] (b) 120.9 g (0.35 mol) of omeprazole and 450 ml of a mixed solvent of acetone-glycerol (3.8:1, v / v) were added to a three-necked reaction flask, and the mixture was stirred at 42-45° C. for 40 min. Then, a sodium hydroxide solution was added under heat preservation and stirring conditions, and the mixture was stirred for 2 hours. After adding 7 g of 3A molecular sieves, the mixture was stirred for 1 hour, and the mixture was filtered. The filter was washed with 20 ml of acetone, and the filtrate and the washing solution were combined to obtain a mixed solution.

[0077] (c) The mixed solution was cooled to 26-28°C and allowed to stand for 3 hours. The mixture was then stirred for 5 minutes and allowed to stand at -8-5°C for 28 hours. The mixture was filtered and washed twice with 50 ml of cold acetone (-5°C). The mixture was dried at 50°C for 3 hours to obtain 102.9 g of a white crystalline powder with a yield of 80.0% and a melting point of 170.4-171.2°C.

[0078] Example 3: Preparation of Omeprazole Sodium

[0079] (a) 14.8 g (0.37 mol) of sodium hydroxide was added to 50 ml of glycerol (38° C.) and dissolved;

[0080] (b) 120.9 g (0.35 mol) of omeprazole and 450 ml of a mixed solvent of acetone-glycerol (4.2:1, v / v) were added to a three-necked reaction flask, and the mixture was stirred at 42-45° C. for 25 min. Then, sodium hydroxide solution was added under heat preservation and stirring conditions, and the mixture was stirred for 2 hours. 5 g of 3A molecular sieve was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter was washed with 20 ml of acetone. The filtrate and the washing solution were combined to obtain a mixed solution.

[0081] (c) The mixed solution was cooled to 26-28°C and allowed to stand for 5 hours. The mixture was then stirred for 5 minutes and allowed to stand at -8-5°C for 22 hours. The mixture was filtered and washed twice with 50 ml of cold acetone (-5°C). The mixture was dried at 50°C for 6 hours to obtain 104.4 g of a white crystalline powder with a yield of 81.2% and a melting point of 170.1-170.7°C.

[0082] Example 4: Preparation of Omeprazole Sodium

[0083] (a) 148 g (3.7 mol) of sodium hydroxide was added to 600 ml of glycerol (35° C.) and dissolved;

[0084] (b) Add 1209 g (3.5 mol) of omeprazole and 4500 ml of a mixed solvent of acetone-glycerol (4:1, v / v) to a three-necked reaction flask, stir at 42-45° C. for 45 min, then add sodium hydroxide solution and stir for 2 hours under heat preservation and stirring conditions, add 6 g of 3A molecular sieve and stir for 1 hour, filter, wash the filter with 250 ml of acetone, combine the filtrate and the washing solution to obtain a mixed solution;

[0085] (c) The mixed solution was cooled to 26-28°C and allowed to stand for 5 hours. The mixture was then stirred for 10 minutes and allowed to stand at -8-5°C for 28 hours. The mixture was filtered and washed twice with 500 ml of cold acetone (-5°C). The mixture was dried at 50°C for 6 hours to obtain 1017.2 g of a white crystalline powder with a yield of 79.1% and a melting point of 170.3-171.4°C.

[0086] Example 11: Referring to Example 1, the only difference is that the glycerol used in step (a) is replaced by an equal volume of acetone (38°C), and 450 ml of acetone is used as the solvent in step (b) instead of a mixed solvent. The remaining operations and conditions are the same, and 82.4 g of white crystalline powder is obtained with a yield of about 64% and a melting point of 170.6-171.3°C. The results show that when acetone is used instead of glycerol in the two steps, although the melting point of the product is the same as in Example 1, its yield is significantly reduced.

[0087] Example 12: Referring to Example 1, the only difference is that the glycerol used in step (a) is replaced by an equal volume of isopropanol, and 450 ml of isopropanol-glycerol (4:1, v / v) mixed solvent is used in step (b), and the remaining operations and conditions are the same, to obtain 105.8 g of white crystalline powder with a yield of about 82% and a melting point of 162.4-164.1°C; the melting point is significantly lower than that of the product in Example 1, indicating that its crystal form is different from the product in Example 1.

[0088] Example 13: Referring to Example 1, the only difference is that in step (c), the mixed solution is directly cooled to -8 to -5°C and allowed to stand for 28 hours, instead of being allowed to stand at 26°C for 4 hours. 95.6 g of white crystalline powder is obtained with a yield of about 74% and a melting point of 171.2 to 175.9°C. Compared with Example 1, the yield of Example 13 is significantly lower, and the product has a wide melting range, indicating that there may be multiple forms of crystals.

[0089] Example 14: This example uses a reference method to prepare omeprazole sodium. A solution containing 13.2 g of sodium hydroxide (0.33 mol) (dissolved in 26.7 g of water), 120 g of omeprazole (0.347 mol), and 480 ml of isopropyl ketone are added to a three-necked reaction flask. The resulting slurry is stirred for 40 minutes at room temperature and then filtered. The filter is washed with 20 ml of isopropyl alcohol, and the isopropyl alcohol washings and the filtrate are combined to obtain a mixed solution; 6 g of type B omeprazole sodium (dissolved in 25 ml of isopropyl alcohol) is used to seed the above-mentioned mixture; the slurry is stirred for 25 hours, the product is filtered, and dried at 40°C for 6 hours to obtain 105.2 g of a white crystalline powder with a yield of about 82.5% and a melting point of 166.3 to 167.1°C.

[0090] Test Example 1: Testing the quality of omeprazole sodium

[0091] Unless otherwise specified, this test example refers to the items under Omeprazole Sodium on page 1679 of Part II of the 2020 edition of the Chinese Pharmacopoeia, and detects Examples 1 to 4 and Examples 11 to 14 as well as a commercially available product (Omeprazole Sodium API produced and sold by a certain enterprise in Nanjing). The detection method and some results are as follows:

[0092] Properties: All samples were white crystalline powder and odorless when observed with the naked eye.

[0093] Solubility: Water, ethanol and dichloromethane were used as solvents for the test, and all samples were shown to be easily soluble in water, slightly soluble in methanol, and slightly soluble in dichloromethane.

[0094] Identification 1: Absorbance ratio. All samples have maximum absorption at wavelengths of 305 nm and 276 nm, and their absorbance ratios are all in the range of 1.66 to 1.75. For example, the absorbance ratio of the sample in Example 1 = 1.71.

[0095] Identification 2: Infrared absorption spectrum, tested using KBr tablet method, all samples are about (±3cm -1 ) at 1615cm -1 、1570cm -1 、1480cm -1 、1385cm -1 、1270cm -1 、1205cm -1 、1155cm -1 、1080cm -1 、1035cm -1 、845cm -1 、810cm -1 There are characteristic peaks.

[0096] Identification 3: The results of the determination according to the method in General Rules 0301 of Part IV of the 2020 edition of the Chinese Pharmacopoeia showed that all tested samples showed the reaction of sodium salt identification (1).

[0097] Alkalinity: Take 0.20 g of the test sample and add 10 ml of water to dissolve it. According to the method described in 0631 of the General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia, the pH value of each sample is in the range of 10.3 to 11.3. For example, the pH values ​​of the samples in Example 1 and Example 14 are 10.81 and 10.63, respectively.

[0098] Solution clarity and color: Take 0.20g of the test sample and add 10ml of water to dissolve it. The results show that the solutions of all samples are clear and colorless.

[0099] Heavy metals: Take 1.0g of the test sample and measure it according to the method described in Method 0821, Part IV, General Rules, 2020 Edition of the Chinese Pharmacopoeia. The heavy metal content of all samples is less than 10 parts per million.

[0100] Residual solvents: According to the residual solvent determination method of the second method of 0861 of the fourth general rules of the 2020 edition of the Chinese Pharmacopoeia, the reference mixed solution contains methanol, ethanol, ethyl acetate, acetone, dichloromethane, glycerol, and isopropanol at appropriate concentrations (determined by preliminary tests); as a result, the residual amounts of the above seven solvents in all samples met the limits specified in the Pharmacopoeia, for example, the acetone and glycerol in the sample of Example 1 were both <0.01%, indicating that the residual solvent amount of omeprazole sodium prepared by the present invention is extremely low.

[0101] Moisture content: Take a sample of this product for testing and determine the moisture content according to the method for determining moisture in Method 1, Part 0832, General Rules of Part 4 of the 2020 edition of the Chinese Pharmacopoeia.

[0102] Content determination: Take about 0.3g of the test sample, weigh it accurately, add 50ml of water to dissolve it, and determine it according to the potentiometric titration method in 0701 of the General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia. Titrate with hydrochloric acid titrant (0.1mol / L), and calculate the content based on 1ml of hydrochloric acid titrant (0.1mol / L) being equivalent to 36.74mg of C17H18N3NaO3S.

[0103] Related substances: refer to the method under the related substances inspection of omeprazole sodium in the European Pharmacopoeia 10.0;

[0104] Test solution: Dissolve 3 mg of the test sample in mobile phase and dilute to 25.0 mL.

[0105] Reference solution (a): Dissolve 1 mg of omeprazole reference substance and 1 mg of omeprazole impurity D reference substance in mobile phase and dilute to 10.0 mL.

[0106] Control solution (b): dilute 1.0 mL of the test solution to 100.0 mL with mobile phase, and then dilute 1.0 mL of the solution to 10.0 mL with mobile phase.

[0107] Control solution (c): 3 mg of omeprazole peak identification reference (containing impurity E, Sigma Aldrich) was dissolved in the mobile phase and diluted to 25.0 mL;

[0108] Chromatographic column: octylsilane bonded silica gel as filler column (125mm×4.6mm, 5μm);

[0109] Mobile phase: a mixture of phosphate solution and acetonitrile in a volume ratio of 73:27, wherein the phosphate solution is a 1.4 g / L disodium hydrogen phosphate dodecahydrate solution and the pH value is adjusted to 7.6 with phosphoric acid;

[0110] Flow rate 1 mL / min, detection wavelength 280 nm, injection volume 40 μL;

[0111] Recording time: 5 times the retention time of omeprazole;

[0112] Impurity identification: Use the chromatogram attached to the omeprazole peak identification reference and the chromatogram obtained from the reference solution (c) to determine the impurity E peak, and use the chromatogram obtained from the reference solution (a) to determine the impurity D peak;

[0113] Relative retention time compared with omeprazole (retention time about 9 min): impurity E = about 0.6, impurity D = about 0.8;

[0114] System suitability test: Using control solution (a) for testing, the separation degree between impurity D and omeprazole is greater than 3.0. If necessary, the pH value of the aqueous phase or the acetonitrile concentration can be adjusted;

[0115] Limits: European Pharmacopoeia stipulates that impurities D and E should be less than 0.15% (not more than 1.5 times the main peak area in the control solution (b)), other individual impurities should be less than 0.1%, and the sum of all impurities should be less than 0.5%. Impurities less than 0.025% are not counted;

[0116] in,

[0117] Impurity D is: 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfonyl]-1H-benzimidazole (omeprazole sulfone), and its structural formula is:

[0118]

[0119] Impurity E is: 4-methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-yl)sulfinyl]methyl]-3,5-dimethylpyridine 1-oxide, and its structural formula is:

[0120] and its enantiomers.

[0121] The method of Test Example 1 was used to detect the moisture, content, and related substances of the omeprazole sodiums of Examples 1 to 4, the omeprazole sodiums of Examples 11 to 14, and the commercially available omeprazole sodium. The results are shown in Table 1.

[0122] Table 1:

[0123]

[0124]

[0125] In the above table, * is the content result directly measured / calculated by potentiometric titration, # is the content result calculated according to the anhydrous substance, the theoretical crystal water content of omeprazole sodium monohydrate is 4.67%, and Example 14 and the commercially available product in the above table contain 1 crystal water and adsorbed water. The higher moisture content of the commercially available product may be related to the slightly longer storage time and water absorption. These data are confirmed in the provided drying loss percentage, where the drying loss is measured by drying to constant weight at 105°C according to the 0831 method of the general rules of the fourth part of the 2020 edition of the Chinese Pharmacopoeia.

[0126] Test Example 2: Hygroscopicity determination

[0127] Take 5 grams of each sample in Table 1 and place them in a flat dish with a radius of 10 cm that has been dried to constant weight in advance, spread them evenly, weigh them accurately, and then place them in a sealed container with a relative humidity of 70% for 5 days, weigh them accurately, and take the percentage of the quotient obtained by dividing the moisture absorption weight by the initial sample weight as the moisture absorption rate.

[0128] As a result, the moisture absorption rates of the five samples of Examples 1 to 4 and Example 11 were all within the range of 1.17 to 1.34%. For example, the moisture absorption rate of the sample of Example 1 was 1.21%, the moisture absorption rates of the two samples of Examples 12 and 13 were 5.53% and 4.16%, respectively, and the moisture absorption rates of Example 14 and the commercial product were 7.53% and 8.31%, respectively. It can be seen that the monohydrate has obvious hygroscopicity, while the moisture absorption rates of the anhydrous substances obtained in Examples 1 to 4 and Example 11 are quite small. The two samples of Examples 12 to 13 are anhydrous substances in terms of water content and drying loss determination results, but their hygroscopicity is significantly higher than that of the samples of Example 1, etc., which may be related to their different crystal forms.

[0129] Test Example 3: Stability Study

[0130] The samples in Table 1 were placed in a sealed, light-proof environment at a temperature of 40°C and a relative humidity of 50% for 6 months. The moisture, content and related substances of the samples at 0 and 6 months were determined using the method of Test Example 1. In addition, the drying loss was determined to compare the moisture. The content calculated as anhydrous was the percentage obtained by dividing the content in 6 months by the content in 0 months and then multiplying it by 100% as the residual rate of active ingredients in 6 months. Results:

[0131] Regarding the moisture content in June, the moisture content of the five samples of Examples 1 to 4 and Example 11 is 1.35-1.53% (the drying loss is within the range of 1.26-1.45%). For example, the moisture content in June of the sample of Example 1 is 1.44% (the drying loss is 1.39%), the moisture content of the two samples of Examples 12 to 13 is 5.74% and 6.32% respectively (the drying loss is 3.42% and 3.87% respectively), and the moisture content of the two samples of Example 14 and the commercial product is 9.64% and 9.13% (the drying loss is 4.91% and 3.38% respectively), indicating that the samples of Examples 1 to 4 will not become hydrates even if they are placed for a long time, while the two samples of Examples 12 to 13 will partially generate hydrates according to the moisture content and drying loss results;

[0132] Regarding the residual rate of active ingredients, the five samples of Examples 1 to 4 and Example 11 were 98.73 to 99.84%. For example, the residual rate of the sample of Example 1 in 6 months was 99.63%, the residual rates of the two samples of Examples 12 to 13 in 6 months were 97.65% and 97.35%, and the residual rates of the two samples of Example 14 and the commercial product in 6 months were 97.28% and 97.52%;

[0133] The main changes of the relevant substances involve impurities D and E, so the results are characterized by the sum of the two (recorded as impurity DE). For each batch of samples, the difference obtained by subtracting the impurity DE in June from the impurity DE in October is divided by the impurity DE in June and then multiplied by 100% to obtain the percentage obtained as the impurity DE growth rate. The results are as follows: the impurity DE growth rate of the five samples of Examples 1 to 4 and Example 11 is within the range of 66 to 83%. For example, the impurity DE growth rate of the sample of Example 1 is 69.3%, and the sum of the two impurities of these samples does not exceed 0.3%. The impurity DE growth rates of the two samples of Examples 12 to 13 are 185.3% and 167.6%, respectively. The impurity DE growth rates of the two samples of Example 14 and the commercial product are 217.5% and 194.3%, respectively, and both exceed 0.3%. The above results show that some omeprazole sodium prepared by the present invention has excellent stability. The sample of Example 14 shows a certain degree of oxidation, which puts higher requirements on the storage conditions of the raw material.

[0134] Test Example 4: Testing of Omeprazole Sodium

[0135] This test example is to test the final product omeprazole sodium of Example 1 of the present invention.

[0136] Elemental analysis was performed using a Perkin Elmer 240B automatic elemental analyzer, and the results were consistent with the molecular formula of C17H18N3NaO3S. The theoretical values ​​of elemental analysis were: C 55.57%, H 4.94%, S 8.73%, N 11.44%, O13.06%, Na 6.26%; the measured values ​​were: C 55.53%, H4.96%, S 8.75%, N 11.40%, O 13.07%, Na6.29%.

[0137] Using the "A. Temperature Transfer Liquid Heating Method" of "0612 Melting Point Determination Method" in Part IV of the 2020 Edition of the Chinese Pharmacopoeia, the melting points of the final product omeprazole sodium of Examples 1 to 4 are all in the range of 170.1 to 171.4°C. It can be expected that the melting point range of the product obtained in the present invention is 169.0 to 172.0°C, for example, 169.5 to 172.0°C, preferably 170.0 to 171.5°C.

[0138] Determination of the X-ray powder diffraction (XRPD) characteristic pattern of the final product omeprazole sodium in Example 1: The XRPD pattern of omeprazole sodium was determined on an Ultima III X-ray powder diffractometer using Cu-Kα rays. The instrument was equipped with a fine focus X-ray tube, and the tube voltage and current were set to 40 kV and 40 mA, respectively. The emission slit and scattering slit were 1°, and the receiving slit was 0.3 mm. The diffraction lines were detected by a scintillation detector. The 2θ angle was continuously scanned from θ to 2θ at 5° / min from 3° to 50°. It is well known that fluctuations of + / -0.2° or + / -0.1° at the 2θ position are completely acceptable and recognized. The XRPD pattern of omeprazole sodium obtained in Example 1 is shown in FIG. Figure 1 , where the 2θ angles and relative intensities of typical diffraction peaks are shown in Table 2.

[0139] Table 2:

[0140]

[0141]

[0142] More typical diffraction peaks are No. 1-7 and No. 9-10.

[0143] In addition, as shown in the stability study of Experimental Example 3, after the sample of Example 1 was placed at 40°C for 6 months, the XRPD was measured by the same method as above, and the 2θ and d-value were basically the same as those in Table 2 (the 2θ value fluctuated by + / -0.2° compared with Table 2), and their I / Io was shown in the fifth column of Table 2, indicating that the crystal form of Example 2 still maintained its original crystal form after long-term storage.

[0144] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A crystalline compound represented by the following formula: ； According to the "0612 Melting Point Determination Method" of Part IV of the 2020 edition of the Chinese Pharmacopoeia, "A. Temperature Transfer Liquid Heating Method", its melting point is 170.0~171.5℃; It uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 26.02°±0.20°, and 26.88°±0.20°; the crystalline compound is prepared using a method comprising the following steps: (a) adding sodium hydroxide to glycerol and dissolving it at a temperature of 32-38°C, wherein the ratio of sodium hydroxide to glycerol is 0.37 mol: 50-70 ml; (b) adding omeprazole and acetone-glycerol mixed solvent to a reaction container at 42-45° C., stirring for 25-40 min, adding sodium hydroxide solution and stirring for 2 hours under heat preservation and stirring conditions, adding 5-7 g of 3A molecular sieve and stirring for 1 hour, then filtering, washing the filter with acetone, combining the filtrate and the washing liquid to obtain a mixed solution; the acetone-glycerol mixed solvent is a mixed solvent with a volume ratio of 3.5-4.5:1; the ratio of omeprazole to the mixed solvent is 0.35 mol:400-500 ml; (c) The mixed solution is cooled to 25-30°C and allowed to stand for 3-5 hours, then stirred for 2-10 minutes, allowed to stand at -8-5°C for 20-30 hours, filtered, washed with cold acetone, and dried to obtain the target compound.

2. The crystalline compound according to claim 1, which uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 26.02°±0.10°, and 26.88°±0.10° in a powder X-ray diffraction pattern expressed in 2θ angles.

3. The crystalline compound according to claim 1, which uses Cu-Kα radiation and has diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 26.02°, and 26.88° in a powder X-ray diffraction pattern expressed in 2θ angles.

4. The crystalline compound according to claim 1, which uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.20°, 14.50°±0.20°, 18.90°±0.20°, 19.74°±0.20°, 20.16°±0.20°, 22.90°±0.20°, 24.00°±0.20°, 24.68°±0.20°, 26.02°±0.20°, 26.88°±0.20°, 27.44°±0.20°, and 31.72°±0.20° in a powder X-ray diffraction pattern expressed in 2θ angles.

5. The crystalline compound according to claim 1, which uses Cu-Kα radiation and has diffraction peaks at 9.46°±0.10°, 14.50°±0.10°, 18.90°±0.10°, 19.74°±0.10°, 20.16°±0.10°, 22.90°±0.10°, 24.00°±0.10°, 24.68°±0.10°, 26.02°±0.10°, 26.88°±0.10°, 27.44°±0.10°, and 31.72°±0.10° in a powder X-ray diffraction pattern expressed in 2θ angles.

6. The crystalline compound according to claim 1, which uses Cu-Kα radiation and has diffraction peaks at 9.46°, 14.50°, 18.90°, 19.74°, 20.16°, 22.90°, 24.00°, 24.68°, 26.02°, 26.88°, 27.44°, and 31.72° in a powder X-ray diffraction pattern expressed in 2θ angles. 7 . The crystalline compound according to claim 1 , which has a powder X-ray diffraction pattern as shown in FIG. 1 using Cu—Kα radiation.

8. The crystalline compound according to claim 1, wherein in step (b), the acetone-glycerol mixed solvent is a mixed solvent with a volume ratio of 3.8-4.2:

1.

9. The crystalline compound according to claim 1, wherein in step (b), the ratio of omeprazole to sodium hydroxide is 0.35 mol:0.37 mol.

10. The crystalline compound according to claim 1, wherein the operation of step (b) is as follows: adding 0.35 mol of omeprazole and 450 ml of an acetone-glycerol mixed solvent to a three-necked reaction flask, stirring at 42-45° C. for 25-40 min, then adding a sodium hydroxide solution under insulation and stirring conditions and stirring for 2 hours, adding 5-7 g of a 3A molecular sieve and stirring for 1 hour, filtering, washing the filter with 20 ml of acetone, combining the filtrate and the washing solution to obtain a mixed solution; the acetone-glycerol mixed solvent is a mixed solvent of acetone and glycerol in a volume ratio of 3.8-4.2:

1.

11. The crystalline compound according to claim 1, wherein the operation of step (c) is: cooling the reaction mixture of the previous step to 26-28°C and standing for 3-5 hours, then stirring for 5 minutes, standing at -8-5°C for 22-28 hours, filtering, washing with 50 ml of -5°C cold acetone twice, and drying at 50°C for 3-6 hours to obtain the target compound; the moisture content is less than 2% according to the moisture determination method of the first method 1 of 0832 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition.

12. A method for preparing the crystalline compound according to any one of claims 1 to 11, comprising the following steps: (a) adding sodium hydroxide to glycerol and dissolving it at a temperature of 32-38°C, wherein the ratio of sodium hydroxide to glycerol is 0.37 mol: 50-70 ml; (b) adding omeprazole and acetone-glycerol mixed solvent to a reaction container at 42-45° C., stirring for 25-40 min, adding sodium hydroxide solution and stirring for 2 hours under heat preservation and stirring conditions, adding 5-7 g of 3A molecular sieve and stirring for 1 hour, then filtering, washing the filter with acetone, combining the filtrate and the washing liquid to obtain a mixed solution; the acetone-glycerol mixed solvent is a mixed solvent with a volume ratio of 3.5-4.5:1; the ratio of omeprazole to the mixed solvent is 0.35 mol:400-500 ml; (c) The mixed solution is cooled to 25-30°C and allowed to stand for 3-5 hours, then stirred for 2-10 minutes, allowed to stand at -8-5°C for 20-30 hours, filtered, washed with cold acetone, and dried to obtain the target compound.

13. Use of the crystalline compound according to any one of claims 1 to 11 in the preparation of a medicament for the following diseases or conditions: Bleeding from peptic ulcer and anastomotic ulcer; Acute gastric mucosal damage during stress and acute gastric mucosal damage caused by nonsteroidal anti-inflammatory drugs; Prevent upper gastrointestinal bleeding caused by stress state of severe illness and gastric surgery; As an alternative treatment for the following conditions when oral therapy is not appropriate: duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome.

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