Refining method of high-purity Vonoprazan fumarate

Abstract

The invention relates to the technical field of medicine purification, in particular to a refining method of high-purity Vonoprazan fumarate. The invention relates to a refining method of high-purity Vonoprazan fumarate, which comprises the following steps: S1, adding a polar solvent, water and lauryl sodium sulfate into a reaction bottle, and uniformly stirring; s2, adding a Vonoprazan fumarate crude product, heating and dissolving, and adding activated carbon; s3, filtering while the solution is hot, and stirring, cooling and separating out solids; s4, filtering and vacuum drying are carried out, and the high-purity Vonoprazan fumarate is obtained. According to the refining method of the Vonoprasone fumarate, the final product is obtained through one-time recrystallization, and the purity of the product is gt; therefore, the pharmaceutical quality standard is met. According to the refining method of the Vonoprazan fumarate, process impurities U2-U5 which are difficult to remove by a conventional recrystallization method can be removed, and the refining method is good in impurity removal effect, high in yield, simple to operate, few in three wastes and suitable for industrial production requirements.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug purification, and particularly relates to a refining method of high-purity vonoprazan fumarate. BACKGROUND

[0002] Vonoprazan fumarate (TAK-438, Vonoprazan fumarate) is a new type of oral anti-acid drug jointly developed by Takeda and Otsuka. The product is a new type of potassium ion (K + ) competitive acid blocker (P-CAB), which can competitively inhibit the combination of K + and H + -K + -ATPase (proton pump) in the final step of gastric wall cell secretion of gastric acid, thereby producing strong and lasting inhibition of gastric acid secretion. The drug is suitable for gastric ulcer, duodenal ulcer, reflux esophagitis, erosive esophagitis, gastroesophageal reflux disease, helicobacter infection and peptic ulcer. The product is jointly developed by Takeda and Otsuka, and was approved for marketing by the Japanese Pharmaceutical and Medical Device Integrated Agency (PMDA) on December 26, 2014, and was approved for marketing in China by the National Medical Products Administration (NMPA) on December 18, 2019.

[0003] Patent CN10242175 discloses a classical preparation method of vonoprazan fumarate. 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde is reacted with pyridine-3-sulfonyl chloride to obtain an intermediate 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-formaldehyde, then a Schiff base is formed with methylamine, and sodium borohydride is used for reduction to obtain vonoprazan, and finally, fumarate is used for salt formation to obtain vonoprazan fumarate. According to the prior art, the process is the best route for realizing industrialized mass production at present.

[0004]

[0005] However, in the process, the reaction step of reducing the Schiff base by sodium borohydride produces a large amount of over-reduction impurities U2-U5. The structure and physicochemical properties of such process impurities are similar to those of vonoprazan, which makes the separation and purification of the product very difficult, and the impurities are difficult to remove through simple refining and purification, and often need to be purified by multiple recrystallizations, which seriously affects the quality of the final product and the production cost.

[0006]

[0007]

[0008] Patents CN101300229 and CN102421753 disclose that after the crude vinorelbine fumarate is prepared, it needs to be refined at least 4 times to obtain a final product with a purity higher than 99.7%, and the average loss of yield reaches nearly 25%.

[0009] Patent CN113861166 discloses that vinorelbine free base is obtained by salting out of vinorelbine free base, and after refining, vinorelbine free base is obtained; vinorelbine free base is salted with fumaric acid, and the finished product is obtained by refining, which is complicated to operate.

[0010] Patents CN107778286 and CN110590746 disclose a method for purifying vinorelbine by preparing inorganic salt, which adopts the method of salting vinorelbine free base with hydrochloric acid or hydrobromic acid, separating and then liberating, and finally preparing vinorelbine fumarate, which is complicated to operate and has relatively low yield.

[0011] In summary, the process impurities U2~U5 of vinorelbine fumarate are extremely difficult to remove by one-step refining method, and the operation is complicated by multiple recrystallization and different salt formation purification, which seriously affects the product quality and greatly increases the production cost. Therefore, a refining method for vinorelbine fumarate with low cost, high yield, good product quality, less waste and suitable for industrial production is urgently needed. SUMMARY

[0012] The purpose of the present application is to provide a refining method for high-purity vinorelbine fumarate.

[0013] The purpose of the present application is to provide a refining method for high-purity vinorelbine fumarate, comprising the following steps: S1, a polar solvent, water and sodium dodecyl sulfate are added to the reaction bottle and stirred uniformly; S2, adding crude vinorelbine fumarate, heating and dissolving, and adding activated carbon; S3, filtering while hot, and stirring and cooling the filtrate to precipitate solids; S4, filtering and vacuum drying to obtain high-purity vinorelbine fumarate.

[0014] Further, in step S1, the polar solvent is one or more of methanol, ethanol and acetonitrile.

[0015] Further, in step S1, the mass ratio of the polar solvent to water is 3~1:1.

[0016] Further, in step S1, the mass ratio of the polar solvent to water is 1.5:1.

[0017] Further, in step S1, the amount of sodium dodecyl sulfate is 0.1% to 1% of the total mass of the polar solvent and water.

[0018] Further, in step S1, the amount of sodium dodecyl sulfate is 0.5% of the total mass of the polar solvent and water.

[0019] Further, in step S2, the mass ratio of the crude vinorelbine fumarate to the total amount of solvent is 1:3 to 10.

[0020] Further, in step S2, the mass ratio of the crude vinorelbine fumarate to the total amount of solvent is 1:5.

[0021] Further, in step S2, the heating and dissolving temperature is 70 to 80℃.

[0022] Further, the mass ratio of the crude vinorelbine fumarate to the activated carbon is 1:0.001 to 0.05.

[0023] The refining method of vinorelbine fumarate provided by the application refines the crude product with a mixed solvent of a polar solvent and water, and adds an appropriate amount of SDS in the refining process, so that the end product is obtained through recrystallization once. The impurity removal effect is good, the removal efficiency of process impurities U2 to U5 is greatly improved, the product purity is greater than 99.9%, and the product quality meets the pharmaceutical requirements. The total yield is greatly improved, and the production cost is reduced.

[0024] The technical route of the application has simple process operation, high product purity, low cost, less waste, and is suitable for industrial production requirements. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The high performance liquid chromatogram of the crude vinorelbine fumarate used in Example 1 is shown in the following figure: Figure 2 The high performance liquid chromatogram of the high purity vinorelbine fumarate refined in Example 1 is shown in the following figure: Figure 3 The high performance liquid chromatogram of the crude vinorelbine fumarate used in Example 2 is shown in the following figure: Figure 4 The high performance liquid chromatogram of the high purity vinorelbine fumarate refined in Example 2 is shown in the following figure: Figure 5 The high performance liquid chromatogram of the crude vinorelbine fumarate used in Example 3 is shown in the following figure: Figure 6 The high performance liquid chromatogram of the high purity vinorelbine fumarate refined in Example 3 is shown in the following figure: DETAILED DESCRIPTION The following are specific embodiments of the application and further describe the technical solutions of the application in conjunction with the drawings, but the application is not limited to these embodiments.

[0026] Example 1 Add 40g methanol, 20g water, and 0.2g SDS to the reaction flask, and then add crude vonoprazan fumarate (purity 99.10%) while stirring. Figure 1 10g of activated carbon was stirred and heated to about 70-80℃ until dissolved. 0.1g of activated carbon was added, and the mixture was kept at this temperature for 10-15 minutes to decolorize. The mixture was then hot-filtered, and the filtrate was stirred to crystallize. After filtration and drying, 8.52g of a white solid with a purity of 99.94% was obtained. Figure 2 The yield was approximately 85.2%.

[0027] Example 2 Add 50g of ethanol, 50g of water, and 0.5g of SDS to the reaction flask. While stirring, add crude vonoprazan fumarate (purity 99.16%). Figure 3 10g of activated carbon was stirred and heated to about 70-80℃ until dissolved. 0.05g of activated carbon was added, and the mixture was kept at this temperature for 10-15 minutes to decolorize. The mixture was then hot-filtered, and the filtrate was stirred to crystallize. After filtration and drying, 8.43g of a white solid with a purity of 99.94% was obtained. Figure 4 The yield was approximately 84.3%.

[0028] Example 3 Add 30g of acetonitrile, 30g of water, and 0.3g of SDS to the reaction flask. While stirring, add crude vonoprazan fumarate (purity 99.12%). Figure 5 10g of activated carbon was stirred and heated to about 70-80℃ until dissolved. 0.2g of activated carbon was added, and the mixture was kept at this temperature for 10-15 minutes to decolorize. The mixture was then hot-filtered, and the filtrate was stirred to crystallize. After filtration and drying, 8.65g of a white solid with a purity of 99.94% was obtained. Figure 6 The yield was approximately 86.5%.

[0029] For any points not covered above, existing technologies shall apply.

[0030] Although specific embodiments of the present invention have been described in detail by way of examples, those skilled in the art should understand that the above examples are for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them, without departing from the direction of the invention or exceeding the scope defined by the appended claims. Those skilled in the art should understand that any modifications, equivalent substitutions, improvements, etc., made to the above embodiments based on the technical essence of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for purifying high purity vonomarcabrin, characterized in that, The method comprises the following steps: S1, adding polar solvent, water and sodium dodecyl sulfate into a reaction bottle and stirring uniformly; S2, adding crude fumarate vorolanib, heating and dissolving, and adding activated carbon; S3, filtering while hot, and stirring and cooling the filtrate to precipitate solid; S4, filtering and vacuum drying to obtain high-purity fumarate vorolanib.

2. The refining method according to claim 1, characterized by, In step S1, the polar solvent is one or more of methanol, ethanol and acetonitrile.

3. The refining method according to claim 1, characterized by, In step S1, the mass ratio of the polar solvent to water is 3-1:

1.

4. The refining method according to claim 1, characterized by, In step S1, the mass ratio of the polar solvent to water is 1.5:

1.

5. The method of claim 1, wherein the refining is performed by a method comprising: In step S1, the amount of sodium dodecyl sulfate is 0.1%-1% of the total mass of the polar solvent and water.

6. The method of claim 1, wherein In step S1, the amount of sodium dodecyl sulfate is 0.5% of the total mass of the polar solvent and water.

7. The method of claim 1, wherein the refining is performed by a method comprising: In step S2, the mass ratio of the crude fumarate vorolanib to the total amount of solvent is 1:3-10.

8. The method of claim 1, wherein the refining is performed by a method comprising: In step S2, the mass ratio of the crude fumarate vorolanib to the total amount of solvent is 1:

5.

9. The method of claim 1, wherein In step S2, the heating and dissolving temperature is 70-80℃.

10. The method of claim 1, wherein The mass ratio of the crude fumarate vorolanib to activated carbon is 1:0.001-0.05.

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