Preparation method of refined rosaxostat product

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a refined rosaxostat product. The preparation method comprises the following steps: (1) dissolving a raw material rosaxostat in an alkali solution, and heating; (2) adding an acetic acid aqueous solution into the system in the step (1), and controlling the temperature of the system; and (3) cooling and crystallizing the system in the step (2), separating the solid after the crystal is separated out, and drying. Different batches of rosaxostat prepared by the preparation method have high particle size range stability, API with stable quality can be provided for preparation of rosaxostat preparations, and the preparation method is simple and safe to operate and is more suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry and relates to a method for preparing a refined rosuvastatin product. Background Art

[0002] Roxadustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor that inhibits the ubiquitination and degradation of HIF, helping the body produce more red blood cells. The chemical structure of Roxadustat is as follows:

[0003]

[0004] In the production of preparations, the stability of the particle size of different batches of raw materials is a key factor in ensuring the consistency of preparation products and the repeatability of the process. Fluctuations in particle size distribution between batches may directly affect the powder properties (such as fluidity and bulk density), resulting in a decrease in mixing uniformity, which in turn causes unqualified content uniformity or excessive tablet weight differences in the tableting stage. In addition, changes in particle size will change the binding force between particles, forcing the adjustment of the adhesive dosage or tableting pressure parameters of wet granulation, increasing the complexity of process validation and the risk of production interruption. During the study of rosuvastatin, the applicant found that the difference in particle size distribution between batches of rosuvastatin significantly led to significant batch differences in the fluidity and dissolution of the prepared rosuvastatin preparation particles. Therefore, it is urgent to develop a rosuvastatin process that can produce a stable particle size distribution.

[0005] CN202111539432.6 discloses a crystallization process for a rosuvastatin API with controlled particle size, comprising the following steps: (1) dissolving the crude rosuvastatin with an aqueous solution of alkali, heating to 65-90°C, slowly dripping the first portion of the acetic acid aqueous solution, and adjusting the pH to 6.4-6.7; (2) maintaining the temperature of the crystallization kettle at 65-90°C, adding rosuvastatin seeds at one time, and quickly adding the second portion of the acetic acid aqueous solution, while the system is kept stirring; (3) centrifuging while hot, and obtaining the rosuvastatin API with controlled particle size after filter cake drying. This process requires the addition of rosuvastatin seeds to assist crystallization, and the acetic acid aqueous solution needs to be added in batches, and finally centrifuged while hot, which is complicated to operate and not very safe;

[0006] CN202310483208.2 discloses a rosuvastatin solid having a particle size distribution range, and specifically discloses a preparation method for the rosuvastatin solid having a particle size distribution range. However, the operation of this preparation method is more complicated. An acetic acid aqueous solution needs to be added to the system in three batches, and rosuvastatin seed crystals also need to be added to assist crystallization. Finally, it also needs to be filtered while hot (60-80°C).

[0007] The above-mentioned existing technologies for the refining process of rosuvastatin all have the problems of complicated operation and low safety. Therefore, the applicant has been working on developing a refining process that can prepare rosuvastatin API with a stable particle size distribution and is simple to operate and safe. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to address the deficiencies of the existing technology and provide a preparation process for a refined rosuvastatin product. The method is simple to operate, has a high yield, and a high product purity. In addition, the refined product prepared between batches has a high degree of stability in the particle size range.

[0009] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows.

[0010] The present invention provides a method for preparing a refined rosuvastatin product, comprising the following steps:

[0011] (1) dissolving rosuvastatin in an alkaline solution and heating the solution;

[0012] (2) adding an aqueous acetic acid solution to the system of step (1) and controlling the temperature of the system;

[0013] (3) Cooling the system of step (2) to crystallize, separating the solid after crystals precipitate, and drying to obtain the refined product of rosuvastatin.

[0014] Furthermore, in step (1), the base is a strong base, further potassium hydroxide, sodium hydroxide, particularly preferably sodium hydroxide; the alkaline solution is an aqueous solution of an alkali, preferably an aqueous sodium hydroxide solution; the molar ratio of the alkali to rosuvastatin is 1.1-2.0, preferably 1.2-1.8, more preferably 1.2:1.4; the concentration of the aqueous solution of the alkali is 0.5-5wt%, preferably 1-3wt%, more preferably 1-2%; the heating temperature is 40-60°C, preferably 45-60°C, more preferably 45-55°C.

[0015] Furthermore, the dissolution process of step (1) is: adding rosuvastatin to the alkaline solution, or pre-mixing rosuvastatin with 1-3 times by weight of purified water, preferably with 1.5-2.5 times by weight of purified water, more preferably with 2-2.5 times by weight of purified water, and then adding it to the alkaline solution.

[0016] Furthermore, in step (2), the molar ratio of acetic acid to rosuvastatin in the acetic acid aqueous solution is 1.2-1.8:1, preferably 1.2-1.6:1, and more preferably 1.2-1.5:1; the volume ratio of the mass of the raw material rosuvastatin to the acetic acid aqueous solution is 1 kg:(2-8) L, preferably 1 kg:(3-6) L, and more preferably 1 kg:(4-5) L; the acetic acid aqueous solution is added in batches; preferably, the acetic acid aqueous solution is added within 0.2-3 h; more preferably, it is added within 1-2 h.

[0017] Furthermore, in step (3), the crystallization temperature is 0-30°C, preferably 10-25°C, more preferably 10-20°C, and the crystallization time is 0.5-5h, preferably 1-3h, more preferably 1.5-2.5h; and the drying is carried out at a temperature of 35-65°C and a vacuum degree of not less than -0.09MPa.

[0018] Furthermore, in step (3), the solid separation step includes the following secondary treatment operation: mixing the separated solid with purified water to form a suspension, stirring for 1-4 hours, and then separating the solid for the second time; preferably, the separated solid is centrifuged; further preferably, the solid is rinsed with purified water during the centrifugal separation.

[0019] Furthermore, the secondary treatment operation is carried out at 0-30° C., and the amount of purified water used in the secondary treatment operation is 1-3 times by weight of the raw material rosuvastatin, preferably 1.5-2.5 times by weight, and more preferably 1.5-2 times by weight.

[0020] Another aspect of the present invention provides a method for preparing a refined rosuvastatin product, comprising the following steps:

[0021] (1) dissolving the raw material rosuvastatin in a sodium hydroxide aqueous solution, heating the solution to 40-60° C., wherein the molar ratio of sodium hydroxide to rosuvastatin is 1.1-2.0, and the concentration of the sodium hydroxide aqueous solution is 0.5-5 wt %;

[0022] (2) adding acetic acid aqueous solution to the system of step (1) in batches and controlling the addition to be completed within 0.25-3 hours, controlling the system temperature to 40-60° C., and stirring for 4-12 hours;

[0023] (3) Cooling the system of step (2) to 0-30°C for crystallization. After the crystals are precipitated, the solid is separated and dried.

[0024] Another aspect of the present invention provides a refined rosuvastatin prepared by the aforementioned purification method.

[0025] Another aspect of the present invention provides an oral pharmaceutical composition comprising the refined rosuvastatin and at least one pharmaceutically acceptable excipient.

[0026] Beneficial effects:

[0027] (1) Compared with the prior art, the preparation process of the refined rosuvastatin provided by the present invention has the advantages of being simple to operate, safe, and suitable for industrial production.

[0028] (2) Compared with the prior art, the rosuvastatin preparation process provided by the present invention can provide API with a stable particle size range between batches, providing raw materials with consistent particle size properties for subsequent preparation of formulations, which is more conducive to the solidification of the formulation process and avoids the problem of inconsistent quality of different batches of products due to the need to adjust the formulation process due to different API properties. DETAILED DESCRIPTION

[0029] The present invention will be described in more detail below through examples. These examples are used for further illustration to better understand the content of the present invention, but should not be regarded as limiting the present invention.

[0030] In the embodiments of the present invention, all concentrations expressed in % are by mass unless otherwise specified.

[0031] The particle size of the present invention is tested using a laser particle size distribution analyzer with a model of Bettersize 2600.

[0032] Example 1:

[0033] A method for preparing a refined rosuvastatin product comprises the following steps:

[0034] (1) Close the bottom valve of the 100L reactor R1, open the feeding port, and add 61.78kg of purified water and 0.99kg

[0035] Sodium hydroxide (1.4eq) was added and stirred evenly, and then 6.18kg of raw material rosuvastatin (1.0eq) was added and stirred.

[0036] Stir until dissolved; filter the reaction solution, transfer the filtrate to 100L reactor R2, and heat to 50±5℃;

[0037] (2) Add acetic acid aqueous solution (made from 1.58 kg acetic acid (1.5 eq) and 30.89 kg purified

[0038] Add the mixture in 2.3-2.5 hours, turn on the heating, and control the temperature at 50±5℃.

[0039] Stir for 8 hours;

[0040] (3) Cool to 15±5℃ and stir for 2.5 hours; centrifuge and collect the solids; add the 100L reactor R3

[0041] Add 12.36 kg of purified water, add centrifuged solids, and stir at 15±5℃ for 2.5 hours;

[0042] The solid was collected by washing with 12.36 kg of purified water; the solid was placed in a vacuum drying oven at 50 ± 5 ° C.

[0043] and dried under a vacuum degree of not less than -0.09MPa until stable (weight loss does not exceed 0.1% for two consecutive times).

[0044] The materials were collected to obtain 5.97 kg of rosuvastatin refined product with a yield of 96.63% and a purity of 99.80%.

[0045] Example 2:

[0046] A method for preparing a refined rosuvastatin product comprises the following steps:

[0047] (1) Close the bottom valve of the 50L reactor R1, open the feeding port, and add 26.00kg of purified water and 0.44kg of hydrogen.

[0048] Sodium oxide (1.2eq), after stirring evenly, add rosuvastatin solution (6.50kg water and 3.25kg

[0049] The reaction mixture was filtered and the filtrate was transferred to

[0050] Transfer to 50L reactor R2 and heat to 50±5℃;

[0051] (2) Add acetic acid aqueous solution (composed of 0.66 kg acetic acid (1.2 eq) and 6.50 kg purified water) into reactor R2.

[0052] Mix and add the mixture, control the addition within 1.3-1.5 hours, turn on the heating, and control the temperature at 50±5℃

[0053] Stir for 8 hours;

[0054] (3) Cool to 25±5℃ and stir for 2.5 hours; centrifuge and collect the solids; add 20L reactor R3

[0055] Add 6.50kg purified water, add centrifuged solids, and stir at 25±5℃ for 2.5 hours;

[0056] The solid was collected by rinsing with 6.50 kg of purified water; the solid was placed in a vacuum drying oven at 50 ± 5 ° C.

[0057] and dried under a vacuum degree of not less than -0.09MPa until stable (weight loss does not exceed 0.1% for two consecutive times).

[0058] The materials were collected to obtain 3.16 kg of rosuvastatin refined product with a yield of 97.23% and a purity of 99.92%.

[0059] Example 3:

[0060] A method for preparing a refined rosuvastatin product comprises the following steps:

[0061] (1) Close the bottom valve of the 50L reactor R1, open the feed port, add 24.00kg of purified water and 0.34kg of sodium hydroxide (1.5eq), stir evenly, add 2.00kg of rosuvastatin raw material (1.0eq), stir until dissolved; filter the reaction solution, transfer the filtrate to the 50L reactor R2, and heat to 50±5°C;

[0062] (2) Add acetic acid aqueous solution (prepared by mixing 0.51 kg acetic acid (1.5 eq) and 8.00 kg purified water) to reactor R2, and control the addition to be complete within 0.8-1 hour. Turn on the heating and control the temperature at 50±5°C and stir for 8 hours;

[0063] (3) Cool to 25±5℃ and stir for 1.5 hours; centrifuge and collect the solid; add 4.00kg purified water to the 10L reactor R3, add the centrifuged solid, and stir at 25±5℃ for 1.5 hours; centrifuge and rinse with 4.00kg purified water, collect the solid; put the solid into a vacuum drying oven at 50±5℃

[0064] and dried under a vacuum degree of not less than -0.09MPa until stable (weight loss does not exceed 0.1% for two consecutive times).

[0065] The materials were collected to obtain 1.95 kg of rosuvastatin refined product with a yield of 97.50% and a purity of 99.86%.

[0066] Example 4:

[0067] A method for preparing a refined rosuvastatin product comprises the following steps:

[0068] (1) Close the bottom valve of the 50L reactor R1, open the feed port, add 23.25kg of purified water and 0.32kg of sodium hydroxide (1.8eq), stir evenly, add 1.55kg of rosuvastatin raw material (1eq), stir until dissolved; filter the reaction solution, transfer the filtrate to the 50L reactor R2, and heat to 50±5°C;

[0069] (2) Add acetic acid aqueous solution (prepared by mixing 0.48 kg acetic acid (1.8 eq) and 12.40 kg purified water) to reactor R2, and control the addition to be completed within 30-45 minutes. Turn on the heating and control the temperature at 50 ± 5 ° C. and stir for 8 hours;

[0070] (3) Cool to 15±5℃ and stir for 1.5 hours; centrifuge and collect the solid; add 3.10kg purified water to the 10L reactor R3, add the centrifuged solid, and stir at 15±5℃ for 1.5 hours; centrifuge and rinse with 3.10kg purified water, collect the solid; put the solid into a vacuum drying oven at 50±5℃

[0071] and dried under a vacuum degree of not less than -0.09MPa until stable (weight loss does not exceed 0.1% for two consecutive times).

[0072] The materials were collected to obtain 1.50 kg of rosuvastatin refined product with a yield of 96.77% and a purity of 99.94%.

[0073] Comparative Example 1

[0074] A method for preparing a refined rosuvastatin product comprises the following steps:

[0075] (1) Close the bottom valve of the 50L reactor R1, open the feed port, add 23.25kg of purified water and 0.32kg of sodium hydroxide (1.8eq), stir evenly, add 1.55kg of rosuvastatin raw material (1.0eq), stir until dissolved; filter the reaction solution, transfer the filtrate to the 50L reactor R2, and heat to 50±5℃;

[0076] (2) Add the first portion of acetic acid aqueous solution (the concentration is the same as in Example 4) to the reactor R2 within 30-45 minutes, adjust the pH to 6.4-6.7, turn on the heating, control the temperature at 50±5°C, add 0.08 kg of roxadustat seed crystals at one time, and quickly add the second portion of acetic acid aqueous solution (the total amount of the first portion of acetic acid aqueous solution and the second portion of acetic acid aqueous solution is the same as in Example 4, a total of 1.8 eq of acetic acid), and maintain the system temperature and stir for 8 hours;

[0077] (3) Cool to 15±5°C and stir for 1.5 hours; discharge the material and centrifuge to collect the solid; add 3.10 kg of purified water to the 10 L reactor R3, add the centrifuged solid, and stir at 15±5°C for 2 hours; discharge the material and centrifuge, rinse with 3.10 kg of purified water, and collect the solid; place the solid in a vacuum drying oven and dry at 50±5°C and a vacuum degree of not less than -0.09 MPa until it is stable (weight loss does not exceed 0.1% for two consecutive times).

[0078] The materials were collected to obtain 1.45 kg of rosuvastatin refined product with a yield of 93.55% and a purity of 99.26%.

[0079] Comparative Example 2

[0080] A method for preparing a refined rosuvastatin product comprises the following steps:

[0081] (1) Close the bottom valve of the 50L reactor R1, open the feed port, add 23.25kg of purified water and 0.32kg of sodium hydroxide (1.8eq), stir evenly, add 1.55kg of rosuvastatin raw material (1.0eq), stir until dissolved; filter the reaction solution, transfer the filtrate to the 50L reactor R2, and heat to 50±5℃;

[0082] (2) Add acetic acid aqueous solution (prepared by mixing 0.48 kg acetic acid (1.8 eq) and 12.40 kg purified water) to reactor R2, and control the addition to be completed within 30-45 minutes. Turn on the heating and control the temperature at 50 ± 5 ° C. and stir for 8 hours;

[0083] (3) Centrifuge while hot and collect the solid; add 3.10 kg of purified water to the 10 L reactor R3, add the centrifuged solid, and stir at 15±5°C for 1.5 hours; discharge the material and centrifuge, rinse with 3.10 kg of purified water, and collect the solid; place the solid in a vacuum drying oven, dry at 50±5°C and a vacuum degree of not less than -0.09 MPa until stable (weight loss does not exceed 0.1% for two consecutive times), collect the material, and obtain 1.48 kg of refined rosuvastatin with a yield of 95.48% and a purity of 98.53%.

[0084] Comparative Example 3:

[0085] A method for preparing a refined rosuvastatin product comprises the following steps:

[0086] (1) Close the bottom valve of the 50L reactor R1, open the feeding port, and add 1.55kg of rosuvastatin raw material (1.0

[0087] eq) and 4.65 kg of purified water, stirred for 10 min, then added alkaline solution (mixed with 23.25 kg of purified water and 0.32 kg of sodium hydroxide (1.8 eq)), stirred evenly, and stirred until dissolved; filtered the reaction solution, transferred the filtrate to 50 L reactor R2, and heated to 50 ± 5 ° C;

[0088] (2) Add acetic acid aqueous solution (prepared by mixing 0.48 kg of acetic acid (1.8 eq) and 12.40 kg of purified water) to reactor R2. The addition was completed within 45 minutes. The heating was turned on and the temperature was controlled at 50 ± 5 ° C. and stirred for 8 hours.

[0089] (3) Cool to 15±5°C and stir for 1.5 hours; discharge the material and centrifuge to collect the solid; add 3.10 kg of purified water to the 10 L reactor R3, add the centrifuged solid, and stir at 15±5°C for 2 hours; discharge the material and centrifuge, rinse with 3.10 kg of purified water, and collect the solid; place the solid in a vacuum drying oven, dry at 50±5°C and a vacuum degree of not less than -0.09 MPa until stable (weight loss does not exceed 0.1% for two consecutive times), collect the material, and obtain 1.42 kg of refined rosuvastatin with a yield of 91.61% and a purity of 98.22%.

[0090] The particle size distribution of the rosuvastatin API prepared in Examples 1-4 and Comparative Examples 1-3 is shown in Table 1 below:

[0091] Table 1

[0092]

[0093] Conclusion: The rosuvastatin particles of different batches prepared by the purification method of the present invention have a high stability in the particle size range, which can provide API with stable quality for the preparation of rosuvastatin preparations. In addition, the purification method of the present invention is simple and safe to operate, and is more suitable for industrial scale-up production.

[0094] The present invention provides a method and concept for purifying rosuvastatin. There are numerous methods and approaches for implementing this technical solution. The above is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also within the scope of protection of the present invention. Any components not specified in this embodiment may be implemented using existing technologies.

Claims

1. A method for preparing a refined rosuvastatin product, characterized in that: The steps include: (1) dissolving the raw material rosuvastatin in an alkaline solution and heating the solution; (2) adding an aqueous acetic acid solution to the system of step (1) and controlling the temperature of the system; (3) The system of step (2) is cooled and crystallized. After the crystals are precipitated, the solid is separated and dried.

2. The preparation method according to claim 1, characterized in that In step (1), the base is a strong base, further potassium hydroxide or sodium hydroxide, and the alkaline solution is an aqueous solution of the base; the molar ratio of the base to rosuvastatin is 1.1-2.0, preferably 1.2-1.8, more preferably 1.2-1.4; the concentration of the aqueous solution of the base is 0.5-5wt%, preferably 1-3wt%, more preferably 1-2%; the heating temperature is 40-60°C, preferably 45-60°C, more preferably 45-55°C.

3. The preparation method according to claim 1, characterized in that The dissolution process of step (1) is: adding rosuvastatin to the alkaline solution, or pre-mixing rosuvastatin with 1-3 times by weight of purified water, preferably with 1.5-2.5 times by weight of purified water, more preferably with 2-2.5 times by weight of purified water, and then adding it to the alkaline solution.

4. The preparation method according to claim 1, characterized in that In step (2), the molar ratio of acetic acid to rosuvastatin in the acetic acid aqueous solution is 1.2-1.8:1, preferably 1.2-1.6:1, and more preferably 1.2-1.5:1; the volume ratio of the mass of the raw material rosuvastatin to the acetic acid aqueous solution is 1 kg: (2-8) L, preferably 1 kg: (3-6) L, and more preferably 1 kg: (4-5) L; the acetic acid aqueous solution is added in batches; preferably, the acetic acid aqueous solution is added within 0.2-3 hours; more preferably, it is added within 1-2 hours.

5. The preparation method according to claim 1, characterized in that In step (3), the crystallization temperature is 0-30°C, preferably 10-25°C, more preferably 10-20°C, and the crystallization time is 0.5-5 h, preferably 1-3 h, more preferably 1.5-2.5 h.

6. The preparation method according to claim 1, characterized in that In step (3), the solid separation step includes the following secondary treatment operation: mixing the separated solid with purified water to form a suspension, stirring for 1-4 hours, and then separating the solid for the second time; preferably, the separated solid is centrifuged; further preferably, the solid is rinsed with purified water during the centrifugal separation.

7. The preparation method according to claim 5, characterized in that The secondary treatment operation is carried out at 0-30° C., and the amount of purified water used in the secondary treatment operation is 1-3 times by weight of the raw material rosuvastatin, preferably 1.5-2.5 times by weight, and more preferably 1.5-2 times by weight.

8. A method for preparing a refined rosuvastatin product, characterized in that: The following steps are included: (1) dissolving the raw material rosuvastatin in a sodium hydroxide aqueous solution, and heating the solution to 40-60° C., wherein the molar ratio of sodium hydroxide to rosuvastatin is 1.1-2.0, and the concentration of the sodium hydroxide aqueous solution is 0.5-5 wt %; (2) Adding acetic acid aqueous solution to the system of step (1) in batches and controlling the addition to be completed within 0.25-3 hours, controlling the system temperature to 40-60°C, and stirring for 4-12 hours; (3) Cooling the system of step (2) to 0-30°C for crystallization. After the crystals are precipitated, the solid is separated and dried.

9. The refined rosuvastatin prepared by the preparation method according to any one of claims 1 to 8.

10. An oral pharmaceutical composition, characterized in that The invention comprises the refined rosuvastatin product according to claim 9, and at least one pharmaceutically acceptable excipient.

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