Crystal form of rosuvastatin calcium intermediate and preparation method thereof
By preparing a specific crystal form of rosuvastatin calcium intermediate, the problems of insufficient purity and stability in the existing technology are solved, and the preparation of high-purity and stable rosuvastatin calcium intermediate is achieved, which is suitable for pharmaceutical preparations and large-scale production.
Patent Information
- Application Number
- CN202510823285.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-19
- Publication Date
- 2025-09-30
AI Technical Summary
In the prior art, it is difficult to efficiently prepare a high-purity crystalline form of rosuvastatin calcium intermediate and a preparation method thereof.
A rosuvastatin calcium intermediate crystal form and a preparation method thereof are adopted, including using a specific compound II and a solvent system for reaction, and controlling the reaction conditions and post-processing steps to obtain a rosuvastatin calcium intermediate with high purity and good stability.
The high purity and stability of the rosuvastatin calcium intermediate are achieved, making it suitable for the preparation and large-scale production of pharmaceutical preparations.
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Figure CN120717993A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of pharmaceutical chemicals, and particularly relates to a crystal form of a rosuvastatin calcium intermediate and a preparation method thereof. Background Art
[0002] Rosuvastatin calcium, also known as bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), and marketed as Crestor, is a cardiovascular disease treatment drug developed by Shionogi & Co., Ltd. of Japan. It was officially approved for marketing in the United States in 2003. Rosuvastatin calcium has potent HMG-CoA reductase inhibitory activity and can treat hypercholesterolemia, mixed dyslipidemia, and isolated hypertriglyceridemia. Due to its excellent tolerability and safety, it is known as a "super statin."
[0003] (4R-CIS)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester (Compound I) is an important intermediate for the preparation of rosuvastatin calcium. Its chemical structure is shown below:
[0004]
[0005] Regarding the synthesis of compound I, most current domestic and foreign patents (such as US5278313A) use a similar route as follows:
[0006] Summary of the Invention
[0007] The purpose of the present invention is to provide a crystal form of a rosuvastatin calcium intermediate with high purity and excellent stability and a preparation method thereof.
[0008] During the research process, the inventor's research team discovered a crystalline form of a rosuvastatin calcium intermediate (i.e., Compound I) with high purity and good stability. The preparation method can effectively separate and purify Compound I from the reaction solution and remove impurities generated during the reaction process, thereby further obtaining a rosuvastatin calcium raw material that meets pharmaceutical standards.
[0009] Specifically, the present invention provides the following technical solutions:
[0010] A crystalline form of a rosuvastatin calcium intermediate, wherein the intermediate is (4R-CIS)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester, and the powder X-ray diffraction pattern thereof has 2θ values of 8.688±0.2°, 10.843±0.2°, 13.708±0.2°, 15.015±0.2°, 16.080±0.2°, 16.930±0.2°, 17.356±0.2°, 21.714±0.2°,
[0011] There are characteristic peaks at 21.992±0.2°, 22.574±0.2° and 23.820±0.2°.
[0012] Wherein, the powder X-ray diffraction pattern is a spectrum obtained by CuKa radiation, and its overall peak shape is as follows Figure 1 shown.
[0013] The present invention also discloses a method for preparing a crystalline form of a rosuvastatin calcium intermediate, comprising the following steps:
[0014] (1) Compound II was added with 2,2-dimethoxypropane and p-toluenesulfonic acid, and stirred for reaction under nitrogen protection;
[0015] (2) Saturated sodium bicarbonate was added to adjust the pH, ethyl acetate was added for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and dried, and then n-heptane was added and heated to reflux to dissolve and clarify, cooled and crystallized, filtered, and dried to obtain compound I; its synthesis route is as follows:
[0016]
[0017] Furthermore, in the step (1), the molar ratio of compound II to 2,2-dimethoxypropane is 1:8-18.
[0018] More preferably, in step (1), the molar ratio of compound II to 2,2-dimethoxypropane is 1:10-16.
[0019] Furthermore, in the step (1), the mass ratio of compound II to p-toluenesulfonic acid is 1:0.005-0.1.
[0020] Further preferably, in step (1), the mass ratio of compound II to p-toluenesulfonic acid is 1:0.01-0.06.
[0021] Furthermore, in the step (1), the reaction temperature is 5 to 40°C.
[0022] More preferably, in step (1), the reaction temperature is 10-30°C.
[0023] Furthermore, in the step (1), the reaction time is 0.5 to 4 hours.
[0024] Compared with the prior art, the present invention has the following beneficial effects:
[0025] The crystal form preparation process of the rosuvastatin calcium intermediate of the present invention is simple, has high purity and good chemical stability, can be better applied to the preparation of pharmaceutical preparations and large-scale production, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 This is the XRPD pattern of the crystal form detection of the target product in Example 1 of the present invention. DETAILED DESCRIPTION
[0027] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.
[0028] Example 1
[0029] A method for preparing a crystalline form of a rosuvastatin calcium intermediate, the synthetic route of which is as follows:
[0030]
[0031] Compound II (2 g, 8.4 mmol) was added with 2,2-dimethoxypropane (10.5 g, 100.8 mmol) and 0.06 g of p-toluenesulfonic acid. The mixture was stirred at 20° C. for 2 h under nitrogen protection.
[0032] Saturated sodium bicarbonate was added to adjust the pH to about 7, ethyl acetate was added for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a yellow oil, which was then added with n-heptane and heated to reflux for dissolution and clarification, cooled to -20°C for crystallization, filtered, and dried in vacuo to obtain Compound I with a yield of 97.5% and a purity of 99.8%.
[0033] The XRPD pattern of the crystal form of compound I is as follows: Figure 1 The data are shown in Table 1.
[0034] Table 1
[0035]
[0036]
[0037] Example 2
[0038] A method for preparing a crystalline form of a rosuvastatin calcium intermediate, the synthetic route of which is as follows:
[0039]
[0040] Compound II (2 g, 8.4 mmol) was added with 2,2-dimethoxypropane (14 g, 134.4 mmol) and 0.02 g of p-toluenesulfonic acid. The mixture was stirred at 10° C. for 2 h under nitrogen protection.
[0041] Saturated sodium bicarbonate was added to adjust the pH to about 7, ethyl acetate was added for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a yellow oil, to which n-heptane was added and the temperature was raised to reflux to dissolve and clarify, the temperature was lowered to -20°C for crystallization, filtered, and dried in vacuo to obtain Compound I with a yield of 94.9% and a purity of 99.5%.
[0042] Example 3
[0043] A method for preparing a crystalline form of a rosuvastatin calcium intermediate, the synthetic route of which is as follows:
[0044]
[0045] Compound II (2 g, 8.4 mmol) was added with 2,2-dimethoxypropane (8.7 g, 84 mmol) and 0.06 g of p-toluenesulfonic acid. The mixture was stirred at 30° C. for 1 h under nitrogen protection.
[0046] Saturated sodium bicarbonate was added to adjust the pH to about 7, ethyl acetate was added for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a yellow oil, to which n-heptane was added and the temperature was raised to reflux to dissolve and clarify, the temperature was lowered to -20°C for crystallization, filtered, and dried in vacuo to obtain Compound I with a yield of 92.1% and a purity of 99.6%.
[0047] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.
Claims
1. A crystalline form of a rosuvastatin calcium intermediate, characterized in that: The rosuvastatin calcium intermediate is (4R-CIS)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester, and its powder X-ray diffraction spectrum has 2θ values of 8.688±0.2°, 10.843±0.2°, 13.708±0.2°, 15.015±0.2°, 16.080±0.2°, 16.930±0.2°, There are characteristic peaks at 17.356±0.2°, 21.714±0.2°, 21.992±0.2°, 22.574±0.2° and 23.820±0.2°.
2. The crystal form of the rosuvastatin calcium intermediate according to claim 1, characterized in that: The powder X-ray diffraction pattern is a spectrum obtained using CuKa radiation, and its overall peak shape is shown in FIG1 .
3. The method for preparing the crystal form of the rosuvastatin calcium intermediate according to claim 1 or 2, characterized in that: The following steps are involved: (1) Compound II was added with 2,2-dimethoxypropane and p-toluenesulfonic acid, and stirred for reaction under nitrogen protection; (2) adding saturated sodium bicarbonate to adjust the pH, adding ethyl acetate for separation, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing with water, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering with suction, and spin-drying, then adding n-heptane and heating to reflux to dissolve and clarify, cooling to crystallize, filtering with suction, and drying to obtain Compound I; Its synthetic route is as follows:
4. The method for preparing the crystal form of rosuvastatin calcium intermediate according to claim 3, wherein: In the step (1), the molar ratio of compound II to 2,2-dimethoxypropane is 1:8-18.
5. The method for preparing the crystal form of rosuvastatin calcium intermediate according to claim 4, characterized in that: In the step (1), the molar ratio of compound II to 2,2-dimethoxypropane is 1:10-16.
6. The method for preparing the crystal form of rosuvastatin calcium intermediate according to claim 3, characterized in that: In the step (1), the mass ratio of compound II to p-toluenesulfonic acid is 1:0.005-0.
1.
7. The method for preparing the crystal form of rosuvastatin calcium intermediate according to claim 6, characterized in that: In the step (1), the mass ratio of compound II to p-toluenesulfonic acid is 1:0.01-0.
06.
8. The method for preparing the crystal form of rosuvastatin calcium intermediate according to claim 3, characterized in that: In the step (1), the reaction temperature is 5-40°C.
9. The method for preparing the crystal form of rosuvastatin calcium intermediate according to claim 8, characterized in that: In the step (1), the reaction temperature is 10-30°C.
10. The method for preparing the crystal form of rosuvastatin calcium intermediate according to claim 3, characterized in that: In the step (1), the reaction time is 0.5 to 4 hours.