A process for synthesizing rosuvastatin propionyl tert-butyl ester

Abstract

This invention discloses a process for synthesizing rosuvastatin acetone tert-butyl ester, comprising the following steps: First, compound I is dissolved in an organic solvent, compound II is added, and the reaction is stirred at room temperature. The reaction is monitored by HPLC. After the reaction is complete, the product is separated to obtain compound III. Second, a palladium catalyst is added to the organic solvent, stirred and mixed evenly, and then compound III and compound IV are added and stirred under the action of the palladium catalyst to obtain compound V. The advantages of this invention are: mild reaction conditions, the entire process is carried out at room temperature, eliminating the need for harsh conditions such as high temperature and high pressure, reducing energy consumption and equipment requirements, and making it suitable for industrial-scale production; excellent stereoselectivity, using a palladium-catalyzed reselective Heck reaction to replace the traditional Witting and Julia olefin reactions, avoiding stereoisomer byproducts, and resulting in higher purity of the target product; fewer byproducts and simpler separation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a synthesis process for rosuvastatin tert-butyl acetone ester. Background Technology

[0002] Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), which can be used to treat hypercholesterolemia and mixed dyslipidemia. It can lower elevated levels of low-density cholesterol, total cholesterol, triglycerides, and apoprotein B, while increasing high-density cholesterol levels. It can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipid metabolism disorders, and homozygous familial hypercholesterolemia, and is known as a super statin.

[0003] Rosuvastatin, administered as a single enantiomer of calcium salt, has been marketed in the United States, Japan, Europe, China, and other countries and regions. Its chemical name is bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), and its chemical structure is as follows: One key step in the existing main methods for synthesizing rosuvastatin involves constructing a carbon-carbon double bond between the rosuvastatin calcium pyrimidine core and a key chiral side chain via an olefination reaction. Currently, there are two main synthetic routes for rosuvastatin calcium: one is through the Witting olefination reaction to construct the carbon-carbon double bond between the rosuvastatin calcium pyrimidine core and the key chiral side chain, and the other is through the Julia olefination reaction to construct the carbon-carbon double bond between the rosuvastatin calcium pyrimidine core and the key chiral side chain. An example of the Witting olefination reaction route (Chemical Invention Publication Document CN200510069557.1) is shown below: The following is an example route for the Julia olefination reaction: Currently, the main routes for the synthesis of double bonds in rosuvastatin are achieved through Witting or Julia reactions. Improvements to these routes by those skilled in the art are limited to adjusting the relative positions of the aldehyde group and the functional groups required for olefination, and replacing them with different types of functional groups that meet the conditions for Witting or Julia olefination. Improvements to the Witting reaction cannot solve the problems of poor stereoselectivity and numerous byproducts. Furthermore, while the Julia reaction itself has extremely high selectivity, the oxidation of side chain groups is difficult. Summary of the Invention

[0004] To address the above shortcomings, the present invention provides the following technical solution: A process for synthesizing rosuvastatin tert-butyl acetone includes the following steps: First, compound I was dissolved in an organic solvent, compound II was added, and the mixture was stirred at room temperature. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III. In the second step, palladium catalyst was added to an organic solvent, stirred and mixed evenly, and then compound III and compound IV were added and stirred under the action of palladium catalyst. The reaction was heated at 100-120°C, and the reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound V.

[0005] Furthermore, the solvent used in the first step reaction is wastewater DMSO or THF.

[0006] Furthermore, in the first step reaction, the molar ratio of compound I to compound II is 1:1.0 to 1.2.

[0007] Furthermore, the first step is carried out under the protection of an inert gas.

[0008] Furthermore, the palladium catalyst used in the second step reaction is a Pd(OAc)2 PPh3 complex.

[0009] Furthermore, in the second step of the reaction, the molar ratio of compound III to compound IV is 1:1 to 1:1.1.

[0010] Furthermore, the amount of palladium catalyst used in the second step reaction is 5–10 mol.

[0011] Furthermore, the ratio of Pd(OAc)2:PPh3 in the palladium catalyst is 1:2 to 4.

[0012] Furthermore, the organic reagent used in the second step reaction is anhydrous DMF.

[0013] Furthermore, the second step reaction was carried out under an inert gas atmosphere.

[0014] The beneficial effects of this invention are: 1. Mild reaction conditions, carried out entirely at room temperature, without the need for harsh conditions such as high temperature and high pressure, reducing energy consumption and equipment requirements, making it suitable for industrial-scale production; 2. Excellent stereoselectivity, using palladium-catalyzed reselective Heck reaction to replace the traditional Witting and Julia olefination reactions, avoiding stereoisomer byproducts, and achieving higher purity of the target product; 3. Fewer byproducts and simple separation: The reaction system is clean, requiring no complex oxidation / reduction steps, and post-processing is simple; 4. Precise raw material ratio and high atom economy: The molar ratio of compounds is controlled at 1:1.0~1.2 and 1:1~1.1, with a catalyst dosage of only 5~10 mol%, resulting in high raw material utilization and reduced production costs; 5. Strong process stability: Both steps of the reaction are carried out under inert gas protection, effectively inhibiting the oxidation and decomposition of raw materials, resulting in good reaction reproducibility and suitability for large-scale continuous production. Attached Figure Description

[0015] Figure 1 This is a schematic diagram of the reaction process of the present invention; Figure 2 The structural formula for rosuvastatin calcium; Figure 3 Example route diagram for the Witting reaction process; Figure 4 Example route diagram for Julia reaction process. Detailed Implementation

[0016] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Example 1

[0017] In the first step of the reaction, under nitrogen protection, 0.1 mol (25.8) I of compound 1 was dissolved in anhydrous THF, and 0.11 mol of compound 2 was added. The reaction was stirred at room temperature, and the reaction was monitored by HPLC. After the reaction was completed, a mixture of diethyl ether and n-hexane (volume ratio 1:1, total volume approximately 100-150 mL) was added to the concentrate. The mixture was stirred vigorously at room temperature for 15-20 minutes, at which point a large amount of white solid (triphenylphosphine oxide) precipitated. The mixture was filtered, and the filter cake (containing triphenylphosphine oxide) was washed twice with a small amount of cold diethyl ether / n-hexane (1:1) (10-15 mL each time). The filtrate was concentrated to dryness under reduced pressure to obtain a pale yellow to white solid. The product was crystallized with 50 mL of toluene to obtain 24.4 g of compound 3, with a yield of 95.3% and a purity of 98.5%.

[0018] Under nitrogen protection, anhydrous DMF (200 mL) was added to the reaction flask, followed by the addition of Pd(OAc)2 (0.005 mol) and 0.01 mol PPh3 with stirring. The mixture was stirred at room temperature for 10 minutes, and then 0.10 mol (25.6 g) of compound III and 0.10 mol of compound IV were added. The mixture was heated to a specified temperature of 100-120°C and the reaction was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature and diluted slowly with water (200-250 mL). The mixture was stirred for 10 minutes and extracted with dichloromethane (150 mL + 100 mL + 100 mL). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was recrystallized from 60 mL of toluene to give 54.8 g of compound III, with a yield of 95.0% and a purity of 98.5%. Example 2

[0019] In the first step of the reaction, under nitrogen protection, 0.1 mol (25.8) I of compound 1 was dissolved in anhydrous THF, and 0.10 mol of compound 2 was added. The reaction was stirred at room temperature, and the reaction was monitored by HPLC. After the reaction was completed, a mixture of diethyl ether and n-hexane (volume ratio 1:1, total volume approximately 100-150 mL) was added to the concentrate. The mixture was stirred vigorously at room temperature for 15-20 minutes, at which point a large amount of white solid (triphenylphosphine oxide) precipitated. The mixture was filtered, and the filter cake (containing triphenylphosphine oxide) was washed twice with a small amount of cold diethyl ether / n-hexane (1:1) (10-15 mL each time). The filtrate was concentrated to dryness under reduced pressure to obtain a pale yellow to white solid. The product was crystallized by charging with 50 mL of toluene to obtain 24.5 g of compound 3, with a yield of 95.7% and a purity of 98.7%. Example 3

[0020] In the first step of the reaction, under nitrogen protection, 0.1 mol (25.8) I of compound Ⅰ was dissolved in anhydrous THF, and 0.12 mol of compound Ⅱ was added. The reaction was stirred at room temperature, and the reaction was monitored by HPLC. After the reaction was completed, a mixture of diethyl ether and n-hexane (volume ratio 1:1, total amount about 100-150 mL) was added to the concentrate. The mixture was stirred vigorously at room temperature for 15-20 minutes. At this time, a large amount of white solid (triphenylphosphine oxide) precipitated. The mixture was filtered, and the filter cake (the filter cake was triphenylphosphine oxide) was washed twice with a small amount of cold diethyl ether / n-hexane (1:1) (10-15 mL each time). The filtrate was concentrated to dryness under reduced pressure to obtain a pale yellow to white solid. The product was crystallized with 50 mL of toluene to obtain 24.0 g of compound Ⅲ, with a yield of 93.7% and a purity of 98.5%. Example 4

[0021] In the second step of the reaction, under nitrogen protection, anhydrous DMF (200 mL) was added to the reaction flask, followed by the addition of Pd(OAc)2 (0.005 mol) and 0.02 mol PPh3 with stirring. The mixture was stirred at room temperature for 10 minutes, and then 0.10 mol (25.6 g) of compound III and 0.10 mol of compound IV were added. The mixture was heated to a specified temperature of 100-120°C and the reaction was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature and diluted slowly with water (200-250 mL). The mixture was stirred for 10 minutes and extracted with dichloromethane (150 mL + 100 mL + 100 mL). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was recrystallized from 60 mL of toluene to give 54.0 g of compound III, with a yield of 93.6% and a purity of 98.7%. Example 5

[0022] In the second step of the reaction, under nitrogen protection, anhydrous DMF (200 mL) was added to the reaction flask, followed by the addition of Pd(OAc)2 (0.005 mol) and 0.02 mol PPh3 with stirring. The mixture was stirred at room temperature for 10 minutes, and then 0.10 mol (25.6 g) of compound III and 0.11 mol of compound IV were added. The mixture was heated to a specified temperature of 100-120°C and the reaction was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature and diluted slowly with water (200-250 mL). The mixture was stirred for 10 minutes and extracted with dichloromethane (150 mL + 100 mL + 100 mL). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was recrystallized from 60 mL of toluene to give 54.5 g of compound III, with a yield of 94.3% and a purity of 98.0%.

[0023] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0024] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A process for synthesizing rosuvastatin tert-butyl acetone, characterized in that... Includes the following steps: First, compound I was dissolved in an organic solvent, compound II was added, and the mixture was stirred at room temperature. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III. In the second step, palladium catalyst was added to an organic solvent, stirred and mixed evenly, and then compound III and compound IV were added and stirred under the action of palladium catalyst. The reaction was heated at 100-120°C, and the reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound V.

2. The synthesis process of rosuvastatin tert-butyl acetone according to claim 1, characterized in that: The solvent used in the first step of the reaction is wastewater DMSO or THF.

3. The synthesis process of rosuvastatin tert-butyl acetone according to claim 1, characterized in that: In the first step of the reaction, the molar ratio of compound I to compound II is 1:1.0 to 1.

2.

4. The synthesis process of rosuvastatin tert-butyl acetone according to claim 1, characterized in that: The first step is carried out under the protection of an inert gas.

5. The synthesis process of rosuvastatin tert-butyl acetone according to claim 1, characterized in that: The palladium catalyst used in the second step reaction is a Pd(OAc)2 PPh3 complex.

6. The process for synthesizing rosuvastatin tert-butyl acetone according to claim 5, characterized in that: In the second step of the reaction, the molar ratio of compound III to compound IV is 1:1 to 1:1.

1.

7. The process for synthesizing rosuvastatin tert-butyl acetone according to claim 6, characterized in that: The amount of palladium catalyst used in the second step reaction is 5–10 mol.

8. The process for synthesizing rosuvastatin tert-butyl acetone according to claim 7, characterized in that: The ratio of Pd(OAc)2:PPh3 in the palladium catalyst is 1:2 to 4.

9. The synthesis process of rosuvastatin tert-butyl acetone according to claim 8, characterized in that: The organic reagent used in the second step of the reaction is anhydrous DMF.

10. The synthesis process of rosuvastatin tert-butyl acetone according to claim 9, characterized in that: The second step of the reaction was carried out under the protection of an inert gas.

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