A new process for the synthesis of statin intermediates

Abstract

The application discloses a new process for synthesizing a statin intermediate, and comprises the following steps: in the first step, under nitrogen protection, compound I is dissolved in an organic solvent, compound II is added, a catalyst and a base reagent are added, reaction is carried out at room temperature, the reaction is monitored by HPLC, after the reaction is completed, a product is separated, and compound III is obtained; in the second step, under nitrogen protection, compound III is dissolved in an organic solvent, a hydrogen source is added, a catalyst is added, reaction is carried out at room temperature, the reaction is monitored by HPLC, after the reaction is completed, a product is separated, and compound IV is obtained. The application has the beneficial effects that: the reaction route of the application can obtain E-form olefin with high selectivity through a specific catalyst system, the synthesis efficiency and subsequent drug efficacy are ensured; the reaction condition is mild, the operation is simple, and the process is suitable for large-scale production; the application has high reaction yield, good stereoselectivity, easy product post-treatment, and less product waste.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a novel process for synthesizing statin drug intermediates. 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 the synthesis via Witting olefination to construct a carbon-carbon double bond connecting the rosuvastatin calcium pyrimidine core and a key chiral side chain; the other is the synthesis via Julia olefination to construct a carbon-carbon double bond connecting the rosuvastatin calcium pyrimidine core and a key chiral side chain. An example of the Witting olefination 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. The technical solution provided in CN201910997404.5 offers a novel side-chain synthesis method, but it still cannot avoid the difficulty of introducing the required reactive groups, resulting in low product yields and poor atom economy. Summary of the Invention

[0004] To address the above shortcomings, the present invention provides the following technical solution: A novel synthetic process for a statin drug intermediate, characterized by comprising the following steps: In the first step of the reaction, under nitrogen protection, compound I was dissolved in an organic solvent, compound II was added, along with a catalyst and a base reagent. The reaction was carried out at room temperature, and the reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III. In the second step of the reaction, under nitrogen protection, compound III was dissolved in an organic solvent, a hydrogen source and a catalyst were added, and the reaction was carried out at room temperature. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound IV.

[0005] Furthermore, the solvent used in the first step reaction is one of MeCN, THF, and EtOAc, preferably THF.

[0006] Furthermore, the alkaline reagent used in the first step reaction is Et2NH or Et3N, and the amount of alkaline reagent used is 2 to 3 eq, preferably Et2NH.

[0007] Furthermore, the catalyst used in the first step reaction includes a main catalyst and a co-catalyst. The main catalyst is Pd(PPh3)4 or Pd(PPh3)2Cl2, and the co-catalyst is cuprous iodide (CuI). The amount of the main catalyst is 0.5-5 mol%, and the amount of the co-catalyst is 2 eq of the main catalyst.

[0008] Furthermore, in the first step reaction, the molar ratio of compound I to compound II is 1:1 to 1.1.

[0009] Furthermore, the solvent used in the second step reaction is DCM.

[0010] Furthermore, the catalyst used in the second step reaction is a second-generation Hoveyda-Grubbs catalyst, with an amount of 5–10 mol.

[0011] Furthermore, the reducing agent used in the second step reaction is formic acid (HCOOH), and the amount used is 2–5 eq.

[0012] Furthermore, the first step reaction is carried out under anaerobic conditions.

[0013] Furthermore, the second step reaction is carried out under anhydrous and oxygen-free conditions.

[0014] The beneficial effects of this invention are: 1. The reaction route of this application, through a specific catalytic system, can obtain E-olefins with high selectivity, ensuring synthesis efficiency and subsequent drug efficacy; the reaction conditions are mild, the operation is simple, and it is suitable for large-scale production; 2. This invention has high reaction yield, good stereoselectivity, easy product post-processing, and low product waste. Attached Figure Description

[0015] Figure 1 This is a schematic diagram of the reaction route of the present invention; Figure 2 This is a schematic diagram of the Witting olefination reaction route of the present invention; Figure 3 This is a schematic diagram of the Julia olefination reaction route of the present invention. 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.

[0017] Example 1

[0018] In the first step of the reaction, under nitrogen protection, 40.2 g (0.1 mol) of compound I was dissolved in 300 mL of anhydrous THF, followed by 0.1 mol of compound II, and then the catalyst Pd(PPh3)4 (0.005 mol, 5 mol%), the co-catalyst cuprous iodide CuI (0.01 mol), and the base reagent Et2NH (0.2 mol, 2 eq). The reaction solution was stirred at room temperature, and the reaction progress was monitored by HPLC. After about 3 hours of reaction, the starting material was almost completely eliminated, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to give 55.0 g of compound III, with a yield of 95.6% and an HPLC purity of 99.3%. In the second step of the reaction, under nitrogen protection, 57.5 g (0.1 mol) of compound III was dissolved in 300 mL of anhydrous dichloromethane (DCM), and formic acid (HCOOH, 0.3 mol, 3 eq) and a second-generation Hoveyda-Grubbs catalyst (0.005 mol, 5 mol%) were added. The reaction mixture was stirred at room temperature, and the reaction progress was monitored by HPLC. After approximately 1.5 hours, the starting material disappeared, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give 54.9 g of compound IV, with a yield of 95.1% and an HPLC purity of 99.5% (of which the E-isomer content was greater than 99%).

[0019] Example 2

[0020] In the first step of the reaction, under nitrogen protection, 40.2 g (0.1 mol) of compound I was dissolved in 300 mL of anhydrous THF, followed by 0.11 mol of compound II, and then the catalyst Pd(PPh3)4 (0.005 mol, 5 mol%), the co-catalyst cuprous iodide CuI (0.01 mol), and the base reagent Et2NH (0.2 mol, 2 eq). The reaction solution was stirred at room temperature, and the reaction progress was monitored by HPLC. After about 3 hours of reaction, the starting material was almost completely eliminated, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain 54.8 g of compound III, with a yield of 95.62% and an HPLC purity of 99.3%. Example 3

[0021] In the first step of the reaction, under nitrogen protection, 40.2 g (0.1 mol) of compound I was dissolved in 300 mL of anhydrous THF, followed by 0.1 mol of compound II, and then the catalyst Pd(PPh3)4 (0.0005 mol, 5 mol%), the co-catalyst cuprous iodide CuI (0.001 mol), and the base reagent Et2NH (0.2 mol, 2 eq). The reaction solution was stirred at room temperature, and the reaction progress was monitored by HPLC. After about 3 hours of reaction, the starting material was almost completely eliminated, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain 54.6 g of compound III, with a yield of 94.9% and an HPLC purity of 99.3%. Example 4

[0022] In the first step of the reaction, under nitrogen protection, 40.2 g (0.1 mol) of compound I was dissolved in 300 mL of anhydrous THF, followed by 0.1 mol of compound II, and then the catalyst Pd(PPh3)4 (0.005 mol, 5 mol%), the co-catalyst cuprous iodide CuI (0.01 mol), and the base reagent Et2NH (0.3 mol, 3 eq). The reaction solution was stirred at room temperature, and the reaction progress was monitored by HPLC. After about 3 hours of reaction, the starting material was almost completely eliminated, and the reaction was stopped. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain 54.7 g of compound III, with a yield of 95.0% and an HPLC purity of 99.3%. Example 5

[0023] In the second step of the reaction, under nitrogen protection, 57.5 g (0.1 mol) of compound III was dissolved in 300 mL of anhydrous dichloromethane (DCM), and formic acid (HCOOH, 0.2 mol, 2 eq) and a second-generation Hoveyda-Grubbs catalyst (0.01 mol, 10 mol%) were added. The reaction mixture was stirred at room temperature, and the reaction progress was monitored by HPLC. After approximately 1.5 hours, the starting material disappeared, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give 54.6 g of compound IV, with a yield of 94.6% and an HPLC purity of 99.5% (of which the E-isomer content was greater than 99%).

[0024] Example 6

[0025] In the second step of the reaction, under nitrogen protection, 57.5 g (0.1 mol) of compound III was dissolved in 200 mL of anhydrous dichloromethane (DCM), and formic acid (HCOOH, 0.5 mol, 5 eq) and a second-generation Hoveyda-Grubbs catalyst (0.005 mol, 5 mol%) were added. The reaction mixture was stirred at room temperature, and the reaction progress was monitored by HPLC. After approximately 1.5 hours, the starting material disappeared, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give 54.7 g of compound IV, with a yield of 94.8% and an HPLC purity of 99.5% (of which the E-isomer content was greater than 99%).

[0026] 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.

[0027] 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 novel synthetic process for a statin drug intermediate, characterized in that... Includes the following steps: In the first step of the reaction, under nitrogen protection, compound I was dissolved in an organic solvent, compound II was added, along with a catalyst and a base reagent. The reaction was carried out at room temperature, and the reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III. In the second step of the reaction, under nitrogen protection, compound III was dissolved in an organic solvent, a hydrogen source was added, along with a catalyst and a base reagent. The reaction was carried out at room temperature, and the reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound IV.

2. The novel synthetic process for a statin drug intermediate according to claim 1, characterized in that: The solvent used in the first step reaction is one of MeCN, THF, or EtOAc.

3. The novel synthetic process for a statin drug intermediate according to claim 1, characterized in that: The alkaline reagent used in the first step reaction is Et2NH or Et3N, and the amount of alkaline reagent used is 1.5 to 3 eq.

4. The novel synthetic process for a statin drug intermediate according to claim 1, characterized in that: The catalyst used in the first step reaction includes a main catalyst and a co-catalyst. The main catalyst is Pd(PPh3)4 or Pd(PPh3)2Cl2, and the co-catalyst is cuprous iodide (CuI). The amount of the main catalyst is 0.5-5 mol%, and the amount of the co-catalyst is 2 eq of the main catalyst.

5. The novel synthetic process for a statin drug intermediate 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 to 1.

1.

6. The novel synthetic process for a statin drug intermediate according to claim 1, characterized in that: The solvent used in the second step of the reaction is DCM.

7. The novel synthetic process for a statin drug intermediate according to claim 1, characterized in that: The catalyst used in the second step reaction is a second-generation Hoveyda-Grubbs catalyst, with an amount of 5–10 mol.

8. The novel synthetic process for a statin drug intermediate according to claim 1, characterized in that: The reducing agent used in the second step of the reaction is formic acid (HCOOH), and the amount used is 2–5 eq.

9. The novel synthetic process for a statin drug intermediate according to claim 1, characterized in that: The first step reaction is carried out under anaerobic conditions.

10. A novel synthetic process for a statin drug intermediate according to claim 1, characterized in that: The second step reaction is carried out under anhydrous and oxygen-free conditions.

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