Synthesis method of atorvastatin calcium
By employing a sodium borohydride/zinc chloride system for reduction and high-temperature cyclization reaction, combined with sulfuric acid hydrolysis and calcium chloride salt formation, the safety risks and low yield issues in the synthesis of atorvastatin calcium have been resolved, achieving a safe, simplified, and efficient synthesis process.
Patent Information
- Application Number
- CN202511857351.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-10
- Publication Date
- 2026-01-23
AI Technical Summary
Existing synthetic routes for atorvastatin calcium have problems such as high risk of spontaneous combustion of Raney nickel, long ring-closing reaction time, low yield, and non-compliance with the concept of green chemistry.
The reduction reaction was carried out using a sodium borohydride/zinc chloride system. The intermediate was cyclized with M4 at high temperature, hydrolyzed with sulfuric acid, and formed a salt with calcium chloride. This avoided the use of Raney nickel and hydrogen, simplifying the reaction steps and time.
It achieves improved safety, shorter reaction time, and higher yield, making it suitable for industrial-scale production and in line with the development concept of green chemistry.
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Figure CN121378091A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of medicine synthesis, in particular to a synthesis method of atorvastatin calcium. BACKGROUND
[0002] Atorvastatin calcium is a statin lipid regulator, and its main action site is in the liver, which can reduce the synthesis of cholesterol, increase the synthesis of low-density lipoprotein receptors, reduce the level of serum cholesterol and low-density lipoprotein cholesterol, and moderately reduce the level of serum triglycerides and increase the level of serum high-density lipoprotein.
[0003] At present, the mainstream route for synthesizing atorvastatin calcium is to use A8 as a raw material, to perform catalytic hydrogenation by using Raney nickel, to perform reflux reaction with M4 in a solvent n-heptane to obtain an intermediate 2, to perform acid hydrolysis, to perform hydrolysis by using sodium hydroxide, and finally to perform salt formation to obtain atorvastatin calcium.
[0004] The route includes five steps of reduction, ring closure, acid hydrolysis, alkaline hydrolysis and salt formation. In the hydrogenation step, Raney nickel is used as a catalyst, and Raney nickel is extremely easy to self-ignite in air, which has a high safety risk. In the ring closure step, reflux reaction is needed, which generally needs more than 20 hours, and the yield is low. In addition, a large amount of salt is generated by first performing hydrolysis by using dilute hydrochloric acid and then performing alkaline hydrolysis, which does not conform to the development concept of green chemistry. Therefore, it is of great significance to develop a synthesis process which is safer, more environmentally friendly, simpler to operate and suitable for scale-up production. SUMMARY
[0005] In view of the above problems, the present application provides a synthesis method of atorvastatin calcium. The present application uses A8 as a starting raw material, first performs reduction reaction in a sodium borohydride / zinc chloride system to generate an intermediate 1, performs ring closure reaction at high temperature between the intermediate 1 and M4 to generate an intermediate 2, and then performs hydrolysis reaction in sulfuric acid to directly generate an intermediate 3, and finally performs salt formation with calcium chloride to generate atorvastatin calcium. The synthesis method is safe and environmentally friendly, the chemical reaction and post-treatment steps are simple, the yield is high, and it is suitable for industrial scale-up production.
[0006] To achieve the above purpose, the technical scheme adopted by the present application is as follows: a synthesis method of atorvastatin calcium, characterized in that it comprises the following steps:
[0007] 1) Reduction: the raw material A8 is subjected to reduction reaction in a sodium borohydride / zinc chloride system to generate an intermediate 1; 2) Ring closure: the intermediate 1 and M4 are subjected to ring closure reaction at high temperature to generate an intermediate 2; 3) Hydrolysis: the intermediate 2 is subjected to hydrolysis reaction in sulfuric acid to directly generate an intermediate 3; 4) salification: intermediate 3 and calcium chloride are salified to form atorvastatin calcium.
[0008] Further, in step 1), the reaction temperature is 40-50℃, and the solvent used is methanol.
[0009] Further, in step 2), the solvent used is DMF, and the reaction temperature is 110-120℃.
[0010] Further, in step 3), the concentration of sulfuric acid is 35-45%, and the solvent used is ethanol.
[0011] Preferably, the specific steps are as follows: 1) reduction: raw material A8 is dissolved in methanol, sodium borohydride is added, and then zinc chloride is added in batches under temperature control of 0-10℃, and the reaction is kept at 40-50℃ for 1-3 hours; after the reaction is completed, the reaction is quenched with dilute hydrochloric acid, and then methanol is distilled out, followed by extraction with dichloromethane to obtain a dichloromethane solution of intermediate 1, which is directly used in the next reaction; 2) ring closure: DMF, M4, acetic acid and tetrabutylammonium bromide are added to the dichloromethane solution of intermediate 1, and atmospheric distillation is performed until the internal temperature reaches 110-120℃, and the reaction is kept for 1-3h; after the reaction is completed, water is added to crystallize to obtain intermediate 2; 3) hydrolysis: intermediate 2 is added to ethanol and 35-45% sulfuric acid, and the reaction is refluxed for 3-4h; after cooling, sodium hydroxide solution is added to adjust the pH to 7-8, and then filtration is performed to obtain a solution of intermediate 3; 4) salification: calcium chloride is dissolved in water, and the temperature is raised to 50-60℃; the solution of intermediate 3 is added dropwise, and after the dropwise addition is completed, the reaction is kept for 0.5-1.5h; then the temperature is lowered, and filtration is performed, and the solid is dried to obtain atorvastatin calcium product.
[0012] Preferably, in step 1), the molar ratio of raw material A8 to sodium borohydride to zinc chloride is 1:1.5-2.0:1.5-2.0.
[0013] Preferably, in step 2), the mass ratio of raw material A8 to acetic acid to tetrabutylammonium bromide is 100:1.5-2.5:2.0-5.0; and the molar ratio of raw material A8 to M4 is 1:0.9-1.1.
[0014] Preferably, in step 3), the volume ratio of 35-45% sulfuric acid to ethanol is 1.0-1.3:1.
[0015] Preferably, in step 4), the molar ratio of intermediate 3 to calcium chloride is 1:0.5-0.6.
[0016] The technical effects of the present application are: 1. The atorvastatin calcium synthesis method provided by the present application avoids the use of Raney nickel and hydrogen, and ensures the safety of the reaction. 2. The ring closure reaction is carried out under the condition of DMF, acetic acid and tetrabutylammonium bromide, and the reaction is completed in 1-3 hours under reflux, thus greatly shortening the reaction time; 3. The hydrolysis reaction is carried out by acid hydrolysis, thus avoiding the problem of producing a large amount of salt by further alkaline hydrolysis, and the overall chemical reaction and post-treatment steps are simple, the yield is high, and the method is suitable for industrial scale production. BRIEF DESCRIPTION OF DRAWINGS
[0017] Figure 1 The hydrogen spectrum of the intermediate 2 in Example 1; Figure 2 The hydrogen spectrum of the product atorvastatin calcium in Example 1. DETAILED DESCRIPTION
[0018] In order to better illustrate the preparation method of atorvastatin calcium provided by the embodiments of the present application, the following further illustrates by examples and drawings.
[0019] Example 1: 1) Reduction: 80 g of raw material A8 was dissolved in 800 mL of methanol, 64.7 g of zinc chloride (1.6 eq) was added, the temperature was lowered to 0-10°C, the temperature was controlled at 0-10°C, 17.0 g of sodium borohydride (1.5 eq) was added in batches, after the addition was completed, the temperature was raised to 40-50°C and the reaction was maintained for 2 h. After the reaction was completed, the temperature was lowered to 10-20°C, dilute hydrochloric acid was added dropwise to adjust pH=6-7, methanol was distilled off under reduced pressure, 600 mL of dichloromethane was added for extraction, and the separated organic phase was a dichloromethane solution of intermediate 1, which was directly used for the next reaction; 2) Ring closure: DMF 400 mL was added to the dichloromethane solution of intermediate 1, then M4 124.0 g (1.0 eq), acetic acid 1.5 g and tetrabutylammonium bromide 2.4 g were added, and atmospheric distillation was carried out until the internal temperature reached 110-120°C, and the reaction was maintained for 2 h; after the reaction was completed, the temperature was lowered to 50-60°C, 900 mL of water was added dropwise, after the dropwise addition was completed, the temperature was lowered to 20-30°C, and filtration was carried out, and the solid was dried to obtain 161.3 g of intermediate 2, with a two-step yield of 82.9% and a purity of >99%; 3) Hydrolysis: 120 g of intermediate 2 was added to 100 mL of ethanol and 120 mL of 40% sulfuric acid, and the reaction was carried out under reflux for 3-4 h, then the temperature was lowered to 20-30°C, 20% sodium hydroxide solution was added to adjust pH=7-8, filtration was carried out, and the filtrate was a solution of intermediate 3; 4) Salting: calcium chloride 10.2 g (0.5 eq) was dissolved in 200 mL of water, the temperature was raised to 50-60°C, the solution of intermediate 3 was added dropwise, after the dropwise addition was completed, the reaction was maintained for 1 h, the temperature was lowered to 20-30°C, and filtration was carried out, and the solid was dried at 50-60°C to obtain 106.9 g of atorvastatin calcium product, with a purity of 99.84% and a two-step yield of 96.5%.
[0020] The hydrogen spectrum of intermediate 2 is as follows:Figure 1 The hydrogen spectrum of the product atorvastatin calcium is shown in Figure 2. Figure 2 The hydrogen spectrum of the product atorvastatin calcium is shown in Figure 2.
[0021] Example 2: 1) Reduction: 100 g of raw material A8 was dissolved in 800 mL of methanol, 91.0 g of zinc chloride (1.8 eq) was added, the temperature was lowered to 0-10 °C, and the temperature was controlled at 0-10 °C, 22.7 g of sodium borohydride (1.6 eq) was added in batches, after the addition was completed, the temperature was raised to 40-50 °C and kept for 2 h. After the reaction was completed, the temperature was lowered to 10-20 °C, dilute hydrochloric acid was added dropwise to adjust pH = 6-7, methanol was distilled off under reduced pressure, 600 mL of dichloromethane was added for extraction, and the separated organic phase was a dichloromethane solution of intermediate 1, which was directly used for the next reaction; 2) Ring closure: To the dichloromethane solution of intermediate 1, 400 mL of DMF was added, then 153.9 g of M4 (1.0 eq), 1.9 g of acetic acid and 3.0 g of tetrabutylammonium bromide were added, and atmospheric distillation was carried out until the internal temperature reached 110-120 °C, and the reaction was kept for 2 h; after the reaction was completed, the temperature was lowered to 50-60 °C, 800 mL of water was added dropwise, after the addition was completed, the temperature was lowered to 20-30 °C, and filtration was carried out, and the solid was dried to obtain 206.2 g of intermediate 2, with a yield of 84.5% and a purity of >99%; 3) Hydrolysis: 200 g of intermediate 2 was added to 100 mL of ethanol and 120 mL of 40% sulfuric acid, and refluxed for 3-4 h, then the temperature was lowered to 20-30 °C, 20% sodium hydroxide solution was added to adjust pH = 7-8, and filtration was carried out, and the filtrate was a solution of intermediate 3; 4) Salting: 17.0 g of calcium chloride (0.5 eq) was dissolved in 250 mL of water, the temperature was raised to 50-60 °C, and the intermediate 3 solution was added dropwise, after the addition was completed, the reaction was kept for 1 h, the temperature was lowered to 20-30 °C, and filtration was carried out, and the solid was dried at 50-60 °C to obtain 176.8 g of atorvastatin calcium product, with a purity of 99.76% and a two-step yield of 95.8%.
[0022] Comparative Example:
[0023] 1) Reduction: 80 g of raw material A8 was dissolved in 1200 mL of methanol, 7.7 g of ammonia was added, and it was transferred to a hydrogenation kettle, 2.5 g of Raney nickel was added, the temperature was controlled at 40-45 °C, the hydrogen pressure was 0.9-1.0 MPa, and the reaction was carried out for 3 h, then the methanol was distilled off under reduced pressure, and 250 mL of n-heptane was used for distillation, and 89 g of crude intermediate 1 was obtained; 2) ring closure: to the crude product of step 1) add n-heptane 900 mL, then add tetrabutylammonium hydrogen sulfate 2 g, diisopropylamine 3 g, tert-pentanoic acid 2.5 g and M4 136.4 g (1.1 eq) in sequence, heat to reflux and separate water for 24 h, then cool to 20-30 °C, evaporate to dryness, take ethanol and evaporate twice, then add 450 mL of ethanol and 350 mL of water to the wet product, heat to dissolve, then cool to 25 °C, filter, and dry the wet product to obtain intermediate 2, 151.9 g, two-step yield 74.3%, purity >99%; 3) acid hydrolysis: take 120 g of intermediate 2 and add to 1800 mL of methanol, then add hydrochloric acid 12 mL, reflux and react for 3-4 h, evaporate to dryness, take ethanol and evaporate twice, then evaporate to dryness to obtain intermediate product 3; 4) basic hydrolysis: add ethanol 1800 mL to intermediate product 3, cool to below 5 °C, then add 10% sodium hydroxide solution 200 mL, control the temperature to 5-10 °C, and keep for 4 h, then evaporate ethanol 1200 mL, add water 800 mL, extract with methyl tert-butyl ether twice, 300 mL each time, adjust the pH of the separated aqueous phase to 7-8 with hydrochloric acid to obtain a solution of intermediate product 4; 5) salt formation: dissolve calcium chloride 10.2 g (0.5 eq) in 1000 mL of water, heat to 50-60 °C, then add the solution of intermediate 4 dropwise, keep for 1 h after dropwise addition, cool to 20-30 °C, filter, and dry the solid at 50-60 °C to obtain atorvastatin calcium product 94.9 g, purity 99.10%, three-step yield 85.7%.
[0024] From the above data, it can be seen that the atorvastatin calcium synthesis method provided by the application avoids the use of Raney nickel and hydrogen, ensures the safety of the reaction, and is simple to operate, has high yield, and is suitable for industrial scale-up production.
Claims
1. A process for the synthesis of atorvastatin calcium, characterized in that, The process comprises the following steps: 1) Reduction: raw material A8 is reduced in a sodium borohydride / zinc chloride system to form intermediate 1; 2) Ring closure: intermediate 1 and M4 are subjected to ring closure reaction at high temperature to form intermediate 2; 3) Hydrolysis: intermediate 2 is subjected to hydrolysis reaction in sulfuric acid to directly form intermediate 3; 4) Salting: intermediate 3 and calcium chloride are subjected to salting to form atorvastatin calcium.
2. The method of synthesis of claim 1, wherein, In step 1), the reaction temperature is 40-50°C, and the solvent used is methanol.
3. The method of synthesis of claim 1, wherein, In step 2), the solvent used is DMF, and the reaction temperature is 110-120°C.
4. The method of synthesis of claim 1, wherein, In step 3), the concentration of sulfuric acid is 35-45%, and the solvent used is ethanol.
5. The method of synthesis according to any one of claims 1 to 4, wherein The specific steps are as follows: 1) Reduction: raw material A8 is dissolved in methanol, sodium borohydride is added, and then zinc chloride is added in batches at a temperature of 0-10°C, and the reaction is maintained at 40-50°C for 1-3 hours. After the reaction is completed, the reaction is quenched with dilute hydrochloric acid, the methanol is evaporated, and then dichloromethane is used for extraction to obtain a dichloromethane solution of intermediate 1, which is directly used for the next step; 2) Ring closure: DMF, M4, acetic acid, and tetrabutylammonium bromide are added to the dichloromethane solution of intermediate 1, and atmospheric distillation is performed until the internal temperature reaches 110-120°C, and the reaction is maintained for 1-3 hours. After the reaction is completed, water is added to precipitate intermediate 2; 3) Hydrolysis: intermediate 2 is added to ethanol and 35-45% sulfuric acid, and the reaction is refluxed for 3-4 hours. After cooling, sodium hydroxide solution is added to adjust the pH to 7-8, and then filtration is performed to obtain a solution of intermediate 3; 4) Salting: calcium chloride is dissolved in water, and the temperature is raised to 50-60°C. The solution of intermediate 3 is added dropwise, and after the addition is completed, the reaction is maintained for 0.5-1.5 hours. Then, the temperature is lowered, and filtration is performed. The solid is dried to obtain atorvastatin calcium product.
6. The method of synthesis of claim 5 wherein, In step 1), the molar ratio of raw material A8 to sodium borohydride to zinc chloride is 1:1.5-2.0:1.5-2.
0.
7. The method of synthesis of claim 5 wherein, In step 2), the mass ratio of raw material A8 to acetic acid to tetrabutylammonium bromide is 100:1.5-2.5:2.0-5.0, and the molar ratio of raw material A8 to M4 is 1:0.9-1.
1.
8. The method of synthesis of claim 5 wherein, In step 3), the volume ratio of 35-45% sulfuric acid to ethanol is 1.0-1.3:
1.
9. The method of synthesis of claim 5 wherein, In step 4), the molar ratio of intermediate 3 to calcium chloride is 1:0.5-0.6.