A method for preparing atorvastatin

Abstract

The application relates to a preparation method of atorvastatin, and belongs to the field of pharmaceutical chemistry. The preparation method comprises a substitution reaction of raw materials under alkalinity to obtain atorvastatin. The preparation method provided by the application is high in product purity, mild in reaction condition, simple in operation and beneficial to industrial implementation.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and specifically to a method for preparing atorvastatin. Background Technology

[0002] Atorvastatin is a statin drug, an inhibitor of hydroxymethylglutaryl-CoA (HMG-CoA) reductase. Its chemical name is (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-isopropyl-pyrrolo-1-yl]-3,5-dihydroxyheptanoic acid, and its molecular formula is C2. 66 H 68 CaF2N4O 10 The structure is as follows:

[0003]

[0004] Atorvastatin is currently the most effective lipid-lowering drug, characterized by low toxicity and high efficacy. It can not only effectively lower total cholesterol (TC) and low-density lipoprotein (LDL), but also lower triglycerides (TG) to a certain extent, and increase high-density lipoprotein (HDL). It has good therapeutic effects on patients with coronary heart disease, ischemic stroke, diabetes, and hypertension, as well as other high-risk cardiovascular patients.

[0005] The preparation of atorvastatin disclosed in patent CN102617440B involves reacting compound I, compound II, and acetonitrile under anhydrous potassium carbonate conditions. After the reaction, a multi-step post-processing step is performed to obtain a reaction intermediate compound. This intermediate compound is then reacted first under hydrochloric acid conditions, and then under sodium hydroxide conditions. After the reaction, a multi-step post-processing step is performed, followed by recrystallization from methanol and dichloromethane to obtain atorvastatin. The reaction formula is shown below.

[0006]

[0007] The methods for preparing atorvastatin disclosed in the prior art have at least one of the following drawbacks:

[0008] (1) The reaction involves many steps and is prone to generating a large amount of pollutants, which is not conducive to environmental protection;

[0009] (2) The post-processing is complex and not conducive to industrial production;

[0010] (3) Low product yield.

[0011] Therefore, there is a need to develop an efficient, environmentally friendly, and simple method for synthesizing atorvastatin. Summary of the Invention

[0012] This invention provides a method for preparing atorvastatin. A method for preparing atorvastatin includes:

[0013]

[0014] Under alkaline conditions, in an organic solvent, compound A and compound B undergo a substitution reaction. After the reaction is complete, the pH is adjusted to acidic with hydrochloric acid. After separation, the organic phase is distilled under reduced pressure to obtain atorvastatin.

[0015] In the compound of formula B, X is selected from halogens and sulfonate groups. In some embodiments, X in the compound of formula B is chlorine. In some embodiments, X in the compound of formula B is bromine. In some embodiments, X in the compound of formula B is a methanesulfonate.

[0016] The molar ratio of compound A to compound B can be 1:1 to 1:2. In some embodiments, the molar ratio of compound A to compound B is 1:1 to 1:1.5, which is beneficial for product formation and acquisition. In some embodiments, the molar ratio of compound A to compound B is 1:1. In some embodiments, the molar ratio of compound A to compound B is 1:1.5. In some embodiments, the molar ratio of compound A to compound B is 1:2.

[0017] The molar ratio of compound A to alkali can be 1:1 to 1:3. In some embodiments, the molar ratio of compound A to alkali can be 1:1.5 to 1:3. In some embodiments, the molar ratio of compound A to alkali can be 1:2 to 1:3. In some embodiments, the molar ratio of compound A to alkali can be 1:2 to 1:3. In some embodiments, the molar ratio of compound A to alkali is 1:1. In some embodiments, the molar ratio of compound A to alkali is 1:1.5. In some embodiments, the molar ratio of compound A to alkali is 1:2. In some embodiments, the molar ratio of compound A to alkali is 1:3.

[0018] The alkali comprises at least one selected from carbonates, bicarbonates, acetates, and phosphates. In some embodiments, the alkali is at least one selected from sodium carbonate, barium carbonate, calcium carbonate, and potassium carbonate. In some embodiments, the alkali is at least one selected from potassium bicarbonate and sodium bicarbonate. In some embodiments, the alkali is at least one selected from potassium acetate and sodium acetate. In some embodiments, the alkali is at least one selected from potassium phosphate and sodium phosphate.

[0019] The substitution reaction temperature can be 0℃-100℃. In some embodiments, the substitution reaction temperature is 20℃-70℃. In some embodiments, the substitution reaction temperature is 30℃-60℃. In some embodiments, the substitution reaction temperature is 40℃-60℃. In some embodiments, the substitution reaction temperature is 40℃-50℃. In some embodiments, the substitution reaction temperature is 50℃-60℃. In some embodiments, the substitution reaction temperature is 60℃-100℃. In some embodiments, the substitution reaction temperature is 0℃. In some embodiments, the substitution reaction temperature is 30℃. In some embodiments, the substitution reaction temperature is 40℃. In some embodiments, the substitution reaction temperature is 50℃. In some embodiments, the substitution reaction temperature is 60℃.

[0020] The concentration of the hydrochloric acid solution can be 15%-20%. In some embodiments, the concentration of the hydrochloric acid solution is 15%-18%. In some embodiments, the concentration of the hydrochloric acid solution is 18%-20%. In some embodiments, the concentration of the hydrochloric acid solution is 15%. In some embodiments, the concentration of the hydrochloric acid solution is 18%. In some embodiments, the concentration of the hydrochloric acid solution is 20%.

[0021] The acidic pH value can be 2-4. In some embodiments, the acidic pH value is 2-3. In some embodiments, the acidic pH value is 3-4. In some embodiments, the acidic pH value is 2. In some embodiments, the acidic pH value is 3. In some embodiments, the acidic pH value is 4.

[0022] The organic solvent may include one selected from dichloromethane, ethyl acetate, tetrahydrofuran, acetone, and methyl tert-butyl ether. In some embodiments, the organic solvent is methyl tert-butyl ether. In some embodiments, the organic phase is tetrahydrofuran. In some embodiments, the organic solvent is dichloromethane.

[0023] The mass-to-volume ratio of the compound of formula A to the organic solvent can be 0.05 mg / mL to 0.2 mg / mL. In some embodiments, the mass-to-volume ratio of the compound of formula A to the organic solvent is 0.1 mg / mL to 0.2 mg / mL. In some embodiments, the mass-to-volume ratio of the compound of formula A to the organic solvent is 0.15 mg / mL to 0.2 mg / mL. In some embodiments, the mass-to-volume ratio of the compound of formula A to the organic solvent is 0.05 mg / mL. In some embodiments, the mass-to-volume ratio of the compound of formula A to the organic solvent is 0.1 mg / mL. In some embodiments, the mass-to-volume ratio of the compound of formula A to the organic solvent is 0.15 mg / mL. In some embodiments, the mass-to-volume ratio of the compound of formula A to the organic solvent is 0.2 mg / mL.

[0024] In some embodiments, a method for preparing atorvastatin includes: in an organic solvent, under alkaline conditions, a substitution reaction is carried out between a compound of formula A and a compound of formula B; after the reaction is complete, the pH is adjusted to acidic with hydrochloric acid, the mixture is allowed to stand and separated, the organic layers are combined, and the organic phase is distilled under reduced pressure to obtain atorvastatin; wherein, X in compound B can be selected from one of halogen or sulfonate groups; the molar ratio of compound A to alkaline can be 1:1-1:3; the molar ratio of compound A to compound B can be 1:1-1:2; the alkaline is at least one of carbonate, bicarbonate, acetate, and phosphate; the organic phase is one of dichloromethane, ethyl acetate, tetrahydrofuran, acetone, and methyl tert-butyl ether; the mass-volume ratio of compound A to organic solvent is 0.05 mg / mL-0.2 mg / mL; the reaction temperature of the substitution reaction is 0℃-100℃; the pH is adjusted to 2-4 with hydrochloric acid, the concentration of which is 15%-20%.

[0025] In some embodiments, a method for preparing atorvastatin includes: in an organic solvent, under alkaline conditions, a substitution reaction is carried out between compound A and compound B; after the reaction is complete, the pH is adjusted to acidic with hydrochloric acid, the mixture is allowed to stand and separated, the organic layers are combined, and the organic phase is distilled under reduced pressure to obtain atorvastatin; wherein, X in compound B may be selected from methanesulfonate; the molar ratio of compound A to alkaline may be 1:1-1:3; the molar ratio of compound A to compound B may be 1:1-1:2; the alkaline is at least one selected from carbonate, bicarbonate, acetate, and phosphate; the organic phase is one selected from dichloromethane, ethyl acetate, tetrahydrofuran, acetone, and methyl tert-butyl ether; the mass-volume ratio of compound A to organic solvent is 0.05 mg / mL-0.2 mg / mL; the reaction temperature of the substitution reaction is 0℃-100℃; the pH is adjusted to 2-4 with hydrochloric acid, the concentration of which is 15%-20%.

[0026] In some embodiments, a method for preparing atorvastatin includes: in an organic solvent, under alkaline conditions, a substitution reaction is carried out between a compound of formula A and a compound of formula B; after the reaction is complete, the pH is adjusted to acidic with hydrochloric acid, the mixture is allowed to stand and separated, the organic layers are combined, and the organic phase is distilled under reduced pressure to obtain atorvastatin; wherein, X in compound B may be selected from chlorine; the molar ratio of compound A to the base may be 1:1-1:3; the molar ratio of compound A to compound B may be 1:1-1:2; the base is at least one selected from carbonate, bicarbonate, acetate, and phosphate; the organic phase is one selected from dichloromethane, ethyl acetate, tetrahydrofuran, acetone, and methyl tert-butyl ether; the mass-volume ratio of compound A to the organic solvent is 0.05 mg / mL-0.2 mg / mL; the reaction temperature of the substitution reaction is 0℃-100℃; the pH is adjusted to 2-4 with hydrochloric acid, the concentration of which is 15%-20%.

[0027] In some embodiments, a method for preparing atorvastatin includes: in an organic solvent, under alkaline conditions, a substitution reaction is carried out between a compound of formula A and a compound of formula B; after the reaction is complete, the pH is adjusted to acidic with hydrochloric acid, the mixture is allowed to stand and separated, the organic layers are combined, and the organic phase is distilled under reduced pressure to obtain atorvastatin; wherein, X in compound B may be selected from bromine; the molar ratio of compound A to the base may be 1:1-1:3; the molar ratio of compound A to compound B may be 1:1-1:2; the base is at least one selected from carbonate, bicarbonate, acetate, and phosphate; the organic phase is one selected from dichloromethane, ethyl acetate, tetrahydrofuran, acetone, and methyl tert-butyl ether; the mass-volume ratio of compound A to the organic solvent is 0.05 mg / mL-0.2 mg / mL; the reaction temperature of the substitution reaction is 0℃-100℃; the pH is adjusted to 2-4 with hydrochloric acid, the concentration of which is 15%-20%.

[0028] The atorvastatin prepared by this invention has a yield of not less than 70% and a purity of not less than 90%.

[0029] Compared with the prior art, the technical solution of the present invention has at least the following technical effects:

[0030] (1) The reaction conditions are mild, which is conducive to industrial production;

[0031] (2) The reagents used are safe and environmentally friendly, and are unlikely to cause harm to production personnel and the environment;

[0032] (3) Simple post-processing;

[0033] (4) The product has high purity and high yield.

[0034] Terminology Explanation:

[0035] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0036] In this invention, expressions such as "compound A" and "compound represented by formula A" refer to the same compound.

[0037] The term "room temperature" refers to a temperature of approximately 20°C-35°C, approximately 23°C-28°C, or approximately 25°C.

[0038] The reaction involved in this invention can be monitored by thin-layer chromatography (TLC) with a developing solvent of cyclohexane and ethyl acetate in a ratio of 2:1. The reaction is considered complete when the spot indicated by the compound of formula A disappears. The reaction time is usually less than 10 hours.

[0039] The method of the present invention can be used to detect the purity of the reactants by liquid chromatography (HPLC). Detailed Implementation

[0040] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0041] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0042] In this invention, mL represents milliliters, h represents hours, g represents grams, mg represents milligrams, mg / mL represents milligrams per milliliter, ℃ represents degrees Celsius, HPLC represents liquid chromatography, and TLC represents thin-layer chromatography.

[0043] In this invention This indicates the optical rotation measured at 23°C under sodium light conditions.

[0044] Example 1

[0045] 5g of compound A, 3.2g of 2-((2R,4R)-4-hydroxy-6-carbonyltetrahydro-2H-pyran-2-yl)ethyl methanesulfonate, and 2.0g of sodium carbonate were added to 50mL of methyl tert-butyl ether. The reaction was maintained at 50℃ until TLC detection (developing solvent: cyclohexane: ethyl acetate = 2:1) showed complete conversion of material A (spots disappeared). The reaction was then terminated. 18% hydrochloric acid solution was added dropwise to adjust the pH to 2. The mixture was allowed to stand and separated. The organic phase was distilled under reduced pressure to obtain atorvastatin: 6.10g of white solid, yield 87%. Its purity was determined to be 92% by liquid chromatography.

[0046] IR(KBr): 3410,2964,2929,1731,1652,1529,1508,1438,1315,1241,1226cm -1 ;

[0047] 1 H NMR(CD3OD)δ: 7.30-7.29(m,2H),7.25-7.20(m,4H),7.15-7.13(m,2H),7.11-7.02(m,6H),4.08(ddd,J=5.3,7.8,16.0Hz 1H),4.02-3.98(m,1H),3.91(ddd,J=5.3,7.6,16.0Hz,1H),3.69-3.63(m,1H),3.40-3.34(m,1H),2.41(dd,J=5.2,15.5Hz,1H),2 .35(dd,J=7.6,15.5Hz,1H),1.75-1.6(m,2H),1.56-1.51(m,1H),1.49(d,J=7.1Hz,3H),1.48(d,J=7.1Hz,3H),1.47-1.43(m,1H);

[0048] 19F NMR (CDCl3) δ -113.8;

[0049] +5 (c 0.94, CH3OH);

[0050] ESI-MS m / z: 581.2 [M+Na] + .

[0051] Example 2

[0052] 5g of compound A, 2.2g of (4R,6S)-6-(2-chloroethyl)tetrahydro-4-hydroxy-2H-pyran-2-one, and 2.6g of sodium carbonate were added to 50mL of tetrahydrofuran and reacted at 40℃ until TLC detection (developing solvent: cyclohexane: ethyl acetate = 2:1) showed complete conversion of material A (spots disappeared). The reaction was then terminated, and 18% hydrochloric acid solution was added dropwise to adjust the pH to 3. The mixture was allowed to stand and separated. The organic phase was distilled under reduced pressure to obtain atorvastatin: 5.7g of white solid, yield 81%. The purity was determined to be 94% by liquid chromatography.

[0053] IR(KBr): 3410,2964,2929,1731,1652,1529,1508,1438,1315,1241,1226cm -1 ;

[0054] 1 H NMR(CD3OD)δ:7.30-7.29(m,2H),7.25-7.20(m,4H),7.15-7.13(m,2H),7.11-7.02(m,6H),4.08(ddd,J=5.3,7.8,16.0Hz 1H),4.02-3.98(m,1H),3.91(ddd,J=5.3,7.6,16.0Hz,1H),3.69-3.63(m,1H),3.40-3.34(m,1H),2.41(dd,J=5.2,15.5Hz,1H),2 .35(dd,J=7.6,15.5Hz,1H),1.75-1.6(m,2H),1.56-1.51(m,1H),1.49(d,J=7.1Hz,3H),1.48(d,J=7.1Hz,3H),1.47-1.43(m,1H);

[0055] 19F NMR (CDCl3) δ -113.8;

[0056] +5 (c 0.94, CH3OH);

[0057] ESI-MS m / z: 581.2 [M+Na] + .

[0058] Example 3

[0059] 5g of compound A, 5.0g of (4R,6S)-6-(2-bromoethyl)tetrahydro-4-hydroxy-2H-pyran-2-one, and 4.0g of sodium carbonate were added to 100mL of dichloromethane and reacted at 50℃ until TLC detection (developing solvent: cyclohexane: ethyl acetate = 2:1) showed complete conversion of material A (spots disappeared). The reaction was then terminated, and 18% hydrochloric acid solution was added dropwise to adjust the pH to 4. The mixture was allowed to stand and separated. The organic phase was distilled under reduced pressure to obtain atorvastatin: 6.2g of white solid, yield 88%. The purity was determined to be 95% by liquid chromatography.

[0060] IR(KBr): 3410,2964,2929,1731,1652,1529,1508,1438,1315,1241,1226cm -1 ;

[0061] 1 H NMR(CD3OD)δ:7.30-7.29(m,2H),7.25-7.20(m,4H),7.15-7.13(m,2H),7.11-7.02(m,6H),4.08(ddd,J=5.3,7.8,16.0Hz 1H),4.02-3.98(m,1H),3.91(ddd,J=5.3,7.6,16.0Hz,1H),3.69-3.63(m,1H),3.40-3.34(m,1H),2.41(dd,J=5.2,15.5Hz,1H),2 .35(dd,J=7.6,15.5Hz,1H),1.75-1.6(m,2H),1.56-1.51(m,1H),1.49(d,J=7.1Hz,3H),1.48(d,J=7.1Hz,3H),1.47-1.43(m,1H);

[0062] 19F NMR (CDCl3) δ -113.8;

[0063] +5 (c 0.94, CH3OH);

[0064] ESI-MS: m / z 581.2 [M+Na] + .

[0065] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing atorvastatin, comprising: ， In an organic solvent, under alkaline conditions, compound A and compound B undergo a substitution reaction. After the reaction is complete, the pH is adjusted to 2-4 with hydrochloric acid. After separation, the organic phase is distilled under reduced pressure to obtain atorvastatin. X in compound B is selected from halogens and sulfonates. The molar ratio of compound A to the base is 1:1-1:

3. The molar ratio of compound A to compound B is 1:1-1:

2. The base is selected from at least one of carbonates, bicarbonates, acetates, and phosphates. The organic solvent is selected from at least one of dichloromethane, ethyl acetate, tetrahydrofuran, acetone, and methyl tert-butyl ether. The mass-volume ratio of compound A to the organic solvent is 0.05 mg / mL-0.2 mg / mL. The reaction temperature of the substitution reaction is 0℃-100℃.

2. The method according to claim 1, wherein, The reaction temperature for the substitution reaction is 20℃-70℃; the concentration of the hydrochloric acid is 15%-20%.

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