Synthesis process of atorvastatin calcium

Abstract

The invention belongs to the field of biological medicine, and discloses a synthesis process of atorvastatin calcium, which comprises the following steps: by taking a compound 1 and a compound 2 as raw materials and acid as a catalyst, carrying out Paal-Knorr reaction on the compound 1 and the compound 2 under the condition of heating reflux, and separating water generated by the reaction by using a water segregator in the reaction process; after the reaction is finished, sequentially crystallizing and recrystallizing to obtain a compound 3; the method comprises the following steps: by taking methanol as a reaction solvent, carrying out deprotection reaction on a compound 3 under an acidic condition to obtain a compound 4, carrying out salt forming reaction on the compound 4 under an alkaline condition to obtain a compound 5, carrying out salt forming reaction on the compound 5 and hydrated calcium acetate to obtain atorvastatin calcium, and refining to obtain an atorvastatin calcium product. In the synthesis process of the compound 3, the reaction process is propelled by adopting the water segregator, so that the reaction completion time is shortened by more than 10 hours; the crystallization process of the compound 3 is optimized by changing the solvent proportion. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of biological medicine, specifically to the field of drug synthesis. Specifically, it relates to a synthesis process of atorvastatin calcium, an HMG-CoA reductase inhibitor. Background Art

[0002] Atorvastatin calcium (Atorvastatin, trade name Lipitor; Compound 6) is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and its structure is shown as follows:

[0003]

[0004] Atorvastatin calcium significantly reduces the levels of total cholesterol and low-density lipoprotein cholesterol in the blood by inhibiting HMG-CoA reductase. It has significant curative effects in the treatment of hypercholesterolemia, mixed hyperlipidemia, etc. Atorvastatin calcium was developed by Warner-Lambert Company (later acquired by Pfizer), and was approved for marketing in the United States in 1996, in Europe in 1998, and in China in 1999.

[0005] The early original research route of atorvastatin calcium (US 4681893A) adopted a linear synthesis method, using ethyl 2-(4-fluorophenyl)-2-bromoacetate (Compound 8) as the raw material, through condensation, amidation, hydrolysis, cyclization, deprotection, condensation, and reduction to obtain a carboxylic acid ester, and then the carboxylic acid ester formed a diastereomeric amide with R-phenylethylamine, and the optically pure atorvastatin calcium isomer was obtained by alkaline treatment. The synthesis route is as follows:

[0006]

[0007]

[0008] This linear synthesis route is long and the steps are cumbersome. The linear synthesis route restricts the synthesis efficiency and yield, and the step of phenylethylamine resolution restricts the atom economy. The total yield reported in the patent is only 3-5%, and it is rarely used now.

[0009] Pfizer later optimized the synthesis route (US 5298627A), changing from the linear synthesis method to the Paal-Knorr convergent synthesis method. First, Compound 1 and Compound 2 were synthesized, then the two were condensed, and then deprotected and salt-formed to finally obtain atorvastatin calcium. The synthesis route is as follows:

[0010]

[0011] The synthesis efficiency and yield of this scheme have been significantly improved. However, the condensation reaction time of compound 1 and compound 2 is more than 48 hours, seriously affecting the reaction efficiency. The inventors used this scheme to synthesize compound 3, and the yield was about 60%.

[0012] Subsequently, Teva Pharmaceutical Industries Ltd. (WO2002043667A2) and Ranbaxy Laboratories Limited (US20090216029A1) successively optimized the synthesis method of compound 3. However, the time required to synthesize compound 3 is still 40 h or longer, and the yield is below 70%, so the optimization effect is not good. Summary of the Invention

[0013] The object of the present invention is to improve the deficiencies of the traditional atorvastatin calcium synthesis process and provide an improved process for synthesizing atorvastatin calcium. The inventors found that by using the synthesis process of the present invention and using commercially available and easily obtained raw materials, through the Paal-Knorr reaction, deprotection reaction, and salt formation reaction, the target product atorvastatin calcium can be successfully prepared. Compared with the traditional technology, in the synthesis process of compound 3 of the present invention, a water separator is used to promote the reaction process, shortening the reaction completion time by more than 10 h; by changing the solvent ratio, the crystallization process and product purity of compound 3 and atorvastatin calcium are optimized. Generally speaking, the present invention optimizes the synthesis steps, reduces the overall reaction time, simplifies the post-treatment of the reaction, uses recrystallization or slurrying for purification, is convenient to operate, has high yield and purity of the product, has a green and environmentally friendly route, and provides a feasible route for the production in the GMP workshop.

[0014] A synthesis process of atorvastatin calcium, and the synthesis route is as follows:

[0015]

[0016] Including:

[0017] Step (1): Using compound 1 and compound 2 as raw materials, with an acid as a catalyst, under heating and reflux conditions, compound 1 and compound 2 carry out the Paal-Knorr reaction, and the water generated in the reaction is separated by a water separator during the reaction; after the reaction ends, through crystallization and recrystallization in sequence, compound 3 is obtained;

[0018] Step (2): Using methanol as the reaction solvent, compound 3 undergoes a deprotection reaction under acidic conditions to obtain compound 4; using methanol as the reaction solvent, compound 4 undergoes a salt formation reaction under basic conditions to obtain compound 5; using methanol as the reaction solvent, compound 5 undergoes a salt formation reaction with calcium acetate hydrate to obtain atorvastatin calcium, and then it is refined to obtain the atorvastatin calcium product.

[0019] In step (1), the contact method between Compound 1 and Compound 2 is not particularly limited. Removing the water generated by the contact reaction between Compound 1 and Compound 2 can promote the reaction process, increase the reaction rate, and further improve the efficiency of preparing Compound 3 by this reaction. The reaction solvent contains tetrahydrofuran (THF). Tetrahydrofuran is miscible with water, and a large amount of tetrahydrofuran may be contained in the lower aqueous phase of the water separator. Since tetrahydrofuran is an essential solvent for the Paal-Knorr reaction, it is necessary to control the temperature of the Paal-Knorr reaction and the proportion of tetrahydrofuran in the reaction solvent during the Paal-Knorr reaction. Otherwise, the reaction will proceed slowly.

[0020] Specifically, it includes the following steps: adding Compound 1, Compound 2, and a catalyst to the reaction solvent, installing a water separator, and carrying out the Paal-Knorr reaction under stirring and reflux. During the reaction, the water generated by the reaction is separated by the water separator; after the reaction is completed, through crystallization and recrystallization in sequence, Compound 3 is obtained.

[0021] The temperature of the Paal-Knorr reaction is 60 °C to 110 °C.

[0022] Preferably, the temperature of the Paal-Knorr reaction is 75 °C to 105 °C, whereby the reaction efficiency can be improved.

[0023] More preferably, the temperature of the Paal-Knorr reaction is 80 °C to 100 °C, whereby the reaction efficiency can be further improved and the yield of Compound 3 can be increased.

[0024] Most preferably, the temperature of the Paal-Knorr reaction is 90 °C to 100 °C.

[0025] The time of the Paal-Knorr reaction is 18 to 30 hours.

[0026] Preferably, the time of the Paal-Knorr reaction is 20 to 24 hours.

[0027] The reaction solvent is one or a mixture of Hexane (n-hexane), THF (tetrahydrofuran), 2-MeTHF (2-methyltetrahydrofuran), 1,4-dioxane (1,4-dioxane), and Toluene (toluene).

[0028] Preferably, the reaction solvent is a mixed solvent with a volume ratio of n-hexane, tetrahydrofuran, and toluene of (3 to 6):(0.8 to 1.2):1 or a mixed solvent with a volume ratio of n-hexane, 2-methyltetrahydrofuran, and toluene of (3 to 6):(0.8 to 1.2):1.

[0029] Preferably, the reaction solvent is a mixture of n-hexane, tetrahydrofuran, and toluene with a volume ratio of (3.5 - 4.7):(0.85 - 1.15):1, which can further improve the reaction efficiency.

[0030] The molar ratio of compound 1 to compound 2 is 1:1.0 - 1:1.5.

[0031] Preferably, the molar ratio of compound 1 to compound 2 is 1:1.2 - 1:1.35, which can further improve the efficiency of preparing compound 3 using this reaction.

[0032] The catalyst is at least one of pivalic acid (PA), acetic acid, dilute hydrochloric acid, dilute sulfuric acid, formic acid, acetic acid, trimethylacetic acid, tartaric acid, and citric acid.

[0033] Preferably, the catalyst is pivalic acid, which can enhance the reaction efficiency.

[0034] The molar ratio of compound 1 to the catalyst is 1:0.6 - 1:1.3.

[0035] Preferably, the molar ratio of compound 1 to the catalyst is 1:0.8 - 1:1.3.

[0036] More preferably, the molar ratio of compound 1 to the catalyst is 1:0.85 - 1:1.05, which can further improve the efficiency of preparing compound 3 using this reaction.

[0037] Compound 2 is a viscous liquid and can be separated from compound 3 during crystallization. However, the crystallization of compound 3 is easily interfered by compound 2, resulting in difficult crystallization and reduced yield. Therefore, it is necessary to control the amount of good solvent used to avoid the interference of compound 2.

[0038] The crystallization process: After the reaction is completed, remove the mixed solvent, add a good solvent to the remaining oily substance, heat to 90 °C, stir under reflux for 10 min, pour it into a poor solvent while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water, and dry it.

[0039] The good solvent for crystallization is at least one of ethanol, methanol, and acetonitrile, preferably absolute ethanol; the poor solvent for crystallization is water; the volume ratio of the good solvent to the poor solvent for crystallization is 1:3 - 1:7, preferably 1:3 - 1:5.

[0040] The mass-volume ratio of compound 1 to the good solvent for crystallization is 1:0.5 - 1:2 g / mL or kg / L, preferably 1:0.8 - 1:1.3 g / mL or kg / L, more preferably 1:0.9 - 1:1.3 g / mL or kg / L.

[0041] The recrystallization: Add a good solvent to the solid obtained by crystallization, heat up to 90 °C, stir under reflux for 10 min to completely dissolve it, pour it into a poor solvent while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3.

[0042] The good solvent for recrystallization is a mixed solvent of at least one selected from isopropanol, ethanol, and methanol and water with a volume ratio of 9:1 to 11:1; the poor solvent for recrystallization is water; the volume ratio of the good solvent to the poor solvent for recrystallization is 1:3 to 1:5.

[0043] The mass-to-volume ratio of Compound 1 to the good solvent for recrystallization is 1:5 to 1:12 g / mL or kg / L.

[0044] In step (2), the contact method of Compound 3 with 10% dilute hydrochloric acid is not particularly limited; the contact method of Compound 4 with 2M sodium hydroxide solution is not particularly limited; the contact method of Compound 5 with calcium acetate hydrate is not particularly limited. This can improve the efficiency of the contact reaction of the above compounds in step (2), accelerate the reaction rate, and further improve the efficiency of preparing Compound 6 by this method.

[0045] The acidic condition of the deprotection reaction is provided by hydrochloric acid, and the pH of the system of the deprotection reaction is 1 to 4, preferably 2 to 3.

[0046] The mass fraction of the hydrochloric acid is 5% to 20%, preferably 8% to 12%. Specifically, the hydrochloric acid can be selected from 10% dilute hydrochloric acid.

[0047] The temperature of the deprotection reaction is 20 °C to 50 °C, preferably 30 °C to 40 °C; the time of the deprotection reaction is 1 to 6 h, preferably 2 to 4.5 h.

[0048] Specifically, for the deprotection reaction: Add Compound 3 to methanol, add hydrochloric acid while stirring, adjust the pH to 1 to 4, and react at a temperature of 20 °C to 50 °C for 1 to 6 h to obtain Compound 4.

[0049] More specifically, for the deprotection reaction: Add Compound 3 to methanol, add hydrochloric acid while stirring, adjust the pH to 2 to 3, and react at a temperature of 30 °C to 40 °C for 2 to 4.5 h to obtain Compound 4.

[0050] The alkaline condition for the salt formation reaction of Compound 4 under alkaline conditions is provided by sodium hydroxide solution, and the pH of the system of the salt formation reaction is 10 to 13, preferably 12 to 13 or 11 to 12.

[0051] The concentration of the sodium hydroxide solution is 1 to 2M, preferably 2M.

[0052] The temperature for the salt formation reaction of the said compound 4 under alkaline conditions is 20°C to 50°C, preferably 30°C to 35°C; the time for the salt formation reaction of compound 4 under alkaline conditions is 0.5 to 2 h, preferably 1.5 to 2 h.

[0053] Specifically, for the salt formation reaction of the said compound 4 under alkaline conditions: while stirring, add sodium hydroxide solution to the reaction solution obtained from the deprotection reaction, adjust the pH to 10 - 13, and react at a temperature of 20°C to 50°C for 0.5 to 2 h to obtain compound 5.

[0054] More specifically, for the salt formation reaction of the said compound 4 under alkaline conditions: while stirring, add sodium hydroxide solution to the reaction solution obtained from the deprotection reaction, adjust the pH to 12 - 13 or 11 - 12, and react at a temperature of 30°C to 35°C for 1.5 to 2 h to obtain compound 5.

[0055] The molar ratio of compound 3 to calcium acetate hydrate is 1:0.5 to 1:0.8.

[0056] The temperature for the salt formation reaction of the said compound 5 with calcium acetate hydrate is 20°C to 50°C, preferably 30°C to 35°C; the time for the salt formation reaction is 0.5 to 2 h, preferably 1 to 2 h.

[0057] Specifically, for the salt formation reaction of the said compound 5 with calcium acetate hydrate: while stirring, add calcium acetate hydrate to the reaction solution obtained from the previous salt formation reaction, and react at a temperature of 20°C to 50°C for 0.5 to 2 h.

[0058] More specifically, for the salt formation reaction of the said compound 5 with calcium acetate hydrate: while stirring, add calcium acetate hydrate to the reaction solution obtained from the previous salt formation reaction, and react at a temperature of 30°C to 35°C for 1 to 2 h.

[0059] The refining process is as follows: add water for crystallization according to the volume ratio of the reaction solution (calculated as methanol) to water of 1:2 to 1:5, filter, and recrystallize the filter cake using an ethyl acetate / petroleum ether system, then filter and dry to obtain compound 5 to improve the purity of the product.

[0060] Preferably, the volume ratio of the reaction solution to water is 1:2.5 to 1:4.

[0061] Preferably, the volume ratio of the ethyl acetate / petroleum ether system to water is 1:1.5 to 1:4, preferably 1:1.6 to 1:3.6.

[0062] Preferably, the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate / petroleum ether system is 1:3 to 1:4.

[0063] Preferably, the temperature for crystallization is room temperature.

[0064] Preferably, the recrystallization temperature is room temperature.

[0065] In this article, "contact" is broadly defined as the form in which at least two chemical substances undergo a chemical reaction under feasible conditions. For example, the mixing of multiple chemical substances in a solvent should be regarded as contact. As needed, various reaction conditions such as generalized stirring and mixing during heating should be regarded as contact.

[0066] Compared with the prior art, the present invention has at least the following beneficial effects:

[0067] The present invention uses commercially available raw materials and synthesizes atorvastatin calcium through the Paal-Knorr reaction, deprotection reaction, and salt formation reaction, with a total of 2 steps.

[0068] The first step is the Paal-Knorr reaction. The reagents are cheap. By using a water separator, the time of this step is shortened by more than 10 hours. The yield of compound 3 is high, at least reaching about 85%, and can reach up to about 98% at most. The post-treatment is simple.

[0069] Compound 3 is made into compound 4 through a deprotection reaction. Compound 4 and sodium hydroxide are made into compound 5 through a salt formation reaction. Compound 5 and calcium acetate hydrate are made into atorvastatin calcium through a salt formation reaction. The reaction reagents are cheap, the conditions are mild, and the post-treatment is simple. The yield of atorvastatin calcium is not less than 92%.

[0070] Generally speaking, the present invention simplifies the synthesis steps. Each step of the reaction has a high yield. The post-treatment uses pulping purification, which is simple, cheap, and the product has a high yield and purity. The total yield can reach at least about 85% at the lowest. The route of the present invention is green and provides a feasible route for the production in a GMP workshop. Brief Description of the Drawings

[0071] Figure 1 is the nuclear magnetic resonance hydrogen spectrum ( 1 H NMR) spectrum of compound 6.

[0072] Figure 2 is the nuclear magnetic resonance carbon spectrum ( 13 C NMR) spectrum of compound 6. Detailed Description of the Embodiments

[0073] The embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as a limitation to the present invention. For those not specified in the embodiments regarding specific technologies or conditions, they shall be carried out according to the technologies or conditions described in the literature in this field or the product specifications. For reagents or instruments without indicating the manufacturer, they can all be obtained through commercially available conventional products.

[0074] Examples 1 - 8

[0075] Synthesis of Compound 3

[0076]

[0077] Add Compound 1 (10 g, 0.024 mol), Compound 2, and pivalic acid to a 250 mL round-bottom flask containing a mixed solvent of 120 mL of n-hexane, tetrahydrofuran (or 2-methyltetrahydrofuran) and toluene in different volume ratios. After the addition is complete, install a water separator, heat up to a certain temperature and reflux with stirring for a certain period of time. During the reaction, separate the water generated by the reaction with the water separator; after the reaction is complete, remove the mixed solvent, add anhydrous ethanol (10 mL) to the remaining oily substance, heat up to 90 °C, stir for 10 min under reflux, pour it into 40 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it. Add a mixed solvent of isopropanol and water with a volume ratio of 10:1 (100 mL), heat up to 90 °C, stir for 10 min under reflux to completely dissolve it, pour it into 400 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3.

[0078] Table 1. Effects of Different Factors on the Yield of Compound 3

[0079]

[0080]

[0081] Examples 9 - 12

[0082] Add Compound 1 (10 g, 0.024 mol), Compound 2 (8.50 g, 0.031 mol), and pivalic acid (2.45 g, 0.024 mol) to a 250 mL round-bottom flask containing n-hexane (80 mL), tetrahydrofuran (20 mL), and toluene (20 mL). After the addition is complete, install a water separator, heat up to 90 °C and reflux with stirring for 24 h. During the reaction, separate the water generated by the reaction with the water separator; after the reaction is complete, remove the mixed solvent, add anhydrous ethanol (good solvent) to the remaining oily substance, heat up to 90 °C, stir for 10 min under reflux, pour it into water (poor solvent) while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it. Add a mixed solvent of isopropanol and water with a volume ratio of 10:1 (100 mL), heat up to 90 °C, stir for 10 min under reflux to completely dissolve it, pour it into 400 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3.

[0083] Table 2. Effects of the Dosages of Good Solvent and Poor Solvent on the Crystallization of Compound 3

[0084]

[0085] Example 14

[0086] To a 500 mL round-bottom flask containing a mixed solvent of n-hexane (160 mL), tetrahydrofuran (40 mL), and toluene (40 mL), add Compound 1 (23.44 g, 0.056 mol), Compound 2 (19.95 g, 0.073 mol), and pivalic acid (5.87 g, 0.057 mol). After addition, install a water separator, heat to 100 °C, and reflux and stir the reaction for 25 h. During the reaction, separate the water generated by the reaction using the water separator; after the reaction is complete, remove the mixed solvent. Add anhydrous ethanol (40 mL) to the remaining oily substance, heat to 90 °C, stir under reflux for 10 min, pour it into 160 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it. Add a mixed solvent of isopropanol and water with a volume ratio of 10:1 (185 mL), heat to 90 °C, stir under reflux for 10 min to completely dissolve it, pour it into 740 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3 (33.83 g), with a yield of 92.32%.

[0087] Example 15

[0088] To a 500 mL round-bottom flask containing a mixed solvent of n-hexane (160 mL), tetrahydrofuran (40 mL), and toluene (40 mL), add Compound 1 (27.81 g, 0.067 mol), Compound 2 (23.77 g, 0.087 mol), and pivalic acid (7.11 g, 0.070 mol). After addition, install a water separator, heat to 90 °C, and reflux and stir the reaction for 28 h. During the reaction, separate the water generated by the reaction using the water separator; after the reaction is complete, remove the mixed solvent. Add anhydrous ethanol (40 mL) to the remaining oily substance, heat to 90 °C, stir under reflux for 10 min, pour it into 160 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it. Add a mixed solvent of isopropanol and water with a volume ratio of 10:1 (200 mL), heat to 90 °C, stir under reflux for 10 min to completely dissolve it, pour it into 800 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3 (42.97 g), with a yield of 98.01%.

[0089] Example 16

[0090] Into a 1000 mL round-bottom flask containing a mixed solvent of n-hexane (300 mL), tetrahydrofuran (60 mL), and toluene (60 mL), add Compound 1 (34.19 g, 0.082 mol), Compound 2 (28.95 g, 0.106 mol), and pivalic acid (8.34 g, 0.082 mol). After the addition is complete, install a water separator, heat to 95 °C, and reflux and stir the reaction for 30 h. During the reaction, separate the water generated by the reaction using the water separator; after the reaction is complete, remove the mixed solvent, add absolute ethanol (40 mL) to the remaining oily substance, heat to 90 °C, stir under reflux for 10 min, pour it into 160 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it, add a mixed solvent (215 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir under reflux for 10 min to completely dissolve it, pour it into 860 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3 (50.73 g) with a yield of 95.70%.

[0091] Example 17

[0092] Into a 1000 mL round-bottom flask containing a mixed solvent of n-hexane (400 mL), tetrahydrofuran (100 mL), and toluene (100 mL), add Compound 1 (40.14 g, 0.096 mol), Compound 2 (34.15 g, 0.125 mol), and pivalic acid (10.20 g, 0.100 mol). After the addition is complete, install a water separator, heat to 90 °C, and reflux and stir the reaction for 25 h. During the reaction, separate the water generated by the reaction using the water separator; after the reaction is complete, remove the mixed solvent, add absolute ethanol (45 mL) to the remaining oily substance, heat to 90 °C, stir under reflux for 10 min, pour it into 160 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it, add a mixed solvent (350 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir under reflux for 10 min to completely dissolve it, pour it into 1400 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3 (61.02 g) with a yield of 97.14%.

[0093] Example 18

[0094] To a 1000 mL round-bottom flask containing a mixed solvent of n-hexane (500 mL), tetrahydrofuran (100 mL), and toluene (100 mL), add Compound 1 (52.27 g, 0.125 mol), Compound 2 (45.51 g, 0.167 mol), and pivalic acid (12.86 g, 0.126 mol). After addition, install a water separator, heat to 90 °C, and reflux and stir the reaction for 22 h. During the reaction, separate the water generated by the reaction using the water separator; after the reaction is complete, remove the mixed solvent, add anhydrous ethanol (50 mL) to the remaining oily substance, heat to 90 °C, stir under reflux for 10 min, pour it into 200 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it, add a mixed solvent (350 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir under reflux for 10 min to completely dissolve it, pour it into 1400 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3 (78.57 g), with a yield of 96.06%.

[0095] Example 19

[0096] To a 2000 mL round-bottom flask containing a mixed solvent of n-hexane (600 mL), tetrahydrofuran (180 mL), and toluene (180 mL), add Compound 1 (60.14 g, 0.144 mol), Compound 2 (47.20 g, 0.173 mol), and pivalic acid (14.29 g, 0.140 mol). After addition, install a water separator, heat to 90 °C, and reflux and stir the reaction for 30 h. During the reaction, separate the water generated by the reaction using the water separator; after the reaction is complete, remove the mixed solvent, add anhydrous ethanol (60 mL) to the remaining oily substance, heat to 90 °C, stir under reflux for 10 min, pour it into 240 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it, add a mixed solvent (480 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir under reflux for 10 min to completely dissolve it, pour it into 2000 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3 (84.99 g), with a yield of 90.20%.

[0097] Example 20

[0098] To a 2000 mL round-bottom flask containing a mixed solvent of n-hexane (660 mL), tetrahydrofuran (220 mL), and toluene (220 mL), add Compound 1 (74.37 g, 0.178 mol), Compound 2 (60.33 g, 0.221 mol), and pivalic acid (18.37 g, 0.180 mol). After the addition is complete, install a water separator and heat to 90 °C for reflux stirring reaction for 30 h. During the reaction, separate the water generated by the reaction using the water separator; after the reaction is complete, remove the mixed solvent. Add absolute ethanol (60 mL) to the remaining oily substance, heat to 90 °C, stir for 10 min under reflux, pour it into 240 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it. Add a mixed solvent (480 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir for 10 min under reflux to completely dissolve it, pour it into 2000 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3 (108.94 g), with a yield of 93.53%.

[0099] Example 21

[0100] To a 1000 mL round-bottom flask containing a mixed solvent of n-hexane (400 mL), tetrahydrofuran (100 mL), and toluene (100 mL), add Compound 1 (15.05 g, 0.036 mol), Compound 2 (12.82 g, 0.047 mol), and pivalic acid (3.68 g, 0.036 mol). After the addition is complete, install a water separator and heat to 90 °C for reflux stirring reaction for 22 h. After the reaction is complete, separate the water generated by the reaction using the water separator during the reaction process; remove the mixed solvent. Add absolute ethanol (30 mL) to the remaining oily substance, heat to 90 °C, stir for 10 min under reflux, pour it into 200 mL of water while it is hot, crystallize at room temperature, filter after the crystals have completely precipitated, wash the filter cake with water and dry it. Add a mixed solvent (200 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir for 10 min under reflux to completely dissolve it, pour it into 800 mL of water while it is hot, crystallize at room temperature, filter, wash the filter cake with water and dry it to obtain Compound 3 (23.30 g), with a yield of 98.91%.

[0101] Example 22

[0102] Synthesis of Compound 6

[0103]

[0104] Compound 3 (10.29 g, 0.016 mol) was added to methanol (100 mL). While stirring, 10% dilute hydrochloric acid was added until the pH reached 2.0. The temperature was maintained at 35 °C and the reaction was carried out for 3 h to obtain compound 4. 2M sodium hydroxide solution was added to the reaction solution to adjust the pH to 13. The temperature was maintained at 35 °C and the reaction was carried out for 2 h to obtain compound 5. Calcium acetate monohydrate (1.94 g, 0.011 mol) was added to the above reaction solution while stirring. The temperature was maintained at 30 °C and the reaction was carried out for 30 min to obtain compound 6. After the reaction was completed, purification was carried out: at room temperature, water (400 mL) was added to the reaction solution for crystallization. After the crystallization was completed, filtration was carried out. The filter cake was washed with water and dried. Ethyl acetate (50 mL) was added and after sufficient stirring, petroleum ether (200 mL) was added. Pulping purification was carried out at room temperature, followed by filtration and drying to obtain a solid, which was compound 6 (8.87 g), with a yield of 93.28% and an HPLC purity of 95.8%.

[0105] 1 H NMR (600 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.27 - 7.16 (m, 6H), 7.08 (d, J = 4.5 Hz, 4H), 7.03 - 6.96 (m, 2H), 6.22 (s, 1H), 4.74 (s, 1H), 4.11 (s, 1H), 4.03 - 3.91 (m, 1H), 3.82 - 3.71 (m, 2H), 3.54 (d, J = 4.3 Hz, 1H), 3.18 (s, 1H), 2.06 (d, J = 15.5 Hz, 1H), 1.94 - 1.84 (m, 1H), 1.61 (s, 1H), 1.52 (s, 1H), 1.38 (d, J = 7.0 Hz, 6H), 1.26 - 1.21 (m, 1H).

[0106] 13 C NMR (151 MHz, DMSO) δ 178.25, 166.65, 162.85, 161.23, 139.87, 136.47, 135.38, 133.86, 133.81, 129.63, 129.21, 129.18, 128.89, 128.08, 127.79, 125.84, 123.46, 121.06, 119.91, 117.93, 115.89, 115.74, 66.76, 66.70, 49.07, 44.35, 44.20, 41.34, 26.12, 22.77, 22.74.

[0107] Example 23

[0108] Compound 3 (18.77 g, 0.029 mol) was added to methanol (240 mL). While stirring, 10% dilute hydrochloric acid was added until the pH reached 2.0, and the temperature was maintained at 30 °C. The reaction was carried out for 4.5 h to obtain Compound 4. 2M sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, and the temperature was maintained at 35 °C. The reaction was carried out for 2 h to obtain Compound 5. Calcium acetate monohydrate (2.99 g, 0.017 mol) was added to the above reaction solution while stirring, and the temperature was maintained at 25 °C. The reaction was carried out for 45 min to obtain Compound 6. After the reaction was completed, purification was carried out: at room temperature, water (780 mL) was added to the reaction solution for crystallization. After the crystallization was completed, filtration was carried out. The filter cake was washed with water and dried. Ethyl acetate (75 mL) was added, and after sufficient stirring, petroleum ether (300 mL) was added. Pulp purification was carried out at room temperature, and filtration and drying were carried out to obtain a solid, which was Compound 6 (16.89 g), with a yield of 97.37% and an HPLC purity of 96.37%.

[0109] Example 24

[0110] Compound 3 (25.17 g, 0.038 mol) was added to methanol (300 mL). While stirring, 10% dilute hydrochloric acid was added until the pH reached 2.0, and the temperature was maintained at 35 °C. The reaction was carried out for 3 h to obtain Compound 4. 2M sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, and the temperature was maintained at 35 °C. The reaction was carried out for 2 h to obtain Compound 5. Calcium acetate monohydrate (4.40 g, 0.025 mol) was added to the above reaction solution while stirring, and the temperature was maintained at 25 °C. The reaction was carried out for 45 min to obtain Compound 6. After the reaction was completed, purification was carried out: at room temperature, water (900 mL) was added to the reaction solution for crystallization. After the crystallization was completed, filtration was carried out. The filter cake was washed with water and dried. Ethyl acetate (75 mL) was added, and after sufficient stirring, petroleum ether (300 mL) was added. Pulp purification was carried out at room temperature, and filtration and drying were carried out to obtain a solid, which was Compound 6 (22.37 g), with a yield of 96.17% and an HPLC purity of 92.19%.

[0111] Example 25

[0112] To methanol (380 mL), compound 3 (33.84 g, 0.052 mol) was added. While stirring, 10% dilute hydrochloric acid was added until the pH reached 2.0. The temperature was maintained at 35 °C and the reaction was carried out for 3.5 h to obtain compound 4. To the reaction solution, 2 M sodium hydroxide solution was added to adjust the pH to 12. The temperature was maintained at 35 °C and the reaction was carried out for 2 h to obtain compound 5. While stirring, calcium acetate monohydrate (5.82 g, 0.033 mol) was added to the above reaction solution. The temperature was maintained at 25 °C and the reaction was carried out for 45 min to obtain compound 6. After the reaction was completed, purification was carried out: at room temperature, water (1000 mL) was added to the reaction solution for crystallization. After crystallization was completed, filtration was carried out. The filter cake was washed with water and dried. Ethyl acetate (100 mL) was added. After sufficient stirring, petroleum ether (400 mL) was added. Pulping purification was carried out at room temperature. Filtration and drying gave a solid, which was compound 6 (29.76 g), with a yield of 95.16% and an HPLC purity of 96.80%.

[0113] Example 26

[0114] To methanol (380 mL), compound 3 (49.31 g, 0.075 mol) was added. While stirring, 10% dilute hydrochloric acid was added until the pH reached 2.0. The temperature was maintained at 40 °C and the reaction was carried out for 3.5 h to obtain compound 4. To the reaction solution, 2 M sodium hydroxide solution was added to adjust the pH to 13. The temperature was maintained at 35 °C and the reaction was carried out for 2 h to obtain compound 5. While stirring, calcium acetate monohydrate (7.74 g, 0.044 mol) was added to the above reaction solution. The temperature was maintained at 25 °C and the reaction was carried out for 45 min to obtain compound 6. After the reaction was completed, purification was carried out: at room temperature, water (1300 mL) was added to the reaction solution for crystallization. After crystallization was completed, filtration was carried out. The filter cake was washed with water and dried. Ethyl acetate (150 mL) was added. After sufficient stirring, petroleum ether (600 mL) was added. Pulping purification was carried out at room temperature. Filtration and drying gave a solid, which was compound 6 (44.50 g), with a yield of 97.65% and an HPLC purity of 97.64%.

[0115] Comparative Example 9

[0116] To a 1000 mL round-bottom flask containing a mixed solvent of n-hexane (400 mL), tetrahydrofuran (100 mL), and toluene (100 mL), add Compound 1 (37.64 g, 0.090 mol), Compound 2 (29.61 g, 0.108 mol), and pivalic acid (9.19 g, 0.090 mol). After the addition is complete, heat to 90 °C and reflux with stirring for 36 h. After the reaction is complete, remove the mixed solvent. Add anhydrous ethanol (30 mL) to the remaining oily substance, heat to 90 °C, stir for 10 min, pour into 200 mL of water, filter after the crystals have completely precipitated, wash the filter cake with water and dry it. Add a mixed solvent (300 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir for 10 min, pour into 1200 mL of water after complete dissolution, filter, wash the filter cake with water and dry it to obtain Compound 3 (36.09 g), with a yield of 61.28%.

[0117] Comparative Example 10

[0118] To a 1000 mL round-bottom flask containing a mixed solvent of n-hexane (400 mL), tetrahydrofuran (100 mL), and toluene (100 mL), add Compound 1 (38.99 g, 0.093 mol), Compound 2 (30.15 g, 0.110 mol), and pivalic acid (9.25 g, 0.091 mol). After the addition is complete, install a water separator, heat to 120 °C and reflux with stirring for 30 h, and separate the water generated during the reaction with the water separator during the reaction. After the reaction is complete, remove the mixed solvent. Add anhydrous ethanol (30 mL) to the remaining oily substance, heat to 90 °C, stir for 10 min under reflux, pour into 200 mL of water, filter after the crystals have completely precipitated, wash the filter cake with water and dry it. Add a mixed solvent (300 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir for 10 min under reflux, pour into 1200 mL of water after complete dissolution, filter, wash the filter cake with water and dry it to obtain Compound 3 (46.41 g), with a yield of 76.26%.

[0119] Comparative Example 11

[0120] To a 1000 mL round-bottom flask containing a mixed solvent of n-hexane (400 mL), tetrahydrofuran (100 mL), and toluene (100 mL), add Compound 1 (34.60 g, 0.083 mol), Compound 2 (27.17 g, 0.099 mol), and pivalic acid (8.68 g, 0.085 mol). After the addition is complete, install a water separator and heat to 120 °C for reflux stirring for 30 h. During the reaction, the water generated by the reaction is separated by the water separator; after the reaction is complete, remove the mixed solvent, add anhydrous ethanol (300 mL) to the remaining oily substance, heat to 90 °C, stir for 10 min under reflux, pour into 2000 mL of water, filter after the crystals have completely precipitated, wash the filter cake with water and dry it, add a mixed solvent (300 mL) with a volume ratio of isopropanol to water of 10:1, heat to 90 °C, stir for 10 min under reflux, filter after completely dissolving, wash the filter cake with water and dry it to obtain Compound 3 (27.51 g), with a yield of 50.65%.

[0121] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined and combined in different embodiments or examples and the features of different embodiments or examples described in any one or more embodiments or examples.

[0122] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A synthetic process for atorvastatin calcium, characterized in that: The synthetic route is as follows: It includes: Step (1): Using compound 1 and compound 2 as raw materials, with an acid as the catalyst, under the condition of heating under reflux, compound 1 and compound 2 carry out the Paal-Knorr reaction, and the water generated in the reaction is separated by a water separator during the reaction; after the reaction is completed, through crystallization and recrystallization in sequence, compound 3 is obtained; Step (2): Using methanol as the reaction solvent, compound 3 undergoes a deprotection reaction under acidic conditions to obtain compound 4; using methanol as the reaction solvent, compound 4 undergoes a salt formation reaction under basic conditions to obtain compound 5; using methanol as the reaction solvent, compound 5 undergoes a salt formation reaction with calcium acetate monohydrate to obtain atorvastatin calcium, and then it is refined to obtain the atorvastatin calcium product.

2. The synthetic process of atorvastatin calcium according to claim 1, characterized in that: In step (1), the temperature of the Paal-Knorr reaction is 60°C to 110°C, preferably 75°C to 105°C, more preferably 80°C to 100°C, and most preferably 90°C to 100°C; the time of the Paal-Knorr reaction is 18 to 30 hours, preferably 20 to 24 hours.

3. The synthetic process of atorvastatin calcium according to claim 1, characterized in that: In step (1), the reaction solvent is one or a mixture of n-hexane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, preferably a mixed solvent with a volume ratio of n-hexane, tetrahydrofuran and toluene of (3 - 6):(0.8 - 1.2):1 or a mixed solvent with a volume ratio of n-hexane, 2-methyltetrahydrofuran and toluene of (3 - 6):(0.8 - 1.2):1, more preferably a volume ratio of n-hexane, tetrahydrofuran and toluene of (3.5 - 4.7):(0.85 - 1.15):

1.

4. The synthetic process of atorvastatin calcium according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to compound 2 is 1:1.0 to 1:1.5, preferably 1:1.2 to 1:1.

35.

5. The synthesis process of atorvastatin calcium according to claim 1, characterized in that: In step (1), the catalyst is at least one of pivalic acid, acetic acid, dilute hydrochloric acid, dilute sulfuric acid, formic acid, acetic acid, trimethylacetic acid, tartaric acid, citric acid, preferably pivalic acid; the molar ratio of compound 1 to the catalyst is 1:0.6 to 1:1.3, preferably 1:0.8 to 1:1.3, more preferably 1:0.85 to 1:1.

05.

6. According to the synthesis process of atorvastatin calcium in claim 1, it is characterized in that: In step (1), the good solvent for crystallization is at least one of ethanol, methanol, acetonitrile, preferably ethanol; the poor solvent for crystallization is water; the volume ratio of the good solvent and the poor solvent for crystallization is 1:3 to 1:7, preferably 1:3 to 1:5; the mass-volume ratio of compound 1 to the good solvent for crystallization is 1:0.5 to 1:2 g / mL or kg / L, preferably 1:0.8 to 1:1.3 g / mL or kg / L, more preferably 1:0.9 to 1:1.3 g / mL or kg / L; The good solvent for recrystallization is a mixed solvent with a volume ratio of at least one selected from isopropanol, ethanol, methanol and water of 9:1 to 11:1; the poor solvent for recrystallization is water; the volume ratio of the good solvent and the poor solvent for recrystallization is 1:3 to 1:5; the mass-volume ratio of compound 1 to the good solvent for recrystallization is 1:5 to 1:12 g / mL or kg / L.

7. The synthetic process of atorvastatin calcium according to claim 1, characterized in that: In step (2), the acidic condition for the deprotection reaction is provided by hydrochloric acid. The pH of the system for the deprotection reaction is 1 - 4, preferably 2 - 3; the mass fraction of the hydrochloric acid is 5% - 20%, preferably 8% - 12%; the temperature of the deprotection reaction is 20°C - 50°C, preferably 30°C - 40°C; the time of the deprotection reaction is 1 - 6 h, preferably 2 - 4.5 h.

8. According to the synthesis process of atorvastatin calcium in claim 1, it is characterized in that: In step (2), the basic condition for the salt formation reaction is provided by sodium hydroxide solution. The pH of the system for the salt formation reaction is 10 - 13, preferably 12 - 13 or 11 - 12; the temperature for the salt formation reaction of compound 4 under basic condition is 20°C - 50°C, preferably 30°C - 35°C; the time for the salt formation reaction of compound 4 under basic condition is 0.5 - 2 h, preferably 1.5 - 2 h.

9. According to the synthetic process of atorvastatin calcium in claim 1, it is characterized in that: In step (2), the molar ratio of compound 3 to calcium acetate monohydrate is 1:0.5 - 1:0.8; the temperature for the salt formation reaction of compound 5 with calcium acetate monohydrate is 20°C - 50°C, preferably 30°C - 35°C; the time for the salt formation reaction is 0.5 - 2 h, preferably 1 - 2 h.

10. According to the synthetic process of atorvastatin calcium as claimed in claim 1, characterized in that: In step (2), the purification is as follows: based on the amount of the reaction solution in terms of methanol, water is added for crystallization according to the volume ratio of the reaction solution to water being 1:2 - 1:5, followed by filtration. The filter cake is recrystallized using an ethyl acetate / petroleum ether system, and then filtered and dried to obtain compound 5; wherein, the volume ratio of the ethyl acetate / petroleum ether system to water is 1:1.5 - 1:4, preferably 1:1.6 - 1:3.6; the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate / petroleum ether system is 1:3 - 1:4.

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