Synthesis process of atorvastatin side chain intermediate

Abstract

The invention discloses a synthesis process of an atorvastatin side chain intermediate, which comprises the following synthesis steps: 1, dissolving a compound II in an organic solvent, adding a compound I, adding an alkali reagent, adding a catalyst, heating to react for 2-4 hours, and cooling to room temperature to obtain a mixed solution of a compound III; and 2, slowly introducing hydrogen into the solution of the reaction compound III in the first step, synchronously heating and pressurizing to react for 2-4 hours, and after the reaction is finished, separating a product to obtain a compound V. The preparation method has the beneficial effects that the atorvastatin intermediate A9 is prepared from the rosuvastatin intermediate, so that the synthesis steps of atorvastatin and rosuvastatin are partially combined, the reaction process is more efficient, the efficiency of the whole synthesis route is improved, expensive or scarce raw materials can be saved, and the cost is reduced. By using the existing rosuvastatin intermediate as the starting point, it is possible to avoid the complicated steps required in the conventional synthesis route of the atorvastatin intermediate A9.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of pharmaceutical intermediates, and specifically to a synthesis process of an atorvastatin side chain intermediate. Background Art

[0002] Atorvastatin calcium, chemically named (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxyheptanoic acid calcium, is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. It was launched by Pfizer in 1997 and is the third-generation statin lipid-regulating drug, which is widely used in clinical practice for the prevention and treatment of hypercholesterolemia. This effect is exerted by reducing the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) in patients with dyslipidemia. In addition, atorvastatin calcium also has an anti-inflammatory effect in atherosclerotic plaques. Due to its high efficiency and safety, etc., it has always been one of the best-selling drugs for the treatment of hypercholesterolemia.

[0003] The synthesis process of ATS-9 disclosed in Patent WO9932434 is the mainstream production process in the industrial field at present, as shown in Scheme II below. In this industrial process, there are still a large number of defects, which increase the cost of industrial production and the EHS risk. For example, sodium cyanide (NaCN), a highly toxic substance in this field, is used in this process; lithium diisopropylamide (LDA), an expensive metal lithium reagent, is used in this process. For those skilled in the art, the industrial preparation and use of LDA often greatly increase the cost of industrial production and the EHS risk. During the preparation process of LDA, liquid nitrogen is required for deep cooling, and the preparation of liquid nitrogen consumes a large amount of electric energy and belongs to a high-energy-consuming raw material. After the use of liquid nitrogen, the gasification temperature is extremely low and it is difficult to recover, resulting in low cold energy utilization efficiency and high energy consumption; the use of expensive metal lithium as a raw material in the preparation process of this reagent greatly increases the process cost; and there are a lot of three wastes, including wastewater containing a large number of inorganic salts and organic salt complex pollution factors such as diisopropylamine hydrochloride, lithium bromide, and lithium chloride, increasing the treatment cost of the three wastes. The EHS risk of LDA during production and use is also extremely high. This reagent releases a large amount of heat when encountering water and is flammable, so anhydrous and anaerobic conditions need to be controlled in the industrial production process, increasing the operation difficulty of industrialization; secondly, the reaction participated by LDA generally releases heat violently, and liquid nitrogen also needs to be used for deep cooling, increasing the cost of industrial production. The synthesis route is as follows:

[0004] Route 1

[0005]

[0006] Both Patent CN107602527 and Patent CN107778279 disclose that D-5, an intermediate of rosuvastatin calcium, is used as a starting material to synthesize ATS-9, as shown in Scheme III below. In the reaction of synthesizing ATS-8 from D-5, the temperature is required to be 100 °C and the reaction time is 30 hours. In this method, NaCN needs to be used in the synthesis process, and reagents such as hydrocyanic acid also need to be used as reaction media. For those skilled in the art, hydrocyanic acid, cyanate, etc. are all highly toxic substances. These substances not only pose a great threat to human health but also seriously pollute the environment, and are major EHS risk sources in the industrial production process. Moreover, using hydrocyanic acid and cyanate as reaction raw materials not only does not conform to the current national environmental protection trend but is also difficult to purchase. This further increases the preparation cost of compound ATS-9, and thus further increases the preparation cost of atorvastatin calcium API. The synthesis route is as follows:

[0007] Route Two

[0008]

[0009] Patent CN109503542B discloses an intermediate of atorvastatin calcium, its preparation method and application. By first synthesizing a dicarbonyl compound and then selectively reducing it to obtain the intermediate compound ATS-9, the reaction steps are numerous, and the number of reaction steps affects the reaction yield. The synthesis route is as follows:

[0010] Route Three

[0011] Summary of the Invention

[0012] Aiming at the above deficiencies, the present invention aims to provide a synthesis process for an atorvastatin side-chain intermediate. After the product obtained by trifluoromethylsulfonylation of the side-chain compound intermediate of rosuvastatin undergoes a simple synthesis method, the atorvastatin intermediate compound ATS-9 is obtained. The technical solution of the present invention is as follows:

[0013] A synthesis process for an atorvastatin side-chain intermediate, comprising the following synthesis steps:

[0014]

[0015] First step, dissolve compound II in an organic solvent, add compound I, add a base reagent, add a catalyst, heat and react for 2 - 4 h, cool to room temperature to obtain a mixed solution of compound III;

[0016] Second step, slowly introduce hydrogen into the solution of compound III obtained in the first step reaction, and simultaneously heat and pressurize the reaction for 2 - 4 h. After the reaction is completed, separate the product to obtain compound V.

[0017] Furthermore, the solvent used in the first-step reaction is one of DMF and DMSO, preferably DMF.

[0018] Furthermore, the reaction temperature of the first-step reaction is 120 - 140 °C.

[0019] Furthermore, the reaction temperature of the second-step reaction is 35 - 40 °C.

[0020] Furthermore, the catalyst used in the first step and the second step is Pd / C, and the palladium content in the catalyst is 5 wt%.

[0021] Furthermore, the reaction pressure of the second-step reaction is 2 - 3 atm.

[0022] Furthermore, the base reagent used in the first-step reaction is one of triethylamine, potassium carbonate, and sodium carbonate, preferably triethylamine.

[0023] Furthermore, the dosage of the catalyst used in the first-step reaction is 10 - 15 wt% of Compound II.

[0024] Furthermore, the molar ratio of Compound II to Compound I in the first-step reaction is 1:1.0 - 1.2.

[0025] Furthermore, the dosage of the base reagent in the first-step reaction is 2 - 3 eq of Compound II.

[0026] The beneficial effects of the present invention are as follows: 1. By preparing Atorvastatin Intermediate A9 from Rosuvastatin Intermediate, part of the synthesis steps of Atorvastatin and Rosuvastatin are combined. The use of the intermediate can make the reaction process more efficient, reduce the required reaction steps, and thus improve the efficiency of the overall synthesis route. 2. Rosuvastatin Intermediate derivatives are relatively easy to obtain or manufacture. Using it as the starting material for synthesizing Atorvastatin Intermediate A9 may be able to save expensive or scarce raw materials. In large-scale production, this cost saving is of great significance to manufacturers; 3. By using the existing Rosuvastatin Intermediate derivatives as the starting point, it may be possible to avoid the complex steps required in the traditional synthesis route of Atorvastatin Intermediate A9. 4. Avoid the use of cyanide, reduce reaction toxicity, and lower the difficulty of product post-treatment, which conforms to the concept of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a schematic diagram of the reaction process of Route 1 of the present invention;

[0028] Figure 2 It is a schematic diagram of the reaction process of Route 2 of the present invention;

[0029] Figure 3Schematic diagram of the reaction process of Route 3 of the present invention;

[0030] Figure 4 Schematic diagram of the reaction process of the route of the present invention. Specific embodiments

[0031] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0032] Combined with Figures 1 to 4 Shown as:

[0033] Example 1

[0034] In the first step, 39.2 g (0.1 mol) of compound II was dissolved in 200 ml of the organic solvent DMF, 0.11 mol of compound I was added, 0.2 mol of the base reagent triethylamine was added, 3.92 g of the catalyst Pd / C was added, and the reaction was heated at 120 - 140 °C for 2 - 4 h. After cooling to room temperature, a mixed solution of compound III was obtained;

[0035] In the second step, hydrogen was slowly introduced into the solution of compound III in the first-step reaction, and simultaneously heated at 35 - 40 °C under 2 - 3 atm for 2 - 4 h. After the reaction was completed, dilute hydrochloric acid was added to neutralize the reaction to neutrality, filtered, the solvent was evaporated under reduced pressure, 100 ml of dichloromethane and 100 ml of saturated brine were added for washing 2 - 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of acetone to obtain 25.6 g of compound IV, with a yield of 93.7% and a purity of 98.2%.

[0036] Example 2

[0037] In the first step, 39.2 g (0.1 mol) of compound II was dissolved in 200 ml of the organic solvent DMF, 0.10 mol of compound I was added, 0.2 mol of the base reagent triethylamine was added, 3.92 g of the catalyst Pd / C was added, and the reaction was heated at 120 - 140 °C for 2 - 4 h. After cooling to room temperature, a mixed solution of compound III was obtained;

[0038] Step 2: Slowly introduce hydrogen gas into the solution of Compound III obtained in Step 1, and simultaneously heat the reaction at 35 - 40 °C under 2 - 3 atm for 2 - 4 h. After the reaction is completed, add dilute hydrochloric acid to neutralize the reaction to neutrality, filter, evaporate the solvent under reduced pressure, add 100 ml of dichloromethane and 100 ml of saturated brine to wash 2 - 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of acetone to obtain 25.0 g of Compound IV, with a yield of 93.0% and a purity of 98.0%.

[0039] Example 3

[0040] Step 1: Dissolve 39.2 g (0.1 mol) of Compound II in 200 ml of the organic solvent DMF, add 0.12 mol of Compound I, add 0.2 mol of the base reagent triethylamine, add 3.92 g of the catalyst Pd / C, and heat the reaction at 120 - 140 °C for 2 - 4 h. Cool to room temperature to obtain a mixed solution of Compound III.

[0041] Step 2: Slowly introduce hydrogen gas into the solution of Compound III obtained in Step 1, and simultaneously heat the reaction at 35 - 40 °C under 2 - 3 atm for 2 - 4 h. After the reaction is completed, add dilute hydrochloric acid to neutralize the reaction to neutrality, filter, evaporate the solvent under reduced pressure, add 100 ml of dichloromethane and 100 ml of saturated brine to wash 2 - 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of acetone to obtain 25.5 g of Compound IV, with a yield of 93.4% and a purity of 98.5%.

[0042] Example 4

[0043] Step 1: Dissolve 39.2 g (0.1 mol) of Compound II in 200 ml of the organic solvent DMF, add 0.11 mol of Compound I, add 0.3 mol of the base reagent triethylamine, add 3.92 g of the catalyst Pd / C, and heat the reaction at 120 - 140 °C for 2 - 4 h. Cool to room temperature to obtain a mixed solution of Compound III.

[0044] Step 2: Slowly introduce hydrogen gas into the solution of Compound III obtained in Step 1, and simultaneously heat the reaction at 35 - 40 °C under 2 - 3 atm for 2 - 4 h. After the reaction is completed, add dilute hydrochloric acid to neutralize the reaction to neutrality, filter, evaporate the solvent under reduced pressure, add 100 ml of dichloromethane and 100 ml of saturated brine to wash 2 - 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of acetone to obtain 25.3 g of Compound IV, with a yield of 92.6% and a purity of 98.2%.

[0045] Example 5

[0046] First step: Dissolve 39.2 g (0.1 mol) of Compound II in 200 ml of the organic solvent DMF, add 0.11 mol of Compound I, add 0.2 mol of the base reagent triethylamine, add 5.88 g of the catalyst Pd / C, and heat and react at 120 - 140 °C for 2 - 4 h. Cool to room temperature to obtain a mixed solution of Compound III.

[0047] Second step: Slowly introduce hydrogen gas into the solution of Compound III obtained from the first-step reaction, and simultaneously heat and react at 35 - 40 °C under 2 - 3 atm for 2 - 4 h. After the reaction is completed, add dilute hydrochloric acid to neutralize the reaction to neutrality, filter, evaporate the solvent under reduced pressure, add 100 ml of dichloromethane and 100 ml of saturated brine for washing 2 - 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of acetone to obtain 25.2 g of Compound IV, with a yield of 92.3% and a purity of 98.2%.

[0048] Example 6

[0049] First step: Dissolve 39.2 g (0.1 mol) of Compound II in 200 ml of the organic solvent DMF, add 0.11 mol of Compound I, add 0.2 mol of the base reagent sodium carbonate, add 3.92 g of the catalyst Pd / C, and heat and react at 120 - 140 °C for 2 - 4 h. Cool to room temperature to obtain a mixed solution of Compound III.

[0050] Second step: Slowly introduce hydrogen gas into the solution of Compound III obtained from the first-step reaction, and simultaneously heat and react at 35 - 40 °C under 2 - 3 atm for 2 - 4 h. After the reaction is completed, add dilute hydrochloric acid to neutralize the reaction to neutrality, filter, evaporate the solvent under reduced pressure, add 100 ml of dichloromethane and 100 ml of saturated brine for washing 2 - 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of acetone to obtain 25.0 g of Compound IV, with a yield of 91.5% and a purity of 98.2%.

[0051] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-described exemplary embodiments, and without departing from the spirit or basic characteristics of the present invention, the present invention can be implemented in other specific forms. Therefore, in any regard, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be encompassed within the present invention. Any reference signs in the claims should not be regarded as limiting the claimed rights.

[0052] In addition, it should be understood that although this specification is described in terms of embodiments, not every embodiment contains only an independent technical solution. This narrative manner of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A process for synthesizing an atorvastatin side chain intermediate, characterized in that The synthesis steps include: The first step is to dissolve compound II in an organic solvent, add compound I, add an alkali reagent, add a catalyst, heat and react for 2 to 4 hours, and cool to room temperature to obtain a mixed solution of compound III; In the second step, hydrogen is slowly introduced into the solution of the compound III produced in the first step, and the mixture is heated and pressurized for 2 to 4 hours. After the reaction is completed, the product is separated to obtain compound IV.

2. The process for synthesizing an atorvastatin side chain intermediate according to claim 1, characterized in that: The solvent used in the first step reaction is one of DMF and DMSO.

3. The synthesis process of a side chain intermediate of atorvastatin according to claim 1, characterized in that: The reaction temperature of the first step reaction is 120-140°C.

4. The process for synthesizing a side chain intermediate of atorvastatin according to claim 1, characterized in that: The reaction temperature of the second step reaction is 35-40°C.

5. The process for synthesizing an atorvastatin side chain intermediate according to claim 1, characterized in that: The catalyst used in the first step and the second step is Pd / C, and the palladium content in the catalyst is 5wt%.

6. The process for synthesizing a side chain intermediate of atorvastatin according to claim 1, characterized in that: The second step reaction pressure is 2-3 atm.

7. The process for synthesizing a side chain intermediate of atorvastatin according to claim 1, characterized in that: The alkaline reagent used in the first step reaction is one of triethylamine, potassium carbonate and sodium carbonate.

8. The process for synthesizing a side chain intermediate of atorvastatin according to claim 1, characterized in that: The amount of catalyst used in the first step reaction is 10-15 wt % of compound II.

9. The process for synthesizing a side chain intermediate of atorvastatin according to claim 1, characterized in that: In the first step reaction, the molar ratio of compound II to compound I is 1:1.0-1.

2.

10. The process for synthesizing a side chain intermediate of atorvastatin according to claim 1, characterized in that: The amount of the alkaline reagent used in the first step reaction is 2 to 3 eq of compound II.

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