Novel synthesis process of atorvastatin intermediate

Abstract

The invention discloses a novel synthesis process of an atorvastatin intermediate. A compound III is prepared from a compound I and a compound II; dissolving the compound III in an organic solvent, adding a reducing agent, carrying out a heating reaction for 4-6 h, adding diluted hydrochloric acid after the reaction is finished, carrying out a neutralization reaction until the product is neutral, and separating the product to obtain a compound IV. The method has the beneficial effects that the process steps are few, the used chemical reagent raw materials are easy to obtain, the price is low, the process is environment-friendly, the operation is simple and convenient, the risk is low, and the method is a green synthesis process suitable for industrial production. According to the process provided by the invention, the synthesis steps of ATS-8 and ATS-9 are effectively shortened, the total yield of synthesis of atorvastatin calcium is improved, and the production cost is effectively reduced; the method is good in product selectivity, high in yield, less in waste, convenient in product post-treatment and suitable for industrial expanded-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field related to the synthesis of pharmaceutical intermediates, in particular to a new synthesis process of an atorvastatin intermediate. Background Art

[0002] Atorvastatin calcium (Atorvastain calium), chemically named (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxyheptanoate calcium, is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Launched by Pfizer in the United States in 1997, it is a third-generation statin lipid-regulating drug and is widely used in clinical practice to prevent and treat hypercholesterolemia. This effect works 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 anti-inflammatory effects in atherosclerotic plaques. Due to its high efficiency and safety, it has always been one of the best-selling drugs for the treatment of hypercholesterolemia.

[0003] Due to the huge market prospects of Atorvastatin Calcium generic drugs, global scientific research institutions and pharmaceutical companies have also developed a lot of processes for it. Although the existing technology has reported a lot on the synthesis of Atorvastatin Calcium, the classic Paal-Knorr pyrrole synthesis method is still the mainstream synthesis method and the mainstream production process suitable for industrial production.

[0004] The original research company Warner-Lambert (now part of Pfizer) first reported the compound formula of atorvastatin calcium and its synthesis process in patent US4681893 in 1987, and subsequently disclosed atorvastatin sodium salt, calcium salt and their synthesis methods in patents US5273995 and WO9416693 in 1993. In 1994, the patent US5298627 submitted by Warner-Lambert Company first disclosed the Paal-Knorr pyrrole method for the synthesis of atorvastatin calcium, and for the first time proposed protection requirements for the key intermediate ATS-9 and its synthesis method in the claims. The Paal-Knorr pyrrole method of atorvastatin calcium reported in the US5298627 patent also became the prototype of the later industrial production process. In the later original research of multiple processes and compound patent layouts, the key intermediates and synthesis steps in the main process were gradually optimized and adjusted, forming the current mainstream industrial production process of atorvastatin calcium, as shown in Scheme 1 below. In the industrial process of synthesizing atorvastatin calcium by the Paal-Knorr pyrrole synthesis method, two key intermediates ATS-9 and B-4 are mainly involved. Among them, the synthesis of the side chain ATS-9 has attracted widespread attention from the chemical academic and process circles due to the high technical difficulty, low yield, high waste, high toxicity of the chemical reagents used, high price, harsh reaction conditions, and high process safety risks. There are many literature reports on its synthesis method.

[0005] The synthesis process of ATS-9 disclosed in patent WO9932434 is the mainstream production process in the industry, as shown in Scheme 2 below. In this industrial process, there are still a large number of defects, which increase the cost and EHS risk of industrial production. For example, sodium cyanide (NaCN), a highly toxic substance in the field, is used in the process; and expensive metal lithium reagent lithium diisopropylamine (LDA) is used in the process. For technicians in this field, the industrial preparation and use of LDA often greatly increase the cost and EHS risk of industrial production. Liquid nitrogen is required for deep cooling during the preparation of LDA. The preparation of liquid nitrogen consumes a lot of electricity and is a high-energy-consuming raw material. The vaporization temperature of liquid nitrogen is extremely low after use, and it is difficult to recover, resulting in low cold utilization efficiency and high energy consumption; the use of expensive metal lithium as a raw material in the preparation of the reagent greatly increases the process cost; and there are many wastes, including wastewater containing a large amount of inorganic salts and organic salts with complex pollution factors such as diisopropylamine hydrochloride, lithium bromide, and lithium chloride, which increases the treatment cost of the three wastes. LDA also has a high EHS risk during production and use. The reagent releases a lot of heat when it comes into contact with water and is flammable. Therefore, the reaction system must be anhydrous and oxygen-free during industrial production, which increases the difficulty of industrial operation. Secondly, the reaction in which LDA participates generally releases heat violently, and liquid nitrogen is also required for deep cooling, which increases the cost of industrial production. The synthesis route is as follows:

[0006] Route 1

[0007]

[0008] Patent CN107602527 and Patent CN107778279 both disclose the use of rosuvastatin calcium intermediate D-5 as a starting material to synthesize ATS-9, as shown in Scheme 3 below. In the reaction of D-5 synthesizing ATS-8, the temperature is required to be 100°C and the reaction time is 30 hours. In addition, this method requires the use of NaCN in the synthesis process, and also requires the use of reagents such as hydrocyanic acid as a reaction medium. For those skilled in the art, hydrocyanic acid, cyanates, etc. are all highly toxic substances. Moreover, the use of hydrocyanic acid and cyanates as reaction raw materials is not only inconsistent with the current national environmental protection trend, but also difficult to purchase. This further increases the preparation cost of compound ATS-9, thereby further increasing the preparation cost of atorvastatin calcium raw materials. The synthesis route is as follows:

[0009] Route 2

[0010]

[0011] Patent CN109503542B discloses an atorvastatin calcium intermediate and its preparation method and application. The intermediate compound ATS-9 is obtained by first synthesizing a dicarbonyl compound and then selectively reducing it. The reaction steps are many, and the reaction yield is affected by many reaction steps. The synthesis route is as follows:

[0012] Route 3

[0013] Summary of the invention

[0014] In view of the above-mentioned shortcomings, the present invention aims to provide a new process for synthesizing an atorvastatin intermediate according to the reaction route of route three, and obtain a new process for synthesizing an atorvastatin intermediate by reducing the reaction steps, optimizing the reaction conditions, and improving the process steps.

[0015] The specific steps are as follows:

[0016] A new process for synthesizing an atorvastatin intermediate.

[0017]

[0018] In the first step, compound I and compound II are dissolved in an organic solvent, a catalyst is added, and the mixture is reacted at room temperature for 2 to 3 hours. After the reaction is completed, the reaction is quenched and the product is separated to obtain compound III.

[0019] In the second step, the compound is dissolved in an organic solvent, a reducing agent and a catalyst are added, and the reaction is heated for 4 to 6 hours. After the reaction is completed, dilute hydrochloric acid is added to neutralize the reaction until it is neutral, and the product is separated to obtain compound IV.

[0020] Furthermore, the solvent used in the first step reaction is one of carbon tetrachloride, cyclohexane and dichloromethane, preferably dichloromethane.

[0021] Furthermore, the solvent used in the second step is one of tetrahydrofuran and dimethyl ether.

[0022] Furthermore, the catalyst used in the first step is sodium hydride.

[0023] Furthermore, the reducing agent used in the second step reaction is borane, and the catalyst used in the second step reaction is chiral oxazolidinone, whose chemical structure is

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

[0025] Furthermore, the molar ratio of the compound III to the reducing agent in the second step reaction is 1:2.2-2.5, and the amount of the catalyst used in the second step reaction is 1-1.5 eq of the compound II, preferably 1.3 eq.

[0026] Furthermore, the molar ratio of the first step reaction compound I to the catalyst is 1:1.2-2, preferably 1:1.5.

[0027] Furthermore, the heating temperature of the second step reaction is 30-40°C.

[0028] Furthermore, the solvent used in the second step reaction is an anhydrous solvent, and the reaction conditions are reaction under anhydrous conditions.

[0029] The beneficial effects of the present invention are as follows: 1. The process steps of the present invention are few, the chemical reagents and raw materials used are easily available, the price is low, the process environment is friendly, the operation is simple, the risk is low, and it is a green synthesis process suitable for industrial production. 2. The intermediate compound prepared by the process provided by the present invention can be simply converted into ATS-8 and ATS-9, which effectively shortens the synthesis steps of ATS-8 and ATS-9, improves the total yield of atorvastatin calcium synthesis, and effectively reduces the production cost; 3. The product of the present invention is well selected, the yield is high, the waste is small, and the product post-processing is convenient, which is suitable for industrial scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is a schematic diagram of the reaction flow of route 1 of the present invention;

[0031] Figure 2 This is a schematic diagram of the reaction flow of route 2 of the present invention;

[0032] Figure 3 This is a schematic diagram of the reaction flow of route three of the present invention;

[0033] Figure 4 The figure is a schematic diagram of the reaction flow of the route of the present invention. DETAILED DESCRIPTION

[0034] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] Example 1

[0036] In the first step, under nitrogen, 8.3 g (0.1 mol) of compound I and 18.8 g (0.1 mol) of compound II were dissolved in 300 ml of organic solvent dichloromethane, 0.15 mol of sodium hydride as a catalyst was added, 0.1 mol of anhydrous calcium chloride was added, and the mixture was stirred and reacted at room temperature for 2 to 3 hours. After the reaction was completed, anhydrous ethanol was slowly added to quench the reaction, and the solution was neutralized with dilute hydrochloric acid to neutrality, and saturated salt was added to wash 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of toluene to separate the product, and 21.4 g of compound III was obtained, with a yield of 95.1% and a purity of 98.8%;

[0037] In the second step, 22.5 g (0.1 mol) of compound III was dissolved in 200 ml of organic solvent tetrahydrofuran, 0.22 mol of reducing agent borane and 0.13 mol of chiral oxazolidinone were added, and the mixture was slowly heated to 30-40°C and heated for reaction for 4-6 hours. After the reaction was completed, dilute hydrochloric acid was slowly added to quench and neutralize the reaction until it was neutral. 100 ml of toluene was added for extraction, and the extract was washed with saturated brine for 2-3 times. The organic phase was separated, and the solvent was evaporated. The product was recrystallized with 40 ml of acetone to obtain 21.6 g of compound IV with a yield of 94.3% and a purity of 97.8%.

[0038] Example 2

[0039] In the first step, under nitrogen, 0.83g (0.1mol) of compound I and 18.8 (0.1mol) of compound II were dissolved in 300ml of organic solvent dichloromethane, 0.12mol of sodium hydride as a catalyst was added, 0.1mol of anhydrous calcium chloride was added, and the mixture was stirred and reacted at room temperature for 2-3h. After the reaction was completed, anhydrous ethanol was slowly added to quench the reaction, and the solution was neutralized with dilute hydrochloric acid to neutrality, and saturated salt was added to wash 2-3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40ml of toluene to separate the product, and 21.2g of compound III was obtained, with a yield of 94.2% and a purity of 98.5%;

[0040] Example 3

[0041] In the first step, under nitrogen, 0.83g (0.1mol) of compound I and 18.8 (0.1mol) of compound II were dissolved in 300ml of organic solvent dichloromethane, 0.20mol of sodium hydride as a catalyst was added, 0.1mol of anhydrous calcium chloride was added, and the mixture was stirred and reacted at room temperature for 2-3h. After the reaction was completed, anhydrous ethanol was slowly added to quench the reaction, and the solution was neutralized with dilute hydrochloric acid to neutrality, and saturated salt was added to wash 2-3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40ml of toluene to separate the product, and 21.1g of compound III was obtained, with a yield of 93.7% and a purity of 98.6%;

[0042] Example 4

[0043] The first step is to dissolve 0.83g (0.1mol) of compound I and 18.8 (0.1mol) of compound II in 300ml of organic solvent carbon tetrachloride under nitrogen, add 0.15mol of sodium hydride as a catalyst, add 0.1mol of anhydrous calcium chloride, stir and mix, and react at room temperature for 2-3h. After the reaction is completed, slowly add anhydrous ethanol to quench the reaction, neutralize the solution with dilute hydrochloric acid to neutrality, add saturated salt to wash 2-3 times, separate the organic phase, evaporate the solvent, and separate the product by recrystallization with 40ml of toluene to obtain 21.3g of compound III with a yield of 94.7% and a purity of 98.6%.

[0044] Example 5

[0045] In the second step, 22.5 g (0.1 mol) of compound III was dissolved in 200 ml of tetrahydrofuran, an organic solvent, 0.25 mol of reducing agent borane and 0.13 mol of catalyst chiral oxazolidinone were added, and the mixture was slowly heated to 30-40° C. and heated for 4-6 hours. After the reaction was completed, dilute hydrochloric acid was slowly added to quench and neutralize the mixture until it was neutral. 100 ml of toluene was added for extraction, and the extract was washed with saturated brine for 2-3 times. The organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of acetone to obtain 21.4 g of compound IV with a yield of 93.4% and a purity of 97.9%.

[0046] Example 6

[0047] In the second step, 22.5 g (0.1 mol) of compound III was dissolved in 200 ml of organic solvent dimethyl ether, 0.22 mol of reducing agent borane and 0.13 mol of catalyst chiral oxazolidinone were added, and the mixture was slowly heated to 30-40° C. and heated for 4-6 hours. After the reaction was completed, dilute hydrochloric acid was slowly added to quench and neutralize the mixture until it was neutral. 100 ml of toluene was added for extraction, and the extract was washed with saturated brine for 2-3 times. The organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of acetone to obtain 21.0 g of compound IV with a yield of 91.7% and a purity of 97.6%.

[0048] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0049] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A novel process for synthesizing an atorvastatin intermediate, characterized in that The preparation steps are as follows: In the first step, compound I and compound II are dissolved in an organic solvent, a catalyst is added, and the mixture is reacted at room temperature for 2 to 3 hours. After the reaction is completed, the reaction is quenched and the product is separated to obtain compound III. In the second step, compound III is dissolved in an organic solvent, a reducing agent and a catalyst are added, and the reaction is heated for 4 to 6 hours. After the reaction is completed, dilute hydrochloric acid is added to neutralize the reaction until it is neutral, and the product is separated to obtain compound IV.

2. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The solvent used in the first step reaction is one of carbon tetrachloride, cyclohexane and dichloromethane.

3. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The solvent used in the second step is one of tetrahydrofuran and dimethyl ether.

4. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The catalyst used in the first step is sodium hydride.

5. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The reducing agent used in the second step reaction is borane, and the catalyst used in the second step reaction is chiral oxazolidinone, whose chemical structure is 6. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: In the first step reaction, the molar ratio of compound I to compound II is 1:

1.

7. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The molar ratio of the compound III to the reducing agent in the second step reaction is 1:2.2-2.5, and the amount of the catalyst used in the second step reaction is 1-1.5 eq of the compound II.

8. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The molar ratio of the first step reaction compound I to the catalyst is 1:1.2-2.

9. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The heating temperature of the second step reaction is 30-40°C.

10. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The solvent used in the second step reaction is an anhydrous solvent.

Images