A process for the synthesis of an atorvastatin intermediate

Abstract

The application discloses a synthesis method of an atorvastatin intermediate. The method comprises the following steps: firstly, using a solidized Brønsted-Lewis acidic ionic liquid as a catalyst, catalyzing a Friedel-Crafts acylation reaction of alpha-chlorobenzene acyl chloride and fluorobenzene, then, under the action of alkali and microwave assistance, performing a condensation reaction of the product and isobutyryl acetanilide, and finally, obtaining the atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide. The method uses the characteristics of a large specific surface area and rich active sites of graphite-like carbon nitride, simultaneously uses the graphite-like carbon nitride as an ionic liquid solid carrier and as a mother nucleus to participate in the preparation process of the ionic liquid, retains the catalytic activity of the ionic liquid, improves the reaction rate and selectivity through simple separation of the catalyst, and has the advantages of low cost, high yield, easy reaction conditions, and improved application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical synthesis technology, specifically relating to a method for synthesizing 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, an intermediate of atorvastatin. Background Technology

[0002] Atastatin calcium is a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, developed in collaboration between Warner-Lambert and Pfizer. It was launched in the UK in 1997 and possesses excellent lipid-lowering capabilities, along with rapid onset and long duration of action, making it widely used clinically. Atastatin calcium is synthesized from 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide as an important intermediate via the Paal-Knorr reaction.

[0003] Currently reported synthetic methods for 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide mainly include the following three reaction routes:

[0004] Route 1: Starting with malonic acid, cyclomalonic acid is first cyclically formed to generate isopropyl malonic acid, then undergoes a condensation reaction with isobutyryl chloride, followed by ring opening with aniline, and then undergoes a Knoevenagel reaction with benzaldehyde and a Stetter reaction with 4-fluorobenzaldehyde to obtain the atorvastatin intermediate.

[0005] Route 2: Starting with 3-methyl-2-butanone, after condensation, it undergoes a substitution reaction with aniline, and then reacts with benzaldehyde and 4-fluorobenzaldehyde to obtain the atorvastatin intermediate.

[0006] Route 3: Starting with phenylacetyl chloride, the product undergoes Friedel-Crafts acylation, bromination, and finally reaction with isobutyrylacetanilide to obtain 2-bromo-1-(4-fluorophenyl)-2-phenylethylone, an important intermediate of atorvastatin.

[0007] Both of the above-mentioned methods, Route 1 and Route 2, resulted in low yields of atorvastatin intermediates due to steric hindrance and competing reactions. Route 3 requires the addition of bromine for bromination, which generates a large amount of hydrogen bromide during the reaction, requiring the consumption of alkali for neutralization and producing a large amount of wastewater. In addition, bromine is highly volatile and corrosive, thus posing certain safety hazards.

[0008] To address this issue, this invention uses α-chlorophenylacetyl chloride as the reactant and designs a two-step reaction to obtain the atorvastatin intermediate. A chlorine reactive group is added to the reactant beforehand to reduce the use of additional reagents in subsequent reactions, thus minimizing environmental pollution and hazard. The chlorine atom at the benzylic position also exhibits reactivity similar to bromine in other methods. Then, under the action of a base, it reacts with isobutyrylacetanilide to obtain the atorvastatin intermediate. Microwave assistance further shortens the reaction time, improves the selectivity of the target product, and significantly increases the reaction yield.

[0009] The first step in the synthesis is the classic Friedel-Crafts acylation reaction. Currently, most Friedel-Crafts acylation reactions use Lewis acids or Brønsted acids as catalysts. Anhydrous AlCl3 is the most commonly used Lewis acid due to its low cost and high activity, making it widely used in Friedel-Crafts acylation reactions. However, it also has several problems, such as generating large amounts of aluminum-containing waste liquid after the reaction and the ease with which anhydrous AlCl3 can complex with the product. Among Brønsted acid catalysts, H2SO4 is the most commonly used, offering high catalytic activity and mild reaction conditions. However, its strong corrosiveness can easily damage pipelines and reactors, placing high demands on production equipment. Furthermore, Friedel-Crafts acylation requires stringent reaction conditions; using H2SO4 as a catalyst can easily generate various byproducts, and the difficulty in recovering H2SO4 itself makes it difficult to meet the requirements of high-end pharmaceutical and chemical processes.

[0010] Ionic liquids, with their high stability, designable structure, recyclability, and low environmental pollution, have gained widespread attention in industrial catalysis. Utilizing the structural designability of ionic liquids, Brønsted-Lewis dual-acid ionic liquids are constructed to fully leverage the high catalytic activity of both Lewis and Brønsted acids and the synergistic effect between the two acids in catalyzing acylation reactions. Simultaneously, the ease of recovery of ionic liquids enables efficient catalyst recycling. However, the high viscosity of ionic liquids makes recycling relatively inconvenient and increases operating costs; therefore, ionic liquid immobilization is a future development direction. Graphitic carbon nitride (C3N4) materials, with their large specific surface area, have been selected as excellent supports due to their wide applications in catalysis, photocatalytic water splitting for hydrogen production, and pollutant degradation. The unique structure of graphitic carbon nitride enables it not only to serve as a support for ionic liquids but also as a nucleus in the preparation of ionic liquids. This ionic liquid, immobilized through chemical bonding, reduces the loss of active components. Its special structure not only preserves the catalytic activity of the ionic liquid but also allows for catalyst separation through simple filtration. The presence of multiple nitrogen atoms in the support structure further enriches the active sites, improves the reaction rate and selectivity, thereby further reducing the synthesis cost of the target product and enhancing its application prospects.

[0011] CN114773221 discloses a method for obtaining 2-chloro-1-(4-fluorophenyl)-2-phenylethylone by reacting 1-(4-fluorophenyl)-2-phenylethylone with hydrochloric acid and cuprous chloride in a water bath and then adding hydrogen peroxide. This method generates a large amount of acidic and heavy metal organic waste liquid, which increases the cost of waste liquid treatment. At the same time, the strong acid and strong oxidizing environment will corrode the equipment and pipelines, increasing the operation and maintenance costs.

[0012] CN 115466196 discloses a method for preparing atorvastatin calcium intermediates from phenylacetic acid as a raw material, via chloroacylation, Friedel-Crafts acylation, Davis oxidation, and chlorination to obtain 2-chloro(or bromo)-1-(4-fluorophenyl)-acetophenone, followed by reaction with phenylisobutyrylacetamide. The strategy of introducing hydroxyl rehalogenation avoids side reactions on the benzene ring, improving selectivity and yield. However, the Davis reagent used in the third step is expensive and has poor stability, requiring recovery via oxidation with m-chloroperoxybenzoic acid. Furthermore, the reaction temperature is -78℃, increasing the complexity and cost of the process. In the third step, trimethylchlorosilane (TMCS) is used for halogenation, which avoids benzene ring halogenation side reactions. However, TMCS is a highly reactive silane reagent with a high price, and the byproducts such as hexamethyldisiloxane generated after the reaction need to be recovered by distillation, increasing the difficulty of post-processing and energy consumption. In addition, the overall yield of this route is approximately 54.3%.

[0013] Therefore, optimizing the synthetic route of atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide has significant commercial value and research significance. Summary of the Invention

[0014] Based on the above problems, the purpose of this invention is to provide a method for synthesizing the atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide. This method uses α-chlorophenylacetyl chloride as a raw material and a Brønsted-Lewis bisacid ionic liquid constructed with graphitic carbon nitride as the parent core as a catalyst to catalyze a Friedel-Crafts acylation reaction. The resulting product is then reacted with isobutyrylacetanilide under microwave-assisted, alkaline conditions to prepare the atorvastatin intermediate.

[0015] This invention provides a method for synthesizing an atorvastatin intermediate, wherein the atorvastatin intermediate is 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, the structural formula of which is shown in (II). The method comprises the following steps:

[0016] (1) Using α-chlorophenylacetyl chloride and fluorobenzene as raw materials, a Friedel-Crafts acylation reaction was carried out under the catalysis of Brønsted-Lewis acidic ionic liquid to obtain 2-chloro-1-(4-fluorophenyl)-2-phenylethyl ketone as shown in formula (Ⅰ). The α-chlorophenylacetyl chloride used in the embodiments of the present invention was prepared by conventional chlorination reaction using mandelic acid as raw material, thionyl chloride as chlorinating agent, and DMF as catalyst.

[0017] (I)

[0018] (2) Under microwave assistance and in the presence of an alkaline substance, 2-chloro-1-(4-fluorophenyl)-2-phenylethylone obtained in step (1) undergoes a condensation reaction with isobutyrylacetanilide in an organic solvent to obtain the atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide as shown in formula (II).

[0019] (II)

[0020] The synthetic route of this invention is shown below:

[0021] .

[0022] Furthermore, the present invention further specifies the preparation steps of the Brønsted-Lewis acidic ionic liquid in step (1) as follows:

[0023] a. Urea is pyrolyzed at 400~800 °C for 2-6 h under a nitrogen atmosphere to obtain graphitic carbon nitride;

[0024] b. Under stirring, the graphitic carbon nitride obtained in step a is added to a chloroform solution of 1,3-propanesulfonate lactone. The sulfonation reaction is carried out under the synergistic effect of microwave and ultrasound. After the reaction is completed, the mixture is filtered, washed with acetonitrile, and vacuum dried to obtain the ionic liquid intermediate sulfonated graphitic carbon nitride.

[0025] c. Weigh the sulfonated graphitic carbon nitride intermediate obtained in step b into distilled water. Under stirring, add sulfuric acid dropwise to the reaction system. After the addition is complete, heat to 80 °C and stir for 5 h. Then remove water under reduced pressure, wash, and dry under vacuum to obtain Brønsted acidic ionic liquid.

[0026] d. Disperse the Brønsted acidic ionic liquid from step c in a 50% ethanol aqueous solution, add a quantitative amount of metal oxide to the reaction system under ultrasonication, stir at room temperature, concentrate, and vacuum dry to obtain the Brønsted-Lewis acidic ionic liquid.

[0027] Furthermore, the present invention further specifies that the molar ratio of graphitic carbon nitride to 1,3-propanesulfonic acid lactone in step b is 1:1 to 5, preferably 1:3; the molar ratio of sulfonated graphitic carbon nitride to sulfuric acid in step c is 1:1 to 5, preferably 1:3; and the molar ratio of Brønsted ionic liquid to metal oxide in step d is 1:1 to 3, preferably 1:1.5, wherein the metal oxide is stannous oxide, copper oxide, cuprous oxide, zinc oxide, chromium oxide, or nickel oxide, preferably stannous oxide or zinc oxide.

[0028] Furthermore, the present invention also specifies that the molar ratio of α-chlorophenylacetyl chloride to fluorobenzene in step (1) is 1:1.2 to 2.0, preferably 1:1.5; and the mass of the Brønsted-Lewis acidic ionic liquid is 4 to 9% of the mass of α-chlorophenylacetyl chloride, preferably 7%.

[0029] Furthermore, the present invention also specifies that the reaction temperature in step (1) is -10~10 ℃, preferably 0~5 ℃; and the reaction time is 1-5 h, preferably 3 h.

[0030] Furthermore, the present invention also specifies that the microwave power in step (2) is 200~500 W, preferably 300 W; the reaction temperature is 20~30 ℃; and the reaction time is 1-4 h, preferably 2 h.

[0031] Furthermore, the present invention also specifies that the molar ratio of isobutyrylacetanilide to 2-chloro-1-(4-fluorophenyl)-2-phenylethylone in step (2) is 1.1 to 1.5:1, preferably 1.3:1.

[0032] Furthermore, the present invention further specifies that the alkaline substance in step (2) is one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or sodium ethoxide, and the molar ratio of the alkali to 2-chloro-1-(4-fluorophenyl)-2-acetophenone is 1~2:1, preferably 1.5:1; the organic solvent is one or more of acetone, N,N-dimethylformamide, dichloromethane or toluene.

[0033] For the preparation of the ionic liquid of this invention, taking a Brønsted acidic ionic liquid to stannous oxide molar ratio of 1:1.5 as an example, the preparation route of the graphite-phase carbon nitride supported ionic liquid catalyst is as follows:

[0034] .

[0035] By employing the above-described technology, the beneficial effects of the present invention compared to the prior art are as follows:

[0036] 1) The Brønsted-Lewis acidic ionic liquid designed in this invention, using graphitic carbon nitride as a support, fully decomposes urea into graphitic carbon nitride. Utilizing the large specific surface area and abundant active sites of graphitic carbon nitride, the unique structure of graphitic carbon nitride serves simultaneously as an ionic liquid immobilization support and a core in the ionic liquid preparation process. The ionic liquid immobilized through chemical bonding reduces the loss of active components, thus not only retaining the catalytic activity of the ionic liquid but also achieving catalyst separation through simple filtration. The presence of multiple nitrogen atoms in the support structure further enriches the active sites, improving the reaction rate and selectivity, thereby further reducing the synthesis cost of the target product and enhancing its application prospects.

[0037] 2) The ionic liquid of the present invention is easy to recycle, which significantly improves the efficiency of catalyst recycling, reduces the cost of catalyst use and catalyst waste treatment, and can effectively enhance the product competitiveness in the synthesis of atorvastatin intermediates.

[0038] 3) This invention uses α-chlorophenylacetyl chloride as a raw material and a special ionic liquid as a catalyst to design a two-step reaction to obtain atorvastatin intermediates. Chlorine reactive groups are added to the raw material in advance to reduce the use of additional reagents in subsequent reactions, which would pollute the environment and cause danger. Then, under the action of a base, it reacts with isobutyrylacetanilide to obtain atorvastatin intermediates. With the assistance of microwaves, the reaction time is further shortened, the selectivity of the target product is improved, and the reaction yield is greatly improved. Attached Figure Description

[0039] Figure 1 The image shows the infrared spectrum of the graphitic carbon nitride-supported Brønsted-Lewis acidic ionic liquid prepared using stannous oxide as a raw material in Example 1. Detailed Implementation

[0040] The present invention will be further described below with reference to the embodiments, but the scope of protection claimed by the present invention is not limited to the scope described in the embodiments.

[0041] Example 1

[0042] (1) Synthesis of Brønsted-Lewis acidic ionic liquids

[0043] 130 g of urea was pyrolyzed at 600 °C for 4 h under a nitrogen atmosphere to obtain graphitic carbon nitride. The obtained graphitic carbon nitride (0.1 mol, 19 g) was added to a solution of 1,3-propanesulfonic acid lactone (0.3 mol, 36.7 g) and chloroform (150 mL) under stirring at room temperature. The reaction was carried out under ultrasonic power of 300 W and microwave power of 200 W for 2 h. After the reaction was completed, the mixture was filtered, the solid was washed several times with ethyl acetate and acetonitrile, and dried under vacuum to obtain a sulfonated ionic liquid intermediate. Infrared spectra of graphitic carbon nitride and sulfonated graphitic carbon nitride are shown in the appendix. Figure 1 a and b in the example.

[0044] The obtained sulfonated ionic liquid intermediate (0.1 mol, 55.6 g) was dissolved in distilled water, and sulfuric acid (0.3 mol) was added dropwise to the reaction system under stirring. After the addition was complete, the temperature was raised to 80 °C and the reaction was stirred for 5 h to stop the reaction. The solution was removed under reduced pressure, washed, and dried under vacuum to obtain the desired Brønsted acidic ionic liquid.

[0045] A certain amount of Brønsted acidic ionic liquid (10 mmol, 8.5 g) was taken and ultrasonically dispersed with an appropriate amount of ethanol. Then, stannous oxide (15 mmol, 2.02 g) was added to the reaction system, stirred at room temperature for 2 h, concentrated, and vacuum dried to obtain graphitic carbon nitride-supported Brønsted-Lewis acidic ionic liquid (SnO). The infrared spectrum is attached. Figure 1 c. Repeat this step, replacing stannous oxide with copper oxide, cuprous oxide, zinc oxide, chromium oxide, nickel oxide, etc., to obtain Brønsted-Lewis acidic ionic liquids of the corresponding metals.

[0046] (2) Synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenylethylone

[0047] In a 100 mL three-necked flask equipped with a constant-pressure dropping funnel, thermometer, and tail gas absorption device, 14.4 g (0.15 mol) of fluorobenzene, 100 g of dichloromethane, and 1.07 g (7%, based on the mass of α-chlorophenylacetyl chloride) of the above-mentioned Brønsted-Lewis acidic ionic liquid were added dropwise through the constant-pressure dropping funnel under ice bath conditions. The addition was completed within 30 min, and the reaction was carried out at 0–5 °C for 3 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled, the catalyst was recovered by filtration, and the filtrate was washed successively with 10% NaHCO3 solution, saturated NaCl solution, and water. The solvent was removed from the organic phase by vacuum distillation, and the mixture was recrystallized from petroleum ether and dried under vacuum to obtain 2-chloro-1-(4-fluorophenyl)-2-acetophenone powder. The effects of different ionic liquids on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-acetophenone are shown in Table 1.

[0048] Table 1. Preparation of 2-chloro-1-(4-fluorophenyl)-2-acetophenone catalyzed by different metallic Brønsted-Lewis acidic ionic liquids

[0049]

[0050] As shown in Table 1, the Brønsted-Lewis acidic ionic liquid prepared from stannous oxide has the best catalytic effect.

[0051] Example 2

[0052] (1) Synthesis of Brønsted-Lewis acidic ionic liquids with different acidity ratios

[0053] Brønsted acidic ionic liquids were prepared according to Example 1. A certain amount of Brønsted acidic ionic liquid was taken, and an appropriate amount of ethanol aqueous solution was added for ultrasonic dispersion. Then, different amounts of stannous oxide were added to the reaction system, stirred at room temperature for 2 h, concentrated, and vacuum dried to obtain Brønsted-Lewis acidic ionic liquids with different acidity ratios.

[0054] (2) Synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenylethylone

[0055] In a 100 mL three-necked flask equipped with a constant-pressure dropping funnel, thermometer, and tail gas absorption device, 14.4 g (0.15 mol) of fluorobenzene, 100 g of dichloromethane, and 1.07 g (7%, based on the mass of α-chlorophenylacetyl chloride) of the above-mentioned Brønsted-Lewis acidic ionic liquids with different acid ratios were added dropwise through the constant-pressure dropping funnel under ice bath conditions. The addition was completed within 30 min, and the reaction was carried out at 0–5 °C for 3 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled, the catalyst was recovered by filtration, and the filtrate was washed successively with 10% NaHCO3 solution, saturated NaCl solution, and water. The solvent was removed from the organic phase by vacuum distillation, and the mixture was recrystallized from petroleum ether and dried under vacuum to obtain 2-chloro-1-(4-fluorophenyl)-2-phenylacetophenone powder. The effect of different acid ratios of ionic liquids on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenylacetophenone is shown in Table 2.

[0056] Table 2. Effect of ionic liquid acidity ratio on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-acetophenone

[0057]

[0058] As shown in Table 2, the Brønsted-Lewis acidic ionic liquid prepared from stannous oxide has the best catalytic effect on acylation reaction when the acidity ratio of Brønsted acid to Lewis acid is 50:50.

[0059] Example 3

[0060] Referring to the catalytic reaction process of Example 1, using Brønsted-Lewis acidic ionic liquid with B / L=50:50 as the catalyst, the reaction results of 2-chloro-1-(4-fluorophenyl)-2-acetophenone were obtained by only changing the amount of catalyst, as shown in Table 3.

[0061] Table 3 Effect of ionic liquid dosage on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-acetophenone

[0062]

[0063] As shown in Table 3, when the catalyst dosage is greater than 6%, the yield is above 90%. Considering both the overall reaction efficiency and the yield of the target product, the optimal catalyst dosage is determined to be 7%.

[0064] Example 4

[0065] Referring to the catalytic reaction process of Example 1, using Brønsted-Lewis acidic ionic liquid with B / L=50:50 as the catalyst, and only changing the molar ratio of fluorobenzene to α-chlorophenylacetyl chloride, the reaction results of 2-chloro-1-(4-fluorophenyl)-2-acetophenone are shown in Table 4.

[0066] Table 4. Effect of starting material molar ratio on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-acetophenone

[0067]

[0068] As shown in Table 4, the yield of fluorobenzene to α-chlorophenylacetyl chloride is above 90% when the molar ratio is in the range of 1.5 to 2.0:1. Considering the conservation of resources and the yield of the target product, the molar ratio of fluorobenzene to α-chlorophenylacetyl chloride is determined to be 1.5:1.

[0069] Example 5

[0070] 2-chloro-1-(4-fluorophenyl)-2-phenylethylone (12.54 g, 0.05 mol), isobutyrylacetanilide (13.34 g, 0.065 mol), potassium carbonate (10.37 g, 0.075 mol), and acetone (50 mL) were added to a three-necked flask. The reaction was carried out at 25 °C for 2 h under different microwave powers. After the reaction was completed, the mixture was filtered, washed, and dried to obtain the crude atorvastatin nucleus 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, which was recrystallized from isopropanol to obtain the target product. The effect of different microwave powers on the synthesis of the atorvastatin nucleus is shown in Table 5.

[0071] Table 5. Effect of microwave power on atorvastatin nucleosynthesis

[0072]

[0073] As shown in Table 5, within the range of microwave power investigated, the yield was above 80%. The highest yield of the target product was achieved with a power of 300-400W. Further increasing the power resulted in a decrease in yield. Considering resource conservation and the yield of the target product, the microwave reaction power was determined to be 300W.

[0074] Example 6

[0075] Following the reaction process of Example 5, atorvastatin nucleus was synthesized at a microwave power of 300W and a temperature of 25°C. Only the molar ratio of isobutyrylacetanilide to 2-chloro-1-(4-fluorophenyl)-2-acetophenone was changed to obtain the atorvastatin nucleus 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide. The reaction results are shown in Table 6.

[0076] Table 6 Effect of reactant molar ratio on atorvastatin nucleus synthesis

[0077]

[0078] As shown in Table 6, the yield of isobutyrylacetanilide to 2-chloro-1-(4-fluorophenyl)-2-acetophenone is above 90% when the molar ratio is in the range of 1.3 to 1.5:1. Considering the conservation of resources and the yield of the target product, the molar ratio of isobutyrylacetanilide to 2-chloro-1-(4-fluorophenyl)-2-acetophenone is determined to be 1.3:1.

[0079] Example 7

[0080] Following the reaction process of Example 5, atorvastatin nucleus was synthesized at a microwave power of 300W and a temperature of 25°C. Only the amount of potassium carbonate was changed to obtain the atorvastatin nucleus 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide. The reaction results are shown in Table 7.

[0081] Table 7 Effect of potassium carbonate content on atorvastatin nucleus synthesis

[0082]

[0083] As shown in Table 7, when the molar ratio of potassium carbonate to 2-chloro-1-(4-fluorophenyl)-2-acetophenone is greater than 1.5:1, the yield is above 90%. Considering resource conservation and the yield of the target product, the molar ratio of potassium carbonate to 2-chloro-1-(4-fluorophenyl)-2-acetophenone is determined to be 1.5:1.

Claims

1. A method for synthesizing an atorvastatin intermediate, wherein the atorvastatin intermediate is 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, the structural formula of which is shown in (II), characterized in that... The synthesis method includes the following steps: (1) Using α-chlorophenylacetyl chloride and fluorobenzene as raw materials, a Friedel-Crafts acylation reaction was carried out under the catalysis of a Brønsted-Lewis acidic ionic liquid to obtain 2-chloro-1-(4-fluorophenyl)-2-phenylethyl ketone as shown in formula (Ⅰ). The mass of the Brønsted-Lewis acidic ionic liquid was 7-9% of the mass of α-chlorophenylacetyl chloride, the reaction temperature was -10 to 10 °C, and the reaction time was 1-5 h. ； (2) Under microwave assistance, in the presence of an alkaline substance, 2-chloro-1-(4-fluorophenyl)-2-acetophenone obtained in step (1) undergoes a condensation reaction with isobutyrylacetanilide in an organic solvent to obtain the atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide as shown in formula (II). The microwave power is 300~500W, the reaction temperature is 20~30 ℃, and the reaction time is 1-4 h. The molar ratio of base to 2-chloro-1-(4-fluorophenyl)-2-acetophenone is 1.5~2:

1. ； The preparation steps of the Brønsted-Lewis acidic ionic liquid in step (1) are as follows: a. Urea is pyrolyzed at 400~800 °C for 2-6 h under a nitrogen atmosphere to obtain graphitic carbon nitride; b. Under stirring, the graphitic carbon nitride obtained in step a is added to a chloroform solution of 1,3-propanesulfonate lactone. The sulfonation reaction is carried out under the synergistic effect of microwave and ultrasound. After the reaction is completed, the mixture is filtered, washed with acetonitrile, and vacuum dried to obtain the ionic liquid intermediate sulfonated graphitic carbon nitride. c. Weigh the sulfonated graphitic carbon nitride intermediate obtained in step b into distilled water. Under stirring, add sulfuric acid dropwise to the reaction system. After the addition is complete, heat to 80 °C and stir for 5 h. Then remove water under reduced pressure, wash, and dry under vacuum to obtain Brønsted acidic ionic liquid. d. Disperse the Brønsted acidic ionic liquid from step c in a 50% ethanol aqueous solution, add a quantitative amount of metal oxide to the reaction system under ultrasonication, stir at room temperature, concentrate, and vacuum dry to obtain the Brønsted-Lewis acidic ionic liquid.

2. The method for synthesizing an atorvastatin intermediate according to claim 1, characterized in that... In step b, the molar ratio of graphitic carbon nitride to 1,3-propanesulfonic acid lactone is 1:1~5.

3. The method for synthesizing an atorvastatin intermediate according to claim 1, characterized in that... In step c, the molar ratio of the ionic liquid intermediate sulfonated graphitic carbon nitride to sulfuric acid is 1:1~5.

4. The method for synthesizing an atorvastatin intermediate according to claim 1, characterized in that... In step d, the molar ratio of the Brønsted ionic liquid to the metal oxide is 1:1 to 3, and the metal oxide is stannous oxide, copper oxide, cuprous oxide, zinc oxide, chromium oxide, or nickel oxide.

5. The method for synthesizing an atorvastatin intermediate according to claim 1, characterized in that... In step (1), the molar ratio of α-chlorophenylacetyl chloride to fluorobenzene is 1:1.2 to 2.

0.

6. A method for synthesizing an atorvastatin intermediate according to any one of claims 1-5, characterized in that... In step (2), the molar ratio of isobutyrylacetanilide to 2-chloro-1-(4-fluorophenyl)-2-phenylethylone is 1.1~1.5:

1.

7. A method for synthesizing an atorvastatin intermediate according to any one of claims 1-5, characterized in that... The alkaline substance in step (2) is one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or sodium ethoxide; the organic solvent is one or more of acetone, N,N-dimethylformamide, dichloromethane or toluene.

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