Synthesis method of atorvastatin intermediate

Abstract

The invention discloses a synthesis method of an atorvastatin intermediate. The method comprises the following steps of: catalyzing alpha-chlorophenylacetyl chloride and fluorobenzene to perform Friedel-Crafts acylation reaction by taking immobilized Bronsted-Lewis acidic ionic liquid as a catalyst, and performing condensation reaction on a product and isobutyryl acetanilide under the action of alkali and the assistance of microwaves, the preparation method comprises the following steps: adding 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenyl pentanamide into an organic solvent to obtain the atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1- By utilizing the characteristics of large specific surface area and abundant active sites of graphite-like carbon nitride, the graphite-like carbon nitride is used as an ionic liquid immobilization carrier and a parent nucleus to participate in the ionic liquid preparation process, the catalytic activity of the ionic liquid is retained, the catalyst is simple to separate, the reaction rate and selectivity are improved, the steps are simple, and the method is suitable for industrial production. The method has the advantages of mild reaction conditions in each step, low cost, high yield and easily available reaction conditions, and improves the application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical and chemical synthesis, and particularly relates to a synthesis method of an atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide. BACKGROUND

[0002] Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is developed by Warner-Lambert and Pfizer in the United States, and is marketed in the United Kingdom in 1997. Atorvastatin calcium has excellent blood lipid-lowering ability, and has a rapid onset time and a long action time, so that it is widely used in clinical practice. 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, as an important intermediate, can be synthesized into atorvastatin calcium through a Paal-Knorr reaction.

[0003] At present, the synthesis methods of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide reported mainly include the following three reaction routes: Route one: propionic acid is used as a starting material, a propionic acid cycloisopropyl ester is first formed, then a condensation reaction is performed with isobutyryl chloride, then a ring-opening reaction is performed with aniline, then a Knoevenagel reaction is performed with benzaldehyde, and a Stetter reaction is performed with 4-fluorobenzaldehyde to obtain the atorvastatin intermediate.

[0004] Route two: 3-methyl-2-butanone is used as a starting material, a substitution reaction is performed with aniline after condensation, and then reactions are performed with benzaldehyde and 4-fluorobenzaldehyde to obtain the atorvastatin intermediate.

[0005] Route three: phenylacetyl chloride is used as a starting material, a Friedel-Crafts acylation reaction and bromination are performed, and finally a reaction is performed with isobutyrylacetanilide to obtain the atorvastatin important intermediate 2-bromo-1-(4-fluorophenyl)-2-phenylethanone.

[0006] The two methods of route one and route two described above both have a low yield of the atorvastatin intermediate due to the influence of steric hindrance and competitive reactions; route three needs to add bromine for bromination, a large amount of hydrogen bromide is generated in the reaction process, and needs to be neutralized by a base, which produces a large amount of wastewater, and on the other hand, bromine is extremely volatile and strongly corrosive, so that there is a certain safety hazard.

[0007] In view of this, the present application uses a-chlorobenzene acyl chloride as a raw material for reaction, and designs a two-step reaction to obtain an atorvastatin intermediate. The chloro group is added to the raw material in advance to reduce the use of additional reagents in the subsequent reaction, which pollutes the environment and causes danger. The chlorine atom at the benzyl position also has similar reactivity to bromine in other methods; then, under the action of a base, it reacts with isobutyryl acetanilide to obtain an atorvastatin intermediate. In the presence of microwave assistance, the reaction time is further shortened, the selectivity of the target product is improved, and the reaction yield is greatly improved.

[0008] The first step of synthesis is a classic Friedel-Crafts acylation reaction. At present, most Friedel-Crafts acylation reactions select Lewis acid or Brønsted acid for catalysis. The most commonly used Lewis acid is anhydrous AlCl3, which is widely used in Friedel-Crafts acylation reactions due to its low price, high activity and other advantages. However, it also has many problems, such as the generation of a large amount of aluminum-containing waste liquid after the reaction, and the complexation of anhydrous AlCl3 with the product. The most commonly used Brønsted acid catalyst is H2SO4, which has high catalytic activity and mild reaction conditions when used as a catalyst. However, it is highly corrosive and can easily damage pipelines, reactors and other equipment, requiring high production equipment. Secondly, Friedel-Crafts acylation requires high reaction conditions, and the use of H2SO4 as a catalyst can easily produce various by-products and H2SO4 itself is difficult to recover, which cannot meet the requirements of high-end pharmaceutical chemicals.

[0009] Ionic liquids have high stability, structural designability, recyclability and low environmental pollution, which have attracted widespread attention in industrial catalysis. By utilizing the structural designability of ionic liquids, a Brønsted-Lewis dual acid ionic liquid is constructed to fully exert the high catalytic activity of Lewis acid and Brønsted acid and the synergistic effect between the two acids in the acylation reaction process. At the same time, by utilizing the recyclability of ionic liquids, the catalyst can be effectively recovered. However, the high viscosity of ionic liquids makes their recycling relatively inconvenient, increasing the cost of use. Ionic liquid immobilization is the future development direction. Graphitic carbon nitride (C3N4) material with a large specific surface area is selected as an excellent carrier due to its wide application in catalysis, water splitting for hydrogen production and pollutant degradation. The unique structure of graphitic carbon nitride not only allows it to be used as an ionic liquid immobilization carrier, but also allows it to participate in the preparation process of ionic liquids as a mother nucleus. This ionic liquid immobilized by chemical bonds reduces the loss of active ingredients, and the special structure not only retains the catalytic activity of ionic liquids, but also allows the catalyst to be separated by simple filtration. The presence of multiple N in the carrier structure further enriches the active sites, improves the reaction rate and selectivity, and thus further reduces the cost of target product synthesis and improves the application prospect.

[0010] CN114773221 discloses a method for obtaining 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone by using 1-(4-fluorophenyl)-2-phenyl ethanone as raw material, adding hydrogen peroxide after hydrochloric acid and cuprous chloride are heated in water bath. This method produces a large amount of acidic and heavy metal organic waste liquid, increases the cost of waste liquid treatment, and the strong acidity and strong oxidation environment can corrode the equipment pipeline, increasing the operation and maintenance cost.

[0011] CN 115466196 discloses a method for obtaining 2-chloro(or bromo)-1-(4-fluorophenyl)-phenyl ethanone by using phenylacetic acid as raw material, and then reacting with phenyl isobutyryl acetamide to prepare atorvastatin calcium intermediate. The strategy of introducing hydroxyl and then halogenation avoids side reactions on the benzene ring, improves selectivity and yield, but the Davis reagent used in the third step is expensive and has poor stability, and needs to be recovered by oxidation with meta-chloroperbenzoic acid, and the reaction temperature is-78℃, which increases the complexity and cost of the process. In the third step, trimethylchlorosilane (TMCS) is used for halogenation, which avoids the side reaction of benzene ring halogenation, but TMCS is a high-activity silane reagent with high price, and the by-products such as hexamethyldisiloxane produced after reaction need to be recovered by rectification, which increases the difficulty and energy consumption of post-treatment. In addition, the overall yield of the route is about 54.3%.

[0012] Therefore, it is of important commercial value and research significance to optimize the synthesis route of atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide. SUMMARY

[0013] Based on the above problems, the purpose of the present application is to provide a synthesis method of atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, which uses α-chlorobenzene acyl chloride as raw material, and a Brønsted-Lewis dual acid type ionic liquid constructed with graphite phase carbon nitride as catalyst to catalyze the Friedel-Crafts acylation reaction. The obtained product is reacted with isobutyryl acetanilide under the assistance of microwave and the action of base to prepare atorvastatin intermediate.

[0014] The synthesis method of atorvastatin intermediate defined in the present application is 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, and its structural formula is shown as (II). The synthesis method comprises the following steps: (1) taking alpha-chlorobenzene acyl chloride and fluorobenzene as raw materials, a Friedel-Crafts acylation reaction is carried out under the catalysis of a Brønsted-Lewis acidic ionic liquid to obtain 2-chloro-1-(4-fluorophenyl)-2-phenylethanone shown in formula (I), the raw material alpha-chlorobenzene acyl chloride used in the embodiment of the application is prepared by chlorination reaction using mandelic acid as a raw material, dichlorosulfide as a chlorinating agent and DMF as a catalyst in a conventional method; (I) (2) under microwave assistance, 2-chloro-1-(4-fluorophenyl)-2-phenylethanone obtained in step (1) and isobutyrylacetanilide are subjected to a condensation reaction in an organic solvent to obtain an atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide shown in formula (II), (II), The synthetic route of the application is shown as follows: .

[0015] Further, the preparation step of the Brønsted-Lewis acidic ionic liquid in step (1) is limited in the application as follows: a pyrolyzing urea at 400-800 ℃ for 2-6 h under a nitrogen atmosphere to obtain graphite phase carbon nitride; b adding the graphite phase carbon nitride obtained in step a to a 1,3-propanesultone chloroform solution under stirring, and performing a sulfonation reaction under the synergistic action of microwave and ultrasonic waves, after the reaction is completed, filtering, washing with acetonitrile, and vacuum drying to obtain an ionic liquid intermediate sulfonated graphite phase carbon nitride; c weighing the ionic liquid intermediate sulfonated graphite phase carbon nitride obtained in step b in distilled water, adding sulfuric acid dropwise to the reaction system under stirring, heating to 80 ℃ after the dropwise addition is completed, stirring for 5 h, removing water under reduced pressure, washing, and vacuum drying to obtain a Brønsted acidic ionic liquid; d dispersing the Brønsted acidic ionic liquid of step c in a 50% ethanol aqueous solution, adding a quantitative metal oxide to the reaction system under ultrasonic action, stirring at room temperature, concentrating, and vacuum drying to obtain a Brønsted-Lewis acidic ionic liquid.

[0016] Further, the present application also limits the molar ratio of the graphite phase carbon nitride to 1,3-propanesultone in step b to 1:1~5, preferably 1:3; the molar ratio of the ionic liquid intermediate sulfonated graphite phase carbon nitride to sulfuric acid in step c to 1:1~5, preferably 1:3; the molar ratio of the Brønsted ionic liquid to the metal oxide in step d to 1:1~3, preferably 1:1.5, and the metal oxide is stannous oxide, copper oxide, cuprous oxide, zinc oxide, chromium oxide or nickel oxide, preferably stannous oxide or zinc oxide.

[0017] Further, the present application also limits the molar ratio of the α-chlorobenzene acetyl chloride to fluorobenzene in step (1) to 1:1.2~2.0, preferably 1:1.5; the mass of the Brønsted-Lewis acidic ionic liquid is 4~9% of the mass of the α-chlorobenzene acetyl chloride, preferably 7%.

[0018] Further, the present application also limits the reaction temperature in step (1) to -10~10 ℃, preferably 0~5 ℃; the reaction time to 1-5 h, preferably 3 h.

[0019] Further, the present application also limits the microwave power in step (2) to 200~500 W, preferably 300 W; the reaction temperature to 20~30 ℃, and the reaction time to 1-4 h, preferably 2 h.

[0020] Further, the present application also limits the molar ratio of the isobutyryl aceto phenylamine to 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone in step (2) to 1.1~1.5:1, preferably 1.3:1.

[0021] Further, the present application also limits the basic substance in step (2) to one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or sodium ethoxide, and the molar ratio of the base to 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone to 1~2:1, preferably 1.5:1; and the organic solvent to one or more of acetone, N,N-dimethylformamide, dichloromethane or toluene.

[0022] For the preparation of the ionic liquid of the present application, taking the molar ratio of the Brønsted acidic ionic liquid to stannous oxide as an example, the preparation route of the graphite phase carbon nitride supported ionic liquid catalyst is as follows: .

[0023] By using the above-mentioned technology, compared with the prior art, the present application has the following beneficial effects: 1) The Brønsted-Lewis acidic ionic liquid with graphite-like carbon nitride as a carrier is designed, the graphite-like carbon nitride is fully pyrolyzed from urea, the specific structure of the graphite-like carbon nitride is used as an ionic liquid immobilization carrier and as a mother nucleus to participate in the ionic liquid preparation process, the ionic liquid immobilized by chemical bond action reduces the loss of active ingredients, so that the catalytic activity of the ionic liquid is retained, the catalyst is separated by simple filtration, the existence of multiple N in the carrier structure further enriches the active sites, improves the reaction rate and selectivity, thereby further reduces the synthesis cost of the target product and improves the application prospect. 2) The ionic liquid is easy to recover, significantly improves the catalyst recovery efficiency, reduces the catalyst use and catalyst waste treatment cost, and can effectively improve the product competitiveness in the synthesis process of atorvastatin intermediates. 3) The atorvastatin intermediate is obtained by designing a two-step reaction with a-chlorobenzene acyl chloride as a raw material and a special ionic liquid as a catalyst, the chloro reaction group is added in the raw material in advance to reduce the pollution of the environment and the danger caused by the use of additional reagents in the subsequent reaction, and then the atorvastatin intermediate is obtained by reacting with isobutyryl acetanilide under the action of alkali, the reaction time is further shortened under the assistance of microwave, the selectivity of the target product is improved, and the reaction yield is greatly improved. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The infrared spectrum of the graphite-like carbon nitride supported Brønsted-Lewis acidic ionic liquid prepared in Example 1 with stannous oxide as a raw material. DETAILED DESCRIPTION

[0025] The present application is further described below in conjunction with examples, but the protection scope required by the present application is not limited to the range expressed by the examples.

[0026] Example 1 (1) Synthesis of Brønsted-Lewis acidic ionic liquid The graphite-like carbon nitride was obtained by pyrolyzing urea 130 g at 600 ℃ for 4 h under nitrogen atmosphere. The obtained graphite-like carbon nitride (0.1 mol, 19 g) was added into a 1,3-propanesultone (0.3 mol, 36.7 g) chloroform (150 mL) solution under stirring at room temperature, and reacted under the conditions of ultrasonic power of 300 W and microwave power of 200 W for 2 h. After the reaction, the solid was filtered, washed with ethyl acetate and acetonitrile for several times, and vacuum dried to obtain a sulfonated ionic liquid intermediate. The infrared spectra of the graphite-like carbon nitride and the sulfonated graphite-like carbon nitride are shown in a and b of FIG. 1, respectively. Figure 1 ​

[0027] Take the obtained sulfonated ionic liquid intermediate (0.1 mol, 55.6 g) in distilled water, and add sulfuric acid (0.3 mol) dropwise to the reaction system under stirring conditions. After the addition is complete, the temperature is raised to 80°C and the reaction is stirred for 5 h before being terminated. Water is removed under reduced pressure, washed, and vacuum dried to obtain the desired Brønsted acidic ionic liquid.

[0028] Take a certain amount of Brønsted acidic ionic liquid (10 mmol, 8.5 g), add an appropriate amount of ethanol and ultrasonically disperse, then add stannous oxide (15 mmol, 2.02 g) to the reaction system, stir at room temperature for 2 h, concentrate, and vacuum dry to obtain a graphite phase carbon nitride supported Brønsted-Lewis acidic ionic liquid (SnO), and the infrared spectrum is shown in Figure c of the accompanying drawings. Figure 1 Repeat this step by replacing stannous oxide with copper oxide, cuprous oxide, zinc oxide, chromium oxide, nickel oxide, etc. to obtain the corresponding metal Brønsted-Lewis acidic ionic liquid.

[0029] (2) Synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone In a 100 mL three-necked flask with a constant pressure dropping funnel, a thermometer, and a tail gas absorption device, add fluorobenzene 14.4 g (0.15 mol), dichloromethane 100 g, and the above Brønsted-Lewis acidic ionic liquid 1.07 g (7%, based on the mass of α-chlorobenzene acetyl chloride), and drop α-chlorobenzene acetyl chloride 15.4 g (0.1 mol) through the constant pressure dropping funnel under ice bath conditions. The dropwise addition is completed within 30 min, and the reaction is carried out at 0-5°C for 3 h. TLC is used to track the reaction, and after the reaction is completed, the catalyst is recovered by cooling and filtering. The filtrate is washed with 10% NaHCO3 solution, saturated NaCl solution, and water in sequence. The organic phase is evaporated under reduced pressure, recrystallized with petroleum ether, and vacuum dried to obtain 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone powder. The effects of different ionic liquids on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone are shown in Table 1: Table 1 Preparation of 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone catalyzed by different metal Brønsted-Lewis acidic ionic liquids

[0030] From the results in Table 1, it can be seen that the Brønsted-Lewis acidic ionic liquid prepared from stannous oxide has the best catalytic effect.

[0031] Example 2 (1) Synthesis of Brønsted-Lewis acidic ionic liquids with different acid ratios The Brønsted acidic ionic liquid was prepared according to the method of Example 1; a certain amount of Brønsted acidic ionic liquid was ultrasonically dispersed in a proper amount of aqueous ethanol solution, 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 acid ratios.

[0032] (2) Synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenylethanone In a 100 mL three-necked flask equipped with a constant pressure dropping funnel, a thermometer and a tail gas absorption device, fluorobenzene 14.4 g (0.15 mol), dichloromethane 100 g and the above Brønsted-Lewis acidic ionic liquid with different acid ratios 1.07 g (7%, based on the mass of α-chlorobenzene acyl chloride) were sequentially added, and α-chlorobenzene acyl chloride 15.4 g (0.1 mol) was added dropwise through the constant pressure dropping funnel under ice bath condition, which was completed within 30 min. The reaction was carried out at 0-5 ℃ for 3 h, and TLC was used to track and monitor the reaction. After the reaction was completed, the catalyst was recovered by cooling and filtration, and the filtrate was washed with 10% NaHCO3 solution, saturated NaCl solution and water in sequence. The organic phase was evaporated under reduced pressure, recrystallized from petroleum ether, and vacuum dried to obtain 2-chloro-1-(4-fluorophenyl)-2-phenylethanone powder. The effects of different ionic liquid acid ratios on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenylethanone are shown in Table 2.

[0033] Table 2 Effects of ionic liquid acid ratio on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenylethanone

[0034] As can be seen from the results in Table 2, the Brønsted-Lewis acidic ionic liquid prepared from stannous oxide as raw material has the best catalytic acylation reaction effect when the acid ratio of Brønsted acid to Lewis acid is 50:50.

[0035] Example 3 Referring to the catalytic reaction process of Example 1, the Brønsted-Lewis acidic ionic liquid with B / L=50:50 was used as catalyst, and only the amount of catalyst was changed to obtain the reaction results of 2-chloro-1-(4-fluorophenyl)-2-phenylethanone as shown in Table 3.

[0036] Table 3 Effects of ionic liquid amount on the synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenylethanone

[0037] From the results of Table 3, when the catalyst dosage is greater than 6%, the yield is more than 90%, and considering the reaction efficiency and the yield of the target product, the catalyst dosage of 7% is determined to be the best.

[0038] Example 4 Referring to the catalytic reaction process of Example 1, the Brønsted-Lewis acidic ionic liquid with B / L=50:50 is used as the catalyst, and only the molar ratio of fluorobenzene to α-chlorobenzene acyl chloride is changed to obtain the reaction results of 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone as shown in Table 4.

[0039] Table 4 Effect of raw material molar ratio on synthesis of 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone

[0040] From the results of Table 4, when the molar ratio of fluorobenzene to α-chlorobenzene acyl chloride is in the range of 1.5-2.0:1, the yield is more than 90%, and considering the resource saving and the yield of the target product, the molar ratio of fluorobenzene to α-chlorobenzene acyl chloride is determined to be 1.5:1.

[0041] Example 5 Into a three-necked flask, 2-chloro-1-(4-fluorophenyl)-2-phenyl ethanone (12.54 g, 0.05 mol), isobutyryl acetanilide (13.34 g, 0.065 mol), potassium carbonate (10.37 g, 0.075 mol) and acetone (50 mL) were added. The reaction was carried out at 25°C for 2 h under different microwave powers. After the reaction was completed, filtration, washing, and drying were carried out to obtain the crude atorvastatin mother nucleus 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, and the target product was obtained by recrystallization with isopropanol. The effect of different microwave powers on the synthesis of atorvastatin mother nucleus is shown in Table 5.

[0042] Table 5 Effect of microwave power on synthesis of atorvastatin mother nucleus

[0043] From the results of Table 5, in the range of the microwave power investigated, the yield is more than 80%, the yield of the target product is the highest when the power is 300-400 W, and the yield decreases when the power is further increased. Considering the resource saving and the yield of the target product, the microwave reaction power is determined to be 300 W.

[0044] Example 6 Referring to the reaction process of Example 5, the atorvastatin mother nucleus was synthesized at a microwave power of 300 W and a temperature of 25°C, with the exception that the molar ratio of isobutyryl acetanilide to 2-chloro-l-(4-fluorophenyl)-2-phenyl ethanone was changed to obtain the atorvastatin mother nucleus 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-N- phenylpentanamide. The reaction results are shown in Table 6.

[0045] Table 6 Effect of molar ratio of raw materials on synthesis of atorvastatin mother nucleus

[0046] As shown in Table 6, when the molar ratio of isobutyryl acetanilide to 2-chloro-l-(4-fluorophenyl)-2-phenyl ethanone was in the range of 1.3-1.5:1, the yield was above 90%. From the perspective of resource saving and yield of target product, the molar ratio of isobutyryl acetanilide to 2-chloro-l-(4-fluorophenyl)-2-phenyl ethanone was determined to be 1.3:1.

[0047] Example 7 Referring to the reaction process of Example 5, the atorvastatin mother nucleus was synthesized at a microwave power of 300 W and a temperature of 25°C, with the exception that the amount of potassium carbonate was changed to obtain the atorvastatin mother nucleus 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-N- phenylpentanamide. The reaction results are shown in Table 7.

[0048] Table 7 Effect of amount of potassium carbonate on synthesis of atorvastatin mother nucleus

[0049] As shown in Table 7, when the molar ratio of potassium carbonate to 2-chloro-l-(4-fluorophenyl)-2-phenyl ethanone was greater than 1.5:1, the yield was above 90%. From the perspective of resource saving and yield of target product, the molar ratio of potassium carbonate to 2-chloro-l-(4-fluorophenyl)-2-phenyl ethanone was 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 comprises the following steps: (1) using alpha-chlorobenzene acyl chloride and fluorobenzene as raw materials, a Friedel-Crafts acylation reaction is carried out under the catalysis of a Brønsted-Lewis acidic ionic liquid to obtain 2-chloro-1-(4-fluorophenyl)-2-phenylethanone shown in formula (I); （Ⅰ） (2) under the assistance of microwave, 2-chloro-1-(4-fluorophenyl)-2-phenylethanone obtained in step (1) and isobutyryl acetanilide are subjected to a condensation reaction in the presence of an alkaline substance in an organic solvent to obtain an atorvastatin intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide shown in formula (II), (I). (II).

2. A process for the synthesis of atorvastatin intermediate as claimed in claim 1, wherein The preparation steps of the Brønsted-Lewis acidic ionic liquid in step (1) are as follows: a pyrolyzing urea at 400-800 ℃ for 2-6 h under a nitrogen atmosphere to obtain graphite phase cyanogum; b under stirring, graphite phase cyanogum obtained in step a is added into a 1,3-propanesultone chloroform solution, and a sulfonation reaction is carried out under the cooperation of microwave and ultrasonic waves; after the reaction is completed, filtration, acetonitrile washing, and vacuum drying are carried out to obtain an ionic liquid intermediate sulfonated graphite phase cyanogum; c the ionic liquid intermediate sulfonated graphite phase cyanogum obtained in step b is weighed in distilled water under stirring, sulfuric acid is added dropwise into the reaction system, and after the dropwise addition is completed, the temperature is increased to 80 ℃ for stirring reaction for 5 h; then, water is removed under reduced pressure, washing, and vacuum drying are carried out to obtain a Brønsted acidic ionic liquid; d the Brønsted acidic ionic liquid in step c is dispersed in a 50% ethanol aqueous solution, a certain amount of metal oxide is added into the reaction system under ultrasonic action, stirring is carried out at room temperature, concentration, and vacuum drying are carried out to obtain a Brønsted-Lewis acidic ionic liquid.

3. A process for the synthesis of atorvastatin intermediate as claimed in claim 2, wherein The molar ratio of graphite phase cyanogum to 1,3-propanesultone in step b is 1:1-5.

4. A process for synthesis of atorvastatin intermediate as claimed in claim 2, wherein The molar ratio of the ionic liquid intermediate sulfonated graphite phase cyanogum to sulfuric acid in step c is 1:1-5.

5. A process for synthesis of atorvastatin intermediate as claimed in claim 2, wherein The molar ratio of the Brønsted ionic liquid to metal oxide in step d is 1:1-3, and the metal oxide is stannous oxide, copper oxide, cuprous oxide, zinc oxide, chromium oxide, or nickel oxide.

6. A process for the synthesis of atorvastatin intermediates according to any one of claims 1 to 5, characterized in that The molar ratio of alpha-chlorobenzene acyl chloride to fluorobenzene in step (1) is 1:1.2-2.0; the mass of the Brønsted-Lewis acidic ionic liquid is 4-9% of the mass of alpha-chlorobenzene acyl chloride.

7. A process for the synthesis of atorvastatin intermediates according to any one of claims 1 to 5, characterized by The reaction temperature in step (1) is -10-10 ℃; the reaction time is 1-5 h.

8. A process for the synthesis of atorvastatin intermediates according to any one of claims 1 to 5, characterized by The microwave power in step (2) is 200-500 W; the reaction temperature is 20-30 ℃, and the reaction time is 1-4 h.

9. A process for the synthesis of atorvastatin intermediate according to any one of claims 1 to 5, characterized by The molar ratio of isobutyryl acetanilide to 2-chloro-1-(4-fluorophenyl)-2-phenylethanone in step (2) is 1.1-1.5:

1.

10. A process for the synthesis of atorvastatin intermediate according to any one of claims 1 to 5, characterized by The alkaline substance in step (2) is one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or sodium ethoxide; the molar ratio of the base to 2-chloro-1-(4-fluorophenyl)-2-phenylethanone is 1-2:1; and the organic solvent is one or more of acetone, N,N-dimethylformamide, dichloromethane, or toluene.

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