A process for the preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide

Abstract

The application discloses a preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, and an atorvastatin intermediate impurity is prepared from 2-methyl-3,5-dicarbonyl-5-anilino butane and benzaldehyde and is prepared through selective coupling reaction of aldehyde groups and olefin groups catalyzed by nickel. The atorvastatin mother nucleus is synthesized from the atorvastatin impurity 2-benzylidene-3-oxo-4-methyl-N-phenylpentanamide, a brand-new catalytic system is adopted, the C-C bond construction mode is changed, and the generation of impurities is inhibited, so that the crude product purity is greatly improved. 2. The reaction route of the application has high reaction selectivity, high product yield, few by-products, good atomic economy, convenient post-treatment, simplified process operation, reduced cost, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a process for preparing 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide. Background Technology

[0002] Atorvastatin calcium is a statin lipid-regulating drug. Due to its low toxicity, unique mechanism of action, and good tolerability, it has a very broad market prospect. The atorvastatin calcium core, 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, is a key intermediate in the synthesis of atorvastatin calcium, and its structural formula is as follows: .

[0003] US Patent 8946479B2 discloses a method for synthesizing atorvastatin calcium core, using acetone as solvent and potassium carbonate as base. Isobutyrylacetanilide and 2-bromo-1-(4-fluorophenyl)-2-phenylethylone are reacted at 25°C for 6 hours. After filtration and concentration, the product is recrystallized from isopropanol. HPLC analysis shows that the crude product obtained by this method has a purity of only 71.1%, indicating incomplete conversion of the raw materials. It also produces an unknown impurity (RRT 1.05) with similar polarity to the product, accounting for approximately 10%, which is relatively high and requires further recrystallization for purification. Even after one recrystallization, the unknown impurity content is still 1.3%, with a melting point of 192.7-193.6°C, which is difficult to meet the enterprise standard of less than 0.1% impurity content and a melting point in the range of 196.0-205.0°C.

[0004] US Patent US20110060164A1 discloses a method for synthesizing the calcium core of atorvastatin. Using isopropanol as a solvent and potassium carbonate as a base, isobutyrylacetanilide and 2-chloro-1-(4-fluorophenyl)-2-phenylethylone are reacted at 45°C for 10 hours. The mixture is extracted with ethyl acetate, concentrated, and then recrystallized from isopropanol to obtain the product. However, this method produces a crude product with a purity of only 36.3%, leaving approximately 50% of the raw material. Unknown impurities (RRT 1.05) account for about 7%, indicating an incomplete reaction conversion. Furthermore, the low purity of the crude product makes it difficult to purify.

[0005] This indicates that the traditional synthetic route for atorvastatin calcium core has some problems, such as incomplete conversion of raw materials and the generation of unknown impurities (RRT 1.05) that are difficult to remove during the reaction. This will directly affect the quality of the final product, leading to problems such as unqualified melting point during product testing and low first-pass yield of the product. These issues require subsequent rework, which directly affects production efficiency and increases product costs. Summary of the Invention

[0006] To address the above shortcomings, the present invention provides the following technical solution: A process for preparing 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, characterized by comprising the following steps: In the first step of the reaction, under nitrogen protection, compound I was dissolved in an organic solvent in a dry reaction flask, heated to reflux for 4–6 h, cooled to room temperature, a catalyst was added, then compound II was added, the mixture was heated to reflux and stirred for 8–12 h, the reaction progress was monitored by HPLC, and after the reaction was completed, the mixture was cooled to room temperature and the product was separated to obtain compound III. In the second step, compound III was dissolved in an organic solvent, compound IV was added, a catalyst was added, and the mixture was heated under reflux for 6–8 hours. The reaction progress was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature, and the product was separated to obtain compound V.

[0007] Furthermore, the organic solvent used in the first step reaction is n-heptane, cyclohexane, or toluene.

[0008] Furthermore, the molar ratio of compound II to compound I in the first step reaction is 1:1.0 to 1.5, preferably 1:1.1.

[0009] Furthermore, the catalyst used in the first step reaction is glycine and glacial acetic acid, wherein the amount of glycine is 1-5 wt% of compound I, and the amount of glacial acetic acid is 3-10 wt% of compound I, preferably 2 wt% glycine and 4-5 wt% glacial acetic acid.

[0010] Furthermore, the molar ratio of compound III to compound IV in the second step reaction is 1:1.0 to 1.2, preferably 1:1.1.

[0011] Furthermore, the organic solvent used in the second step reaction is anhydrous toluene or THF, preferably THF.

[0012] Furthermore, the catalyst used in the second step reaction is a complex composed of zero-valent nickel [Ni(0)] and a monophosphine ligand.

[0013] Furthermore, the nickel source of the zero-valent nickel [Ni(0)] is Ni(cod)2, and the monophosphine ligand is tricyclohexylphosphine (PCy3).

[0014] Furthermore, in the second step reaction, the ratio of zero-valent nickel [Ni(0)] to the monophosphine ligand is Ni:P = 1:1 to 1:2.

[0015] Furthermore, the amount of catalyst used in the second step is 5 to 10 mol of compound III.

[0016] The beneficial effects of this invention are: 1. This invention synthesizes atorvastatin nucleus from the atorvastatin impurity 2-benzoxylene-3-oxo-4-methyl-N-phenylpentanamide. By adopting a novel catalytic system and changing the construction mode of the C-C bond, the generation of impurities is suppressed, which significantly improves the purity of the crude product; 2. The reaction route of this invention has high reaction selectivity, high product yield, few by-products, good atom economy, convenient post-processing, simplified process operation, reduced cost, and is suitable for industrial-scale production; 3. Through the optimization of the reaction route and the new catalytic strategy, the problems of impurity control and conversion rate that have long plagued the synthesis of atorvastatin nucleus are precisely solved. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of the atorvastatin calcium core structure of the present invention; Figure 2 This is a schematic diagram of the reaction process of the present invention. Detailed Implementation

[0018] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Example 1

[0019] In the first step of the reaction, under nitrogen protection, 20.5 g (0.1 mol) of compound I was dissolved in 200 mL of cyclohexane in a dry reaction flask, heated to reflux for 4–6 h, cooled to room temperature, and 2 wt% glycine and 5 wt% glacial acetic acid catalyst were added. Then, 0.11 mol of compound II was added, and the mixture was heated to reflux and stirred for 8–12 h. The reaction progress was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature, washed 2–3 times with 50 mL of saturated sodium chloride solution, and 100 mL of cyclohexane was added. The organic phase was separated and dried with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the product was recrystallized with 40 mL of toluene to obtain 27.6 g of the target product, compound III; yield 94.2%, purity 98.3%.

[0020] In the second step of the reaction, 29.3 g (0.1 mol) of compound III was dissolved in 200 ml of organic solvent THF, and 0.11 mol of compound IV was added. Then, 10 mol% of catalyst (Ni(cod)₂ and PCy₃ dissolved in THF under nitrogen protection, stirred for a few minutes, during which the COD ligand in Ni(cod)₂ was substituted, resulting in the in-situ formation of a catalytically active zero-valent nickel-monophosphine complex at a concentration of 0.5 mol / L, Ni:P = 1:1) was added. ) The reaction was refluxed for 6–8 h, and the reaction progress was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated, 100 ml of toluene was added to dissolve the product, and the mixture was washed with saturated brine. The organic phase was separated, the product was evaporated under reduced pressure, and the product was recrystallized with 40 ml of toluene. The product was then separated to obtain 39.2 g of compound V, with a yield of 94.0% and a purity of 98.3%. Example 2

[0021] In the first step of the reaction, under nitrogen protection, 20.5 mol (0.1 mol) of compound I was dissolved in 200 mL of the organic solvent n-heptane in a dry reaction flask, heated to reflux for 4–6 h, cooled to room temperature, and 2 wt% glycine and 5 wt% glacial acetic acid catalyst were added. Then, 0.11 mol of compound II was added, and the mixture was heated to reflux and stirred for 8–12 h. The reaction progress was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature, washed 2–3 times with 50 mL of saturated sodium chloride solution, and 100 mL of n-heptane was added. The organic phase was separated and dried with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the product was recrystallized with 40 mL of toluene to obtain the target product, compound III, 27.3 mol; yield 93.1%, purity 98.5%. Example 3

[0022] In the first step of the reaction, under nitrogen protection, 20.5 g (0.1 mol) of compound I was dissolved in 200 mL of cyclohexane in a dry reaction flask, heated to reflux for 4–6 h, cooled to room temperature, and 2 wt% glycine and 4 wt% glacial acetic acid catalyst were added. Then, 0.11 mol of compound II was added, and the mixture was heated to reflux and stirred for 8–12 h. The reaction progress was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature, washed 2–3 times with 50 mL of saturated sodium chloride solution, and 100 mL of cyclohexane was added. The organic phase was separated and dried with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the product was recrystallized with 40 mL of toluene to obtain 27.4 g of the target product, compound III; yield 93.5%, purity 98.2%. Example 4

[0023] In the second step, 29.3 g (0.1 mol) of compound III was dissolved in 200 ml of organic solvent THF, 0.11 mol of compound IV was added, and 10 mol% catalyst (Ni(cod)2 and PCy3 dissolved in THF under nitrogen protection, stirred for a few minutes, the COD ligand in Ni(cod)2 was replaced, and a catalytically active zero-valent nickel-monophosphine complex was generated in situ, with a concentration of 0.5 mol / L and Ni:P = 1:2) was added. The mixture was heated to reflux for 6–8 h, and the reaction progress was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated, 100 ml of toluene was added to dissolve the compound, and the mixture was washed with saturated brine. The organic phase was separated, evaporated under reduced pressure, and the product was recrystallized from 40 ml of toluene. The product was then separated to obtain 39.0 g of compound V, with a yield of 93.5% and a purity of 98.9%. Example 5

[0024] In the second step of the reaction, 29.3 g (0.1 mol) of compound III was dissolved in 200 ml of organic solvent THF, and 0.11 mol of compound IV was added. Then, 10 mol% catalyst (Ni(cod)₂ and PCy₃ dissolved in THF under nitrogen protection, stirred for a few minutes, during which the COD ligand in Ni(cod)₂ was substituted, generating a catalytically active zero-valent nickel-monophosphine complex in situ, with a concentration of 0.5 mol / L and Ni:P = 1:2) was added. The reaction was heated under reflux for 6–8 h, and the reaction progress was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated, 100 ml of toluene was added to dissolve the product, and the mixture was washed with saturated brine. The organic phase was separated, the product was evaporated under reduced pressure, and the product was recrystallized with 40 ml of toluene. The product was then separated to obtain 39.1 g of compound V, with a yield of 93.8% and a purity of 98.7%.

[0025] It will be apparent to those skilled in the art that the present 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 its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0026] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider 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 preparing 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide, characterized in that... Includes the following steps: In the first step of the reaction, under nitrogen protection, compound I was dissolved in an organic solvent in a dry reaction flask, heated to reflux for 4–6 h, cooled to room temperature, a catalyst was added, then compound II was added, the mixture was heated to reflux and stirred for 8–12 h, the reaction progress was monitored by HPLC, and after the reaction was completed, the mixture was cooled to room temperature and the product was separated to obtain compound III. In the second step, compound III was dissolved in an organic solvent, compound IV was added, a catalyst was added, and the mixture was heated under reflux for 6–8 hours. The reaction progress was monitored by HPLC. After the reaction was completed, the mixture was cooled to room temperature, and the product was separated to obtain compound V.

2. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: The organic solvents used in the first step reaction are n-heptane, cyclohexane, and toluene.

3. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: The molar ratio of compound II to compound I in the first step reaction is 1:1.0 to 1.

5.

4. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: The catalyst used in the first step reaction is glycine and glacial acetic acid, wherein the amount of glycine used is 1-5 wt% of compound I, and the amount of glacial acetic acid used is 3-10 wt% of compound I.

5. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: In the second step reaction, the molar ratio of compound III to compound IV is 1:1.0 to 1.

2.

6. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: The organic solvent used in the second step of the reaction is anhydrous toluene or THF.

7. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: The catalyst used in the second step reaction is a complex composed of zero-valent nickel [Ni(0)] and a monophosphine ligand.

8. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: The nickel source of the zero-valent nickel [Ni(0)] is Ni(cod)2, and the monophosphine ligand is tricyclohexylphosphine (PCy3).

9. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: In the second step reaction, the ratio of zero-valent nickel [Ni(0)] to monophosphine ligand is Ni:P = 1:1 to 1:

2.

10. The preparation process of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide according to claim 1, characterized in that: The amount of catalyst used in the second step is 5-10 mol of compound III.

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