Synthesis process of a high-purity pitavastatin calcium intermediate

Abstract

The invention discloses a synthesis process of a high-purity pitavastatin calcium intermediate, wherein 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-formaldehyde is dissolved in an organic solvent, an aminating reagent is added to the solution, a catalytic amount of glacial acetic acid is added, back flow reaction is performed, and product is separated after the reaction is completed to obtain compound II; the compound II obtained by the first step reaction is then dissolved in an organic solvent, compound III is added, heated to reflux reaction, and after the reaction is completed, product is separated to obtain target intermediate compound IV. The invention has the beneficial effects of: by the olefination reaction of imines and sulfone carbonyl compounds, the reaction product possesses a single selectivity, effectively reduces the generation of by-products while also increasing the yield of the product, and the present invention is simple to operate, mild reaction conditions, high product yield, generates little waste, meets the needs of green chemistry, and is suitable for industrialized scale-up production.

Description

Technical Field

[0001] The present invention relates to the technical field related to the synthesis of pharmaceutical intermediates, and in particular to a synthesis process of a high-purity pitavastatin calcium intermediate. Background Art

[0002] Pitavastatin calcium, chemically known as (3S,5R,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoic acid calcium salt, is the first fully synthetic HMG-CoA reductase inhibitor developed by Nissan Chemical Company and Kowa Co., Ltd. It was registered in Japan in November 1999 and first approved for marketing in Japan on July 17, 2003. Pitavastatin calcium antagonizes HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, thereby inhibiting hepatic cholesterol synthesis.

[0003] Currently, the key to the synthesis of pitavastatin calcium lies in the synthesis of products derived from the coupling of quinoline rings and side chains. There are two main routes for this: one is the Wittig reaction, where an aldehyde or ketone reacts with a phosphorus ylide (Wittig reagent) to form an olefin via nucleophilic addition (e.g., Routes 1 and 2); the other is the Julia reaction, where a sulfone reacts with an aldehyde or ketone to form an ester, which is then functionalized with a reducing agent and undergoes reductive elimination to form an olefin. The primary product of this reaction is a trans-olefin (e.g., Routes 3).

[0004] Patent WO2007 / 132482 reports a method for preparing pitavastatin and its salts, wherein 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline reacts with triphenylphosphine to form triphenylphosphine bromide, which is then subjected to a Wittig reaction with a side chain aldehyde and then hydrolyzed with hydrochloric acid to obtain pitavastatin tert-butyl ester. In this method, the Wittig reaction produces 20% of cis-isomers, resulting in a low yield. Furthermore, due to the generation of a large amount of triphenylphosphine, the three wastes produced are numerous, which is unfriendly to the environment (route one). CN1876633 reports a method for obtaining an olefin compound by coupling quinolinealdehyde with an alkyl triphenylphosphine salt via the Wittig reaction. The alkyl triphenylphosphine salt in this method is relatively expensive, the reaction selectivity is relatively difficult to control, the three wastes are relatively numerous, and the isomers are relatively difficult to purify (route two). The synthetic route is as follows:

[0005]

[0006] Route 2

[0007]

[0008] Patent CN111875538B reports a method for preparing pitavastatin tert-butyl ester. This method involves condensing (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester with a thiolate, oxidizing it to a sulfone, and then coupling it with a quinoline aldehyde. The reaction proceeds under alkaline conditions to yield the pitavastatin calcium intermediate. However, this method requires a long process, deep cooling, and harsh conditions. Furthermore, it undergoes multiple column chromatography steps, resulting in low efficiency. An example synthetic route is shown below:

[0009] Route 3

[0010]

[0011] The side chain coupling method of pitavastatin tert-butyl ester synthesized by the above route inevitably produces a Z-form product, which affects the purity of the product and results in insufficient purity of the obtained product. In addition, the isomeric products make subsequent separation and purification difficult, and increase the processing steps. Column chromatography is often required to obtain a high-purity product, but it will reduce the product yield, and the column chromatography method is not suitable for the needs of industrial production. Summary of the Invention

[0012] In view of the shortcomings of the side chain coupling method in the prior art for synthesizing pitavastatin calcium, such as insufficient purity, low product yield, and difficulty in product separation, the present invention aims to provide a synthesis process for a high-purity pitavastatin calcium intermediate. The Schiff base compound II is prepared by amination of the aldehyde group of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde. The Schiff base compound is then subjected to an olefination reaction with an α-(benzothiazolyl-2-sulfone) carbonyl compound to selectively obtain the E-form pitavastatin intermediate compound IV. Both steps of the reaction are high-yield reactions, effectively increasing the reaction yield and reducing the generation of reaction by-products, thereby obtaining a high-purity product. The synthesis route of the present invention is as follows:

[0013]

[0014] The technical solution of the present invention is as follows

[0015] A process for synthesizing a high-purity pitavastatin calcium intermediate comprises the following steps:

[0016] In the first step, 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde is dissolved in an organic solvent, an amination reagent is added to the solution, and a catalytic amount of glacial acetic acid is added, and the mixture is refluxed. After the reaction is completed, the product is separated to obtain compound II;

[0017] In the second step, the compound II obtained in the first step is dissolved in an organic solvent, and the compound III is added, and the mixture is heated under reflux for reaction. After the reaction is completed, the product is separated to obtain the target intermediate compound IV.

[0018] Furthermore, the organic solvent used in the first step reaction is ethanol, and the organic solvent ethanol is anhydrous ethanol.

[0019] Furthermore, the amination reagent used in the first step reaction is one of p-methoxyaniline and aniline, preferably p-methoxyaniline.

[0020] Furthermore, the molar ratio of the reactant compound I in the first step reaction to the amination reagent is 1:1.0 to 1.05, preferably 1:1.0.

[0021] Furthermore, the reflux temperature of the first step reaction is 75-80°C, preferably 78°C.

[0022] Furthermore, the solvent used in the second step reaction is tetrahydrofuran (THF).

[0023] Furthermore, the reaction temperature of the second step reaction is 65-75°C, preferably 70°C.

[0024] Furthermore, the molar ratio of reactant II to reactant III in the second step reaction is 1:1.0-1.5, preferably 1:1.2.

[0025] Furthermore, the reflux reaction time of the second step reaction is 22 to 26 hours, preferably 24 hours.

[0026] Furthermore, the reflux operation of the first step reaction is water separation reflux, and water in the reflux gas is removed by setting a water separation reflux device.

[0027] The beneficial effects of the present invention are as follows: the present invention divides the original step into two steps through amination and olefination, thereby improving the stereoselectivity of the reaction, effectively avoiding the generation of Z-isomer products in the reaction, greatly improving the purity of the product, and reducing the difficulty of product separation. The two-step reaction is a high-yield reaction, reducing the generation of by-products while also increasing the product yield. The present invention has simple operation, mild reaction conditions, high product yield, and less waste generation, meets the requirements of green chemistry, and is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is a schematic diagram of the reaction flow of the process route of the present invention;

[0029] Figure 2 This is a schematic diagram of the reaction flow of Route 1 of the present invention;

[0030] Figure 3 This is a schematic diagram of the reaction flow of Route 2 of the present invention;

[0031] Figure 4 Schematic diagram of the reaction flow of route three of the present invention. DETAILED DESCRIPTION

[0032] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the embodiments of the present invention and the accompanying drawings. Obviously, the embodiments described 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 making creative efforts are within the scope of protection of the present invention.

[0033] Example 1

[0034] In the first step, 14.6 g (0.05 mol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde was dissolved in 200 ml of anhydrous ethanol, 6.1 g (0.05 mol) of p-methoxyaniline was added to the solution, and 3 to 5 drops of glacial acetic acid were added. The mixture was heated to 78°C and kept at 78°C for reflux reaction. After the reaction, the mixture was dried over anhydrous sodium sulfate, concentrated by evaporation, filtered, and the filter cake was washed with a small amount of anhydrous ethanol. Finally, it was recrystallized from 50 ml of toluene to obtain 18.9 g of the product compound II with a yield of 95.1% and a purity of 97.4%.

[0035] Example 2

[0036] In the second step, 19.8 g (0.05 mol) of compound II obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 28.3 g (0.06 mol) of compound III was added. The temperature was gradually raised to 70°C over 30 minutes, and the reaction was refluxed at a constant temperature for 24 hours. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution and 50 ml of deionized water were added to wash 2 to 3 times. The organic phase was separated, the solvent was evaporated, and 50 ml of toluene was added for recrystallization to obtain 25.2 g of the target intermediate compound IV with a yield of 92.1% and an ee value of >99%.

[0037] Example 3

[0038] In the first step, 14.6 g (0.05 mol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde was dissolved in 200 ml of anhydrous ethanol, 5.8 g (0.0510 mol) of p-methoxyaniline was added to the solution, and 3 to 5 drops of glacial acetic acid were added. The mixture was heated to 78°C and kept at 78°C for reflux reaction. After the reaction, the mixture was dried over anhydrous sodium sulfate, concentrated by evaporation, filtered, and the filter cake was washed with a small amount of anhydrous ethanol. Finally, it was recrystallized from 50 ml of toluene to obtain 19.0 g of the product compound II with a yield of 95.6% and a purity of 97.5%.

[0039] Example 4

[0040] In the first step, 14.6 g (0.05 mol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde was dissolved in 200 ml of anhydrous ethanol, 6.5 g (0.0525 mol) of p-methoxyaniline was added to the solution, and 3 to 5 drops of glacial acetic acid were added. The mixture was heated to 78°C and kept at 78°C for reflux reaction. After the reaction, the mixture was dried over anhydrous sodium sulfate, concentrated by evaporation, filtered, and the filter cake was washed with a small amount of anhydrous ethanol. Finally, it was recrystallized from 50 ml of toluene to obtain 19.0 g of the product compound II with a yield of 95.6% and a purity of 97.6%.

[0041] Example 5 (Comparative Example)

[0042] In the first step, 14.6 g (0.05 mol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde was dissolved in 200 ml of anhydrous ethanol, 4.6 g (0.05 mol) of aniline was added to the solution, and 3 to 5 drops of glacial acetic acid were added. The mixture was heated to 78° C. and kept at 78° C. for reflux reaction. After the reaction was completed, the mixture was dried over anhydrous sodium sulfate, concentrated by evaporation, filtered, and the filter cake was washed with a small amount of anhydrous ethanol. Finally, it was recrystallized from 50 ml of toluene to obtain 17.5 g of the product with a yield of 95.3% and a purity of 96.8%.

[0043] Example 6

[0044] In the second step, 19.8 g (0.05 mol) of compound II obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 23.6 g (0.05 mol) of compound III was added. The temperature was gradually raised to 70°C over 30 minutes, and the reaction was refluxed at a constant temperature for 24 hours. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution and 50 ml of deionized water were added to wash 2 to 3 times. The organic phase was separated, the solvent was evaporated, and 50 ml of toluene was added for recrystallization to obtain 24.3 g of the target intermediate compound IV with a yield of 88.8% and an ee value of >99%.

[0045] Example 7

[0046] In the second step, 19.8 g (0.05 mol) of compound II obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 35.4 g (0.075 mol) of compound III was added. The temperature was gradually raised to 70° C. over 30 minutes, and the reaction was refluxed at a constant temperature for 24 hours. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution and 50 ml of deionized water were added to wash 2 to 3 times. The organic phase was separated, the solvent was evaporated, and 50 ml of toluene was added for recrystallization to obtain 25.3 g of the target intermediate compound IV with a yield of 92.4% and an ee value of >99%.

[0047] Example 8

[0048] In the second step, 19.8 g (0.05 mol) of compound II obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 28.3 g (0.06 mol) of compound III was added. The temperature was gradually raised to 65° C. over 30 minutes, and the reaction was refluxed at a constant temperature for 24 hours. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution and 50 ml of deionized water were added to wash 2 to 3 times. The organic phase was separated, the solvent was evaporated, and 50 ml of toluene was added for recrystallization to obtain 24.6 g of the target intermediate compound IV with a yield of 89.9% and an ee value of >99%.

[0049] Example 9

[0050] In the second step, 19.8 g (0.05 mol) of compound II obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 28.3 g (0.06 mol) of compound III was added. The temperature was gradually raised to 75° C. over 30 minutes, and the reaction was refluxed at a constant temperature for 24 hours. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution and 50 ml of deionized water were added to wash 2 to 3 times. The organic phase was separated, the solvent was evaporated, and 50 ml of toluene was added for recrystallization to obtain 25.0 g of the target intermediate compound IV with a yield of 91.4% and an ee value of >99%.

[0051] Example 10

[0052] In the second step, 19.8 g (0.05 mol) of compound II obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 28.3 g (0.06 mol) of compound III was added. The temperature was gradually raised to 70°C over 30 minutes, and the reaction was refluxed at a constant temperature for 22 hours. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution and 50 ml of deionized water were added to wash 2 to 3 times. The organic phase was separated, the solvent was evaporated, and 50 ml of toluene was added for recrystallization to obtain 24.5 g of the target intermediate compound IV with a yield of 89.6% and an ee value of >99%.

[0053] Example 11

[0054] In the second step, 19.8 g (0.05 mol) of compound II obtained in the first step was dissolved in 200 ml of tetrahydrofuran, and 28.3 g (0.06 mol) of compound III was added. The temperature was gradually raised to 70°C over 30 minutes, and the reaction was refluxed at a constant temperature for 26 hours. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution and 50 ml of deionized water were added to wash 2 to 3 times. The organic phase was separated, the solvent was evaporated, and 50 ml of toluene was added for recrystallization to obtain 25.1 g of the target intermediate compound IV with a yield of 91.8% and an ee value of >99%.

[0055] Example 12 (Comparative Example)

[0056] In the second step, 18.3 g (0.05 mol) of the compound obtained in the first step of the reaction in Example 5 was dissolved in 200 ml of tetrahydrofuran, and 28.3 g (0.06 mol) of compound III was added. The temperature was gradually raised to 70° C. over 30 minutes, and the reaction was refluxed at a constant temperature for 26 hours. After the reaction was completed, 50 ml of saturated sodium bicarbonate solution and 50 ml of deionized water were added, washed 2 to 3 times, and the organic phase was separated. The solvent was evaporated and 50 ml of toluene was added for recrystallization to obtain 24.5 g of the target intermediate compound IV with a yield of 89.6% and an ee value of >99%.

[0057] Example of comparative document (CN103508946B)

[0058] Example 1-1

[0059] Operation steps: Add 29.1 g of compound I, 17.2 g of methyldichlorosilane, 8 g of ferric chloride, 40.2 g of halogenating reagent phosphorus tribromide, and 60 ml of acetonitrile to a 100 ml three-necked flask, stir and reflux at 75-85 ° C under nitrogen protection, and complete the reaction by TLC detection. Add dilute hydrochloric acid to the reaction system to terminate the reaction, let it stand and separate the organic layer, separate the organic layer, and wash it with sodium bicarbonate and saturated brine. The washing liquid is separated from the organic layer, and anhydrous magnesium sulfate is added to the organic layer, dried, filtered, and the filtrate is concentrated under reduced pressure to obtain 30.5 g of compound II, which is confirmed to be compound II by comparison with the melting point data of standard compound II. The melting point of compound II is 138-140 ° C, and the yield of compound II is 86%.

[0060] Example 2-1

[0061] Operation steps: Add 30 g of compound II, 30.76 g of triethoxyphosphine, and 300 ml of toluene to a three-necked flask, stir and reflux at 100-110 ° C until the reaction is complete by TLC detection. After the reaction solution is concentrated under reduced pressure, a 1:1 mixed crystallization solution of chloroform-petroleum ether is added and recrystallized to obtain 33.5 g of crystals, which are confirmed to be compound III by comparison with the melting point data of standard compound III. The melting point of compound III is 89-90 ° C, and the yield of compound III is 96%.

[0062] Example 3-1

[0063] Procedure: Add 30 g of compound III dropwise to 200 ml of tetrahydrofuran solution to prepare reaction solution III-I. Add 15 g of compound IV dropwise to 200 ml of tetrahydrofuran solution to prepare reaction solution III-II. Add 200 ml of THF (tetrahydrofuran) to a 1000 ml four-necked flask, cool to -10°C, add 30 ml of n-butyl lithium under nitrogen, stir and cool to -70-80°C, add reaction solution III-I dropwise, stir for at least 1 hour, then add reaction solution III-II dropwise, continue stirring until the reaction is complete as determined by TLC, and terminate the reaction by adding saturated sodium bicarbonate solution. Add ethyl acetate to the reaction mixture, extract by vortexing, and allow to stand for separation. The organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and frozen to obtain 27.4 g of compound V, melting point: 44-46°C, yield: 71%.

[0064] In summary, compared with the prior art, the technical solution of the present invention has higher yield, simpler operation and higher optical purity when preparing pitavastatin calcium intermediate.

[0065] 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 embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be included therein. Any reference sign in a claim should not be construed as limiting the claim to which it relates.

[0066] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method 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 can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A synthesis process for a high-purity pitavastatin calcium intermediate, characterized in that The following steps are involved: In the first step, 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde is dissolved in anhydrous ethanol, an amination reagent is added to the solution, and a catalytic amount of glacial acetic acid is added. The reaction temperature is 75-80°C, water is separated and refluxed, and the product is separated after the reaction is completed to obtain compound II; In the second step, the compound II obtained in the first step is dissolved in tetrahydrofuran (THF), and the compound III is added. The reaction temperature is 65-75°C and refluxed for 22-26 hours. After the reaction is completed, the product is separated to obtain the target intermediate compound IV. The amination reagent used in the first step reaction is p-methoxyaniline; The molar ratio of the reactant compound I to the amination reagent in the first step is 1:1.0-1.05; In the second step reaction, the molar ratio of reactant II to reactant III is 1:1.0-1.5.

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