Novel preparation method of atorvastatin intermediate

Abstract

The invention discloses a novel preparation method of an atorvastatin intermediate. The method comprises the following steps: fluorinating a compound I to obtain a compound II; dissolving the compound II and the compound III in an organic solvent, adding a catalyst, reacting at 40-60 DEG C for 6-8 hours, and separating a product after the reaction is finished to obtain a compound IV; and dissolving the compound IV in an organic solvent, introducing hydrogen, adding a catalyst, carrying out a heating reaction at 2-5atm for 4-6h, and after the reaction is finished, separating the product to obtain the compound IV. The method has the beneficial effects that the reaction route is short, the operation is less, the operation is simple, the product yield and selectivity are high, the post-treatment of the product is convenient, and the industrial expanded-scale production is convenient; the reaction route provided by the invention provides a new synthesis direction for an atorvastatin parent nucleus synthesis process; the reaction raw materials are easy to obtain, expensive reagents are not used, the product yield is high, and the production cost is further reduced.

Description

Technical Field

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

[0002] Atorvastatin calcium is a statin lipid-regulating drug. Due to its low toxicity and side effects, unique mechanism of action, and good tolerance, it has a broad market application prospect. Among them, the atorvastatin calcium mother core is the key intermediate for the synthesis of atorvastatin calcium, and its structural formula is as follows:

[0003]

[0004] US Patent No. 8946479B2 discloses a method for synthesizing the mother core of atorvastatin calcium, using acetone as solvent and potassium carbonate as base, isobutyrylacetanilide and 2-bromo-1-(4-fluorophenyl)-2-acetophenone react at 25°C for 6 hours, filter, concentrate and then recrystallize from isopropanol to obtain the product. Analysis by HPLC shows that the crude product concentrated by this method has a content of only 71.1%, the raw material conversion is incomplete, and an unknown impurity (RRT1.05) with a polarity similar to that of the product is produced, with a content of about 10%, which accounts for a high proportion and needs to be recrystallized and refined again. After one recrystallization, the unknown single impurity content is still 1.3%, and the melting point is 192.7-193.6°C, which is difficult to reach the enterprise standard single impurity content of less than 0.1%, and the melting point is in the range of 196.0-205.0°C.

[0005] US Patent US20110060164Al discloses a method for synthesizing the mother core of atorvastatin calcium, using isopropanol as solvent, potassium carbonate as base, isobutyrylacetanilide and 2-chloro-1-(4-fluorophenyl)-2-acetophenone react at 45°C for 10 hours, extract with ethyl acetate, concentrate and then recrystallize with isopropanol to obtain the product. The crude product generated by the method is concentrated with a content of only 36.3%, the raw material remains about 50%, and the content of unknown impurities (RRT1.05) accounts for about 7%. The reaction conversion is extremely incomplete, and because the crude product has a low purity, it is difficult to purify.

[0006] It can be seen that there are some problems in the traditional synthesis route of atorvastatin calcium core, such as incomplete conversion of raw materials and the generation of unknown impurities (RRT1.05) that are difficult to remove during the reaction, which will directly affect the quality of the final product, resulting in unqualified melting point during product testing and low qualified rate of product refining in one time, which requires subsequent rework, directly affecting production efficiency and increasing product costs. Summary of the invention

[0007] In view of the above-mentioned deficiencies of the current atorvastatin core synthesis process, the present invention adopts the following technical solutions:

[0008] A novel method for preparing an atorvastatin intermediate comprises the following preparation steps:

[0009]

[0010] The first step is to dissolve compound I in an organic solvent, add a fluorinating agent, react at -5 to 0°C for 8 to 10 hours, and separate the product after the reaction to obtain compound II;

[0011] The second step is to dissolve compound II and compound III in an organic solvent, add a catalyst, react at 40-60°C for 6-8h, and separate the product after the reaction to obtain compound IV;

[0012] The third step is to dissolve compound IV in an organic solvent, introduce hydrogen, add a catalyst, heat to 30-40°C at 2-5 atm and react for 4-6 hours. After the reaction is completed, separate the product to obtain compound IV.

[0013] Furthermore, the solvent used in the first step reaction and the third step reaction is hexane or tetrahydrofuran, preferably tetrahydrofuran.

[0014] Furthermore, the solvent used in the second step reaction is dichloromethane or chloroform, preferably dichloromethane.

[0015] Furthermore, the fluorinating agent used in the first step reaction is hydrogen fluoride.

[0016] Furthermore, the catalyst used in the second step reaction is piperidine, and the amount of the catalyst used is 5-10 mol%, preferably 10 mol%, of compound II.

[0017] Furthermore, the catalyst used in the third step is Pd / C, and the palladium content in the catalyst is 5wt%.

[0018] Furthermore, the amount of the catalyst used in the third step reaction is 5 to 10 mol% of compound IV.

[0019] Furthermore, the amount of the fluorinating agent used in the first step reaction is 1 eq of compound I.

[0020] Furthermore, the molar ratio of compound II to compound III in the second step reaction is 1:1 to 1.2.

[0021] Furthermore, the solvent used in the second step is an anhydrous solvent.

[0022] The beneficial effects of the present invention are: 1. The reaction route of the present invention is short, the operation is less, the operation is simple, the product yield and selection are high, the product post-processing is convenient, and it is convenient to expand the scale of industrial production; 2. The reaction route of the present invention provides a new synthesis direction for the atorvastatin mother nucleus synthesis process; 3. The reaction raw materials of the present invention are easy to obtain, no expensive reagents are used, the product yield is high, and the production cost is further reduced, which provides a new research direction for the atorvastatin mother nucleus synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is a schematic structural diagram of the atorvastatin intermediate mother core of the present invention;

[0024] Figure 2 The figure is a flow chart of the reaction route of the present invention. DETAILED DESCRIPTION

[0025] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] Combination Figure 1 to Figure 2 Shown:

[0027] Example 1

[0028] The first step is to dissolve 21.0 g (0.1 mol) of compound I in 300 ml of anhydrous tetrahydrofuran, an organic solvent, and slowly add 0.1 mol of fluorinating agent hydrogen fluoride at -5 to 0°C, react at -5 to 0°C for 8 to 10 hours, add dilute sodium hydroxide solution to neutralize the reaction until neutral, separate the organic phase, wash the organic phase with saturated brine 2 to 3 times, evaporate the solvent, and recrystallize the product with 50 ml of toluene to obtain 21.5 g of compound II with a yield of 94.2% and a purity of 98.9%;

[0029] The second step is to dissolve 22.8g (0.1mol) of compound II and 0.1mol of compound III in 250ml of organic solvent dichloromethane, add 0.01mol of piperidine as a catalyst, react at 40-60°C for 6-8h, and after the reaction is completed, separate the organic phase, wash the organic phase with saturated brine 2-3 times, evaporate the solvent, and recrystallize the product with 40ml of acetone to obtain 39.4g of compound IV with a yield of 94.9% and a purity of 98.6%;

[0030] The third step is to dissolve 20.7 g (0.05 mol) of compound IV in 200 ml of organic solvent tetrahydrofuran under nitrogen protection, and then add 0.005 mol of catalyst Pd / C (5 wt%) after hydrogen is introduced to fill the container. The mixture is heated to 30-40° C. at 2-5 atm and reacted for 4-6 hours. After the reaction is completed, the product is separated by filtration, and the filtrate is washed with saturated brine for 2-3 times. The solvent is evaporated and the product is recrystallized with 50 ml of xylene to obtain 19.6 g of compound IV with a yield of 94.2% and a purity of 98.2%.

[0031] Example 2

[0032] The second step is to dissolve 22.8g (0.1mol) of compound II and 0.1mol of compound III in 250ml of organic solvent dichloromethane, add a catalyst 0.005mol of piperidine, react at 40-60°C for 6-8h, and after the reaction is completed, separate the organic phase, wash the organic phase with saturated brine 2-3 times, evaporate the solvent, and recrystallize the product with 40ml of acetone to obtain 39.0g of compound IV with a yield of 94.0% and a purity of 98.7%;

[0033] Example 3

[0034] In the second step, 22.8 g (0.1 mol) of compound II and 0.12 mol of compound III were dissolved in 250 ml of organic solvent dichloromethane, and 0.01 mol of piperidine was added as a catalyst. The mixture was reacted at 40-60° C. for 6-8 hours. After the reaction was completed, the organic phase was separated, and the organic phase was washed with saturated brine for 2-3 times. The solvent was evaporated, and the product was recrystallized with 40 ml of acetone to obtain 39.1 g of compound IV with a yield of 94.2% and a purity of 98.5%.

[0035] Example 4

[0036] The third step is to dissolve 20.7 g (0.05 mol) of compound IV in 200 ml of tetrahydrofuran, an organic solvent, under nitrogen protection. After hydrogen is introduced to fill the container, 0.0025 mol of catalyst Pd / C (5 wt%) is added, and the mixture is heated to 30-40° C. at 2-5 atm and reacted for 4-6 hours. After the reaction is completed, the product is separated by filtration, and the filtrate is washed with saturated brine for 2-3 times. The solvent is evaporated and the product is recrystallized with 50 ml of xylene to obtain 19.5 g of compound IV with a yield of 93.7% and a purity of 98.8%.

[0037] Example 5

[0038] The third step is to dissolve 20.7 g (0.05 mol) of compound IV in 200 ml of organic solvent hexane under nitrogen protection, and then add 0.005 mol of catalyst Pd / C (5 wt%) after hydrogen is introduced to fill the container. The mixture is heated to 30-40° C. at 2-5 atm and reacted for 4-6 hours. After the reaction is completed, the product is separated by filtration, and the filtrate is washed with saturated brine for 2-3 times. The solvent is evaporated and the product is recrystallized with 50 ml of xylene to obtain 19.2 g of compound IV with a yield of 92.3% and a purity of 98.9%.

[0039] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0040] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A novel method for preparing an atorvastatin intermediate, characterized in that The method comprises the following preparation steps: The first step is to dissolve compound I in an organic solvent, add a fluorinating agent, react at -5 to 0°C for 8 to 10 hours, and separate the product after the reaction to obtain compound II; The second step is to dissolve compound II and compound III in an organic solvent, add a catalyst, react at 40-60°C for 6-8h, and separate the product after the reaction to obtain compound IV; The third step is to dissolve compound IV in an organic solvent, introduce hydrogen, add a catalyst, heat to 30-40°C at 2-5 atm and react for 4-6 hours. After the reaction is completed, separate the product to obtain compound IV.

2. The novel method for preparing an atorvastatin intermediate according to claim 1, characterized in that: The solvent used in the first step reaction and the third step reaction is hexane or tetrahydrofuran.

3. The novel method for preparing an atorvastatin intermediate according to claim 1, characterized in that: The solvent used in the second step reaction is dichloromethane or chloroform.

4. The novel method for preparing an atorvastatin intermediate according to claim 1, characterized in that: The fluorinating agent used in the first step reaction is hydrogen fluoride.

5. The novel method for preparing an atorvastatin intermediate according to claim 1, characterized in that: The catalyst used in the second step reaction is piperidine, and the amount of the catalyst used is 5-10 mol% of compound II.

6. The novel method for preparing an atorvastatin intermediate according to claim 1, characterized in that: The catalyst used in the third step is Pd / C, and the palladium content in the catalyst is 5wt%.

7. The novel method for preparing an atorvastatin intermediate according to claim 1, characterized in that: The amount of the catalyst used in the third step reaction is 5-10 mol% of compound IV.

8. The novel method for preparing an atorvastatin intermediate according to claim 1, characterized in that: The amount of the fluorinating agent used in the first step reaction is 1 eq of compound I.

9. The novel method for preparing an atorvastatin intermediate according to claim 1, characterized in that: The molar ratio of the second step reaction compound II to the compound III is 1:1-1.

2.

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

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