Novel method for synthesizing side chain of rosuvastatin intermediate

Abstract

The invention discloses a novel method for synthesizing a rosuvastatin intermediate side chain. The method comprises the following steps: preparing a compound III from a compound I and a compound II; preparing a compound V from the compound III and the compound IV; and reducing the compound V to obtain a 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 the current side chain synthesis process; the reaction raw materials are easy to obtain, expensive reagents are not used, the product yield is high, the production cost is further reduced, and a new direction is provided for side chain synthesis of rosuvastatin.

Description

Technical Field

[0001] The invention relates to the technical field related to the synthesis of pharmaceutical intermediates, and in particular to a new method for synthesizing the side chain of a rosuvastatin intermediate. Background Art

[0002] Rosuvastatin calcium (ROSUVASTATIN CALCIUM) was first successfully developed by Shionogi Co., Ltd. of Japan. Later, Shionogi transferred the drug technology to AstraZeneca of the United Kingdom. The drug is a new type of HMG-CoA reductase inhibitor, which can effectively reduce blood lipids. Because it has the advantages of high efficiency and low toxic side effects, it is very popular among people, so the drug has a very broad prospect. The compound and its preparation method are disclosed in European patent EP0521471A. The preparation method is characterized in that the pyrimidine parent nucleus is prepared to obtain a multi-substituted formaldehyde, and in addition, the chiral side chain is synthesized into a phosphonium salt, and then the rosuvastatin skeleton is obtained by Wittig reaction condensation. The key synthesis steps are as follows:

[0003] The methyl ester side chain The synthesis process of phosphonium salts is referred to J.Org.C hem.1994,59,7849-7854, and the synthesis route is as follows:

[0004]

[0005] The starting material of its methyl ester side chain phosphonium salt is 3-TBDMS oxoglutaric anhydride. The chiral purity of the compound obtained by splitting it using chiral benzyl mandelate is not high, and most of the intermediates are liquids, which are difficult to purify during industrialization and the technical difficulty is very high. Summary of the invention

[0006] In view of the shortcomings of the above-mentioned synthesis route, the present invention provides a new method for synthesizing the side chain of rosuvastatin intermediates to synthesize methyl ester side chain phosphonium salts. The technical scheme of the present invention is as follows:

[0007] A novel method for synthesizing the side chain of a rosuvastatin intermediate comprises the following steps:

[0008]

[0009] In the first step, compound I and compound II are dissolved in an organic solvent, a catalyst is added, and the mixture is reacted at room temperature for 2 to 3 hours. After the reaction is completed, the reaction is quenched and the product is separated to obtain compound III.

[0010] The second step is to dissolve compound III and compound IV in an organic solvent, react at low temperature for 8 to 10 hours, and after the reaction is completed, separate the product to obtain compound V;

[0011] The third step is to dissolve compound V in an organic solvent, add a reducing agent, and react at -10 to 0°C for 6 to 8 hours. After the reaction is completed, separate the product to obtain compound IV.

[0012] Furthermore, the solvent used in the first step reaction is toluene, and the solvent used in the second step is tetrahydrofuran.

[0013] Furthermore, the solvent used in the third step reaction is tetrahydrofuran.

[0014] Furthermore, the catalyst used in the first step is sodium hydride.

[0015] Furthermore, the reducing agent used in the third step reaction is borane, and the catalyst used is diisopinocamphenyl borane (DIP-Chloride).

[0016] Furthermore, the molar ratio of compound I to compound II in the first step reaction is 1:1.

[0017] Furthermore, the molar ratio of compound III to compound IV in the second step reaction is 1:1.0-1.1.

[0018] Furthermore, the molar ratio of the first step reaction compound I to the catalyst is 1:1.2-2.

[0019] Furthermore, the temperature of the second step reaction is -20 to 0°C.

[0020] Furthermore, in the third step reaction, the amount of the reducing agent used is 1 eq of compound V, and the amount of the catalyst used is 10-20 mol% of compound V.

[0021] 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 easy to expand the scale of industrial production; 2. The reaction route of the present invention provides a new synthesis direction for the current side chain 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 direction for the side chain synthesis of rosuvastatin. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the rosuvastatin synthesis route of the present invention;

[0023] Figure 2 Schematic diagram of the side chain structure of the present invention;

[0024] Figure 3 The schematic diagram of the side chain synthesis route of the prior art of the present invention;

[0025] Figure 4 Schematic diagram of the side chain synthesis route of the present invention. DETAILED DESCRIPTION

[0026] 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.

[0027] Example 1

[0028] In the first step, under nitrogen, 16.7 g (0.05 mol) of compound I and 18.8 g (0.05 mol) of compound II were dissolved in 300 ml of organic solvent toluene, 0.075 mol of sodium hydride as a catalyst was added, 0.1 mol of anhydrous calcium chloride was added, and the mixture was stirred and reacted at room temperature for 2 to 3 hours. After the reaction was completed, anhydrous ethanol was slowly added to quench the reaction, and the solution was neutralized with dilute hydrochloric acid to neutrality, and saturated salt was added to wash 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of toluene to separate the product, and 17.7 g of compound III was obtained, with a yield of 94.1% and a purity of 98.8%;

[0029] The second step, under nitrogen protection, 18.8 (0.05 mol) of compound III was dissolved in 200 ml of organic solvent tetrahydrofuran at 0°C, 6.1 g (0.05 mol) of compound IV was slowly added, and the reaction was continued at low temperature of -20 to 0°C for 8 to 10 hours. After the reaction was completed, dilute hydrochloric acid was added to neutralize the reaction until neutrality, the solvent was evaporated, 100 ml of dichloromethane and water were added for extraction, the product was separated, the solvent was evaporated, and the product was recrystallized from 50 ml of toluene to obtain 21.8 g of compound V, with a yield of 94.7% and a purity of 97.8%;

[0030] The third step is to dissolve 23.0g (0.05mol) of compound V in an organic solvent, tetrahydrofuran, add 0.05mol of reducing agent borane, add 0.0075mol of catalyst diisopine camphoryl borane DIP-Chloride, react at -10-0°C for 6-8h, add dilute hydrochloric acid to neutralize the reaction until neutral, extract with 100ml of toluene, wash the extract with saturated brine 2-3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40ml of acetone to obtain 22.1g of compound IV with a yield of 95.6% and a purity of 97.9%.

[0031] Example 2

[0032] In the first step, under nitrogen, 16.7 g (0.05 mol) of compound I and 18.8 g (0.05 mol) of compound II were dissolved in 300 ml of organic solvent toluene, 0.06 mol of sodium hydride as a catalyst was added, 0.1 mol of anhydrous calcium chloride was added, and the mixture was stirred and reacted at room temperature for 2 to 3 hours. After the reaction was completed, anhydrous ethanol was slowly added to quench the reaction, and the solution was neutralized with dilute hydrochloric acid to neutrality, and saturated salt was added to wash 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of toluene to separate the product, and 17.7 g of compound III was obtained, with a yield of 92.5% and a purity of 98.5%;

[0033] Example 3

[0034] In the first step, under nitrogen, 16.7 g (0.05 mol) of compound I and 18.8 g (0.05 mol) of compound II were dissolved in 300 ml of organic solvent toluene, 0.1 mol of sodium hydride as a catalyst was added, 0.1 mol of anhydrous calcium chloride was added, and the mixture was stirred and reacted at room temperature for 2 to 3 hours. After the reaction was completed, anhydrous ethanol was slowly added to quench the reaction, and the solution was neutralized with dilute hydrochloric acid to neutrality, and saturated salt was added to wash 2 to 3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 40 ml of toluene to separate the product, and 17.7 g of compound III was obtained, with a yield of 93.6% and a purity of 98.7%;

[0035] Example 4

[0036] In the second step, under nitrogen protection, 18.8 (0.05 mol) of compound III was dissolved in 200 ml of tetrahydrofuran, an organic solvent, and 6.1 g (0.06 mol) of compound IV was slowly added at -20 to 0°C. The reaction was continued for 8 to 10 hours at low temperature. After the reaction was completed, dilute hydrochloric acid was added to neutralize the reaction until it was neutral, the solvent was evaporated, 100 ml of dichloromethane and water were added to extract, the product was separated, the solvent was evaporated, and the product was recrystallized from 50 ml of toluene to obtain 21.3 g of compound V, with a yield of 93.4% and a purity of 97.5%;

[0037] Example 5

[0038] The third step is to dissolve 23.0g (0.05mol) of compound V in an organic solvent, tetrahydrofuran, add 0.05mol of reducing agent borane, add 0.01mol of diisopinecamphenylborane (DIP-Chloride) as a catalyst, react at -10-0°C for 6-8h, add dilute hydrochloric acid to neutralize the reaction until neutral, extract with 100ml of toluene, wash the extract with saturated brine for 2-3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40ml of acetone to obtain 21.5g of compound IV with a yield of 93.0% and a purity of 97.9%.

[0039] Example 6

[0040] The third step is to dissolve 23.0g (0.05mol) of compound V in an organic solvent, tetrahydrofuran, add 0.05mol of reducing agent borane, add 0.005mol of catalyst diisopine camphoryl borane DIP-Chloride, react at -10-0°C for 6-8h, add dilute hydrochloric acid to neutralize the reaction until neutral, extract with 100ml of toluene, wash the extract with saturated brine 2-3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40ml of acetone to obtain 21.8g of compound IV with a yield of 94.3% and a purity of 97.9%.

[0041] 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.

[0042] 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 synthesizing the side chain of a rosuvastatin intermediate, characterized in that The following steps are involved: In the first step, compound I and compound II are dissolved in an organic solvent, a catalyst is added, and the mixture is reacted at room temperature for 2 to 3 hours. After the reaction is completed, the reaction is quenched and the product is separated to obtain compound III. The second step is to dissolve compound III and compound IV in an organic solvent, react at low temperature for 8 to 10 hours, and after the reaction is completed, separate the product to obtain compound V; The third step is to dissolve compound V in an organic solvent, add a reducing agent, and react at -10 to 0°C for 6 to 8 hours. After the reaction is completed, separate the product to obtain compound IV.

2. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The solvent used in the first step reaction is toluene, and the solvent used in the second step is tetrahydrofuran.

3. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The solvent used in the third step reaction is tetrahydrofuran.

4. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The catalyst used in the first step is sodium hydride.

5. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The reducing agent used in the third step reaction is borane, and the catalyst used is diisopinocamphenyl borane (DIP-Chloride).

6. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: In the first step reaction, the molar ratio of compound I to compound II is 1:

1.

7. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The molar ratio of the compound III to the compound IV in the second step reaction is 1:1.0-1.

1.

8. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The molar ratio of the first step reaction compound I to the catalyst is 1:1.2-2.

9. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: The temperature of the second step reaction is -20 to 0°C.

10. The novel process for synthesizing an atorvastatin intermediate according to claim 1, characterized in that: In the third step reaction, the amount of the reducing agent used is 1 eq of compound V, and the amount of the catalyst used is 10-20 mol% of compound V.

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