Rosuvastatin intermediate side chain connection process

Abstract

The invention discloses a rosuvastatin intermediate side chain connection process which comprises the following steps: dissolving a compound I and a compound II in an organic solvent, adding a catalyst, reacting at 55-60 DEG C for 3-5 hours, and after the reaction is finished, separating a product to obtain a compound III; and dissolving the compound III in an organic solvent, introducing hydrogen, adding a catalyst, heating to 30-40 DEG C at 2-5atm, reacting for 4-6 hours, and separating a product after the reaction is finished 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 a rosuvastatin synthesis process; the reaction raw materials are easy to obtain, expensive reagents are not used, the product yield is high, the production cost is reduced, and a new research direction is provided for atorvastatin parent nucleus synthesis.

Description

Technical Field

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

[0002] Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and can be used to treat hypercholesterolemia and mixed dyslipidemia. It can reduce elevated low-density lipoprotein cholesterol, total cholesterol, triglycerides and apoprotein B concentrations, while increasing high-density lipoprotein concentrations. It can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia and is known as a super statin.

[0003] Rosuvastatin is administered as its single enantiomer calcium salt, chemically named bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), with the following chemical formula:

[0004]

[0005] The main method for synthesizing rosuvastatin currently has a key step in which a carbon-carbon double bond connecting the calcium pyrimidine core of rosuvastatin and the key chiral side chain is constructed by an olefination reaction.

[0006] At present, there are two main synthetic routes for rosuvastatin calcium. One is to construct a carbon-carbon double bond synthesis connecting the pyrimidine parent core of rosuvastatin calcium and the key chiral side chain through Witting olefination reaction. The other is to construct a carbon-carbon double bond synthesis connecting the pyrimidine parent core of rosuvastatin calcium and the key chiral side chain through Julia olefination reaction. The Witting olefination reaction route (Chemical Invention Publication Document CN200510069557.1) is exemplified as follows:

[0007]

[0008] The following is an example of a Julia olefination reaction:

[0009]

[0010] At present, the double bond synthesis of the main route of rosuvastatin is achieved through Witting reaction or Julia reaction. The improvement scheme of the route by those skilled in the art is also limited to adjusting the relative position of the aldehyde group and the functional group required for olefination and replacing different types of functional groups required to meet the reaction conditions of Witting olefination or Julia olefination. The improvement of Witting reaction cannot solve the problem of poor stereoselectivity and numerous by-products of Witting reaction. In addition, for Julia reaction, it has extremely high selectivity, but the side chain group is difficult to oxidize. The technical solution provided by the public document CN201910997404.5 provides a new side chain synthesis method, but it still cannot avoid the problem of difficulty in introducing the required reactive groups, so the product yield is not high and the atom economy is poor. Summary of the invention

[0011] In view of the above shortcomings, the present invention adopts the following technical solutions:

[0012] A rosuvastatin intermediate side chain connection process, characterized by comprising the following synthesis steps:

[0013]

[0014] The first step is to dissolve compound I and compound II in an organic solvent, add a catalyst, react at 55-60°C for 3-5 hours, and after the reaction is completed, separate the product to obtain compound III;

[0015] In the second step, compound III is dissolved in an organic solvent, hydrogen is introduced, a catalyst 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 to obtain compound IV.

[0016] Furthermore, the solvent used in the first step reaction is carbon tetrachloride or dichloromethane, preferably dichloromethane.

[0017] Furthermore, the catalyst used in the first step reaction is triphenylphosphine.

[0018] Furthermore, the molar ratio of the compound I to the compound II in the first step reaction is 1.0:1.0-1.2.

[0019] Furthermore, the solvent used in the second step reaction is one of THF, carbon tetrachloride and dimethylformamide, preferably carbon tetrachloride.

[0020] Furthermore, the catalyst used in the second step reaction is Pd / C.

[0021] Furthermore, the catalyst for the second step reaction is Pd / C in an amount of 0.1 to 0.2 eq of compound III.

[0022] Furthermore, the amount of catalyst used in the first step reaction is 0.15 to 0.25 eq of compound I, preferably 0.2 eq.

[0023] Furthermore, the palladium content of the catalyst Pd / C used in the second step reaction is 5 wt%.

[0024] Furthermore, the amount of solvent used in the first step reaction is 1 to 2 eq of compound I.

[0025] 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 is high, the reaction selectivity is good, the product purity is 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 rosuvastatin synthesis process, expands the research direction of the rosuvastatin synthesis process route, and provides an effective new synthesis route; 3. The reaction raw materials of the present invention are easy to obtain, no expensive reagents are used, the product yield is high, the production cost is further reduced, and a new research direction is provided for the synthesis of rosuvastatin. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a schematic diagram of the reaction flow of the present invention;

[0027] Figure 2 is the structural formula of rosuvastatin calcium;

[0028] Figure 3 Example roadmap for the Witting reaction process;

[0029] Figure 4 Example roadmap for Julia reaction flow. DETAILED DESCRIPTION

[0030] 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.

[0031] Combination Figures 1 to 4 Shown:

[0032] Example 1

[0033] The first step is to dissolve 17.57g (0.05mol) of compound I and 17.45g (0.05mol of compound II) in 10ml of organic solvent dichloromethane, add 0.01mol of catalyst triphenylphosphine, react at 55-60°C for 3-5h, cool to room temperature after the reaction, add 100ml of dichloromethane, wash the solution with saturated brine 2-3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40ml of toluene to obtain 32.3g of compound III with a yield of 94.4% and a purity of 98.6%;

[0034] In the second step, 34.2 g (0.05 mol) of compound III was dissolved in 200 ml of organic solvent carbon tetrachloride under nitrogen protection, and hydrogen was introduced to fill the container, and then 0.005 mol of catalyst Pd / C (5 wt%) was added, and the mixture was heated to 30-40° C. at 2-5 atm and reacted for 4-6 hours. After the reaction was completed, the product was separated by filtration, and the filtrate was washed with saturated brine for 2-3 times. The solvent was evaporated, and the product was recrystallized with 50 ml of xylene to obtain 31.0 g of compound IV with a yield of 95.4% and a purity of 98.9%.

[0035] Example 2

[0036] The first step is to dissolve 17.57g (0.05mol) of compound I and 20.94g (0.05mol of compound II) in 10ml of organic solvent dichloromethane, add 0.01mol of catalyst triphenylphosphine, react at 55-60°C for 3-5h, cool to room temperature after the reaction, add 100ml of dichloromethane, wash the solution with saturated brine 2-3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40ml of toluene to obtain 31.8g of compound III with a yield of 92.9% and a purity of 98.2%;

[0037] Example 3

[0038] The first step is to dissolve 17.57g (0.05mol) of compound I and 17.45g (0.05mol of compound II) in 10ml of organic solvent dichloromethane, add 0.075mol of catalyst triphenylphosphine, react at 55-60°C for 3-5h, cool to room temperature after the reaction, add 100ml of dichloromethane, wash the solution with saturated brine 2-3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40ml of toluene to obtain 32.0g of compound III with a yield of 93.5% and a purity of 98.3%;

[0039] Example 4

[0040] The first step is to dissolve 17.57g (0.05mol) of compound I and 17.45g (0.05mol of compound II) in 10ml of organic solvent dichloromethane, add 0.0125mol of catalyst triphenylphosphine, react at 55-60°C for 3-5h, cool to room temperature after the reaction, add 100ml of dichloromethane, wash the solution with saturated brine 2-3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40ml of toluene to obtain 32.1g of compound III with a yield of 93.8% and a purity of 98.5%;

[0041] Example 5

[0042] The first step is to dissolve 17.57g (0.05mol) of compound I and 17.45g (0.05mol) of compound II in 10ml of organic solvent carbon tetrachloride, add 0.01mol of catalyst triphenylphosphine, react at 55-60°C for 3-5h, cool to room temperature after the reaction, add 100ml of carbon tetrachloride, wash the solution with saturated brine 2-3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40ml of toluene to obtain 32.0g of compound III with a yield of 93.5% and a purity of 98.7%;

[0043] Example 6

[0044] In the second step, 34.2 g (0.05 mol) of compound III was dissolved in 200 ml of organic solvent carbon tetrachloride under nitrogen protection, and hydrogen was introduced to fill the container, and then 0.01 mol of catalyst Pd / C (5 wt%) was added, and the mixture was heated to 30-40° C. at 2-5 atm and reacted for 4-6 hours. After the reaction was completed, the product was separated by filtration, and the filtrate was washed with saturated brine for 2-3 times. The solvent was evaporated, and the product was recrystallized with 50 ml of xylene to obtain 30.6 g of compound IV with a yield of 94.2% and a purity of 98.9%.

[0045] 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.

[0046] 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 rosuvastatin intermediate side chain connection process, characterized in that The synthesis steps include: The first step is to dissolve compound I and compound II in an organic solvent, add a catalyst, react at 55-60°C for 3-5 hours, and after the reaction is completed, separate the product to obtain compound III; In the second step, compound III is dissolved in an organic solvent, hydrogen is introduced, a catalyst 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 to obtain compound IV.

2. A rosuvastatin intermediate side chain connection process according to claim 1, characterized in that: The solvent used in the first step reaction is carbon tetrachloride or dichloromethane.

3. A rosuvastatin intermediate side chain connection process according to claim 1, characterized in that: The catalyst used in the first step reaction is triphenylphosphine.

4. A rosuvastatin intermediate side chain connection process according to claim 1, characterized in that: The molar ratio of the compound I to the compound II in the first step reaction is 1.0:1.0-1.

2.

5. A rosuvastatin intermediate side chain connection process according to claim 1, characterized in that: The solvent used in the second step reaction is one of THF, carbon tetrachloride and dimethylformamide.

6. A rosuvastatin intermediate side chain connection process according to claim 1, characterized in that: The catalyst used in the second step reaction is Pd / C.

7. A rosuvastatin intermediate side chain connection process according to claim 1, characterized in that: The catalyst for the second step reaction is Pd / C in an amount of 0.1 to 0.2 eq of compound III.

8. A rosuvastatin intermediate side chain connection process according to claim 1, characterized in that: The amount of catalyst used in the first step reaction is 0.15 to 0.25 eq of compound I.

9. The process for connecting the side chain of a rosuvastatin intermediate according to claim 1, characterized in that: The palladium content of the catalyst Pd / C used in the second step reaction is 5wt%.

10. A rosuvastatin intermediate side chain connection process according to claim 1, characterized in that: The amount of solvent used in the first step reaction is 1 to 2 eq of compound I.

Images