CN113004209A - Synthetic method of rosuvastatin calcium intermediate - Google Patents
Synthetic method of rosuvastatin calcium intermediate Download PDFInfo
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- CN113004209A CN113004209A CN202110251650.3A CN202110251650A CN113004209A CN 113004209 A CN113004209 A CN 113004209A CN 202110251650 A CN202110251650 A CN 202110251650A CN 113004209 A CN113004209 A CN 113004209A
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Abstract
The invention discloses a method for synthesizing a rosuvastatin calcium intermediate, which comprises the following steps of preparing 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol, and generating the rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde by using air as an oxidant under the catalysis of mixed salt and 2,2,6, 6-tetramethylpiperidinyloxy. The mixed salt is common nitrate and halide salt, the price is low, the oxidant is air, the source is convenient, and the production cost is greatly reduced; meanwhile, the method has the advantages of less three wastes, environmental friendliness, mild and controllable reaction conditions, high yield and high product purity, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of medicine processing, and particularly relates to a synthetic method of a rosuvastatin calcium intermediate.
Background
Rosuvastatin calcium is an aminopyrimidine derivative obtained by screening Japanese Yeyi pharmaceutical Co-Ltd in the end of the last eighties, and is then assigned to Aslicon, UK, and developed into a new generation of hypolipidemic drugs by Aslicon. Under the trade name of Kedin, is a statin drug which is a selective HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitors are rate-limiting enzymes that convert 3-hydroxy-3-methylglutaryl-coenzyme a to mevalonate, a precursor to cholesterol. The main site of action of rosuvastatin is the liver, a cholesterol-lowering targeting organ, increases the number of hepatic LDL cell surface receptors, promotes LDL absorption and catabolism, inhibits hepatic synthesis of VLDL, thereby reducing the total number of VLDL and LDL particles. It is used in combination with exercise, dietary management and weight loss to treat hypercholesterolemia and other associated conditions, and also to prevent cardiovascular disease.
4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-carbaldehyde (1) is a key intermediate for synthesizing rosuvastatin calcium (2), and the intermediate is mainly synthesized by oxidizing 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol at present, wherein the chemical formula of the 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde (1) is shown as above, and the chemical formula of the rosuvastatin calcium (2) is shown as above.
Regarding the synthesis method of the intermediate (1), the following methods are mainly reported in the literature:
the first synthetic route is that patent W02006/017357 reports a method for preparing rosuvastatin calcium intermediate. The method comprises the steps of taking 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol as a raw material, NaClO as an oxidant, 2,2,6, 6-tetramethylpiperidine oxide (TEMPO) and potassium bromide as salt catalysts, acetonitrile as a solvent, and mechanically stirring for reacting for 6 hours at 5 ℃ to obtain the desired rosuvastatin calcium intermediate, namely 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde. Although the product obtained by the method has good purity and the yield can reach 99%, NaClO is used as an oxidant, the wastewater generated in the post-treatment process is difficult to treat and is not environment-friendly, and the reaction formula is shown as follows.
The second synthetic route is a synthetic method of the rosuvastatin calcium intermediate reported in patent CN 1958593. It is also 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino]Pyrimidine-5-methanol as starting material, but with K2Cr2O7Is used as an oxidant, and is completely oxidized by taking dichloromethane and water as solvents under the catalysis of concentrated sulfuric acid to obtain the target product. The reaction time of the method is short, the product can be quickly obtained, but the reaction yield is only 93 percent, and further exploration is needed, and the reaction formula is shown as follows.
The third synthetic route is a synthetic method of the rosuvastatin calcium intermediate reported in patent WO 2008/059519. Firstly, 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino]Pyrimidine-5-methanol in DMSO and CH2Cl2Cooling the reaction mass to 0-5O ℃, stirring for 15min, then adding N, N-diisopropylethylamine and stirring. In another flask, Py-SO was added3Pyridine and DMSO, stirring for 10min at room temperature, adding the obtained suspension into the above alcoholic solution, and stirring for 1h at 0-5O deg.C to complete the reaction. The synthesis method is complex in operation, strict temperature control is required, the post-treatment process is also segmented in temperature control, the yield of the product is only 91%, further exploration is required, and the reaction formula is shown as follows.
The fourth synthetic route is the preparation method of the rosuvastatin calcium intermediate described in the publication reported in the Heterocyclic Communications in 2014, volume 20, phase 1, pages 11-13. It uses oxygen as oxidant, Co (NO)3)2Dimethylglyoxime, 2,6, 6-tetrakisThe methylpiperidine oxide is used as a catalyst, and is heated and refluxed for reaction for 3 hours and prepared by 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino]Oxidation of pyrimidine-5-methanol to give 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino]Pyrimidine-5-carbaldehyde. The preparation method has short reaction time and good yield which can reach 96%. However, the salt catalyst contains heavy metal divalent cobalt ions which are difficult to remove in wastewater, and the salt catalyst is avoided in industrial production, and meanwhile, oxygen belongs to a combustion improver, so that the safety risk is high. The reaction formula is shown below.
Synthetic route five is the synthetic method reported in volume 19, phase 11, page 1548 and 1553 of Organic Process Research & Development in 2015. It also uses oxygen as oxidant, and the salt catalyst is 1-methylimidazole, ABNO and CuI. Such an oxidation process can give very high yields, up to 98%. But the experimental operation is complex, the used solvent is NMP (N-methyl pyrrolidone), the NMP belongs to a toxic substance, and cannot be directly discharged, and the NMP is difficult to recycle and apply due to high boiling point and mutual solubility with water. The reaction formula is shown below.
The sixth synthetic route is Advanced Synthesis in 2019&The preparation method of the rosuvastatin calcium intermediate is reported in Catalysis at volume 361, stage 10, page 2262-2267. 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino]Pyrimidine-5-methanol in SO2F2、K2CO3Under the action of DMSO, carrying out reflux reaction for 2h to obtain an oxidation product-4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino]Pyrimidine-5-carbaldehyde. The synthesis method is simple to operate, and the yield can reach 99%. However, the SO2F2 is an inorganic compound, and it is emitted into the air to become a strong greenhouse gas, which pollutes the environment and is not easy to obtainAnd the cost is high. The reaction formula is shown below.
In conclusion, the existing synthetic method of rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde has the main problems that the experimental operation is complex, the waste water and waste gas generated in the post-treatment process are difficult to discharge, the method is not environment-friendly, and the method is not suitable for industrial production.
Disclosure of Invention
Aiming at the problems, the invention provides a method for synthesizing a rosuvastatin calcium intermediate. The method can effectively reduce cost, and has high yield and good purity. Meanwhile, the method is simple in post-treatment, green and environment-friendly, and easy for industrial production.
The purpose of the invention can be realized by the following technical scheme:
a synthetic method of a rosuvastatin calcium intermediate comprises the following specific steps:
uniformly mixing 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol, a catalyst and a solvent, keeping a reaction system open, stirring and reacting at the reaction temperature, after the reaction is finished, adding distilled water into the reaction liquid, standing and layering, taking an organic phase A, extracting a water phase by using a solvent to obtain an organic phase B, mixing the organic phase A and the organic phase B, adding anhydrous sodium sulfate into the mixed organic phase, drying and concentrating to obtain a rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde, wherein the reaction formula is shown as follows;
further, the catalyst is a mixture of the mixed salt and 2,2,6, 6-tetramethylpiperidine oxide in any ratio, and preferably, the mixed molar mass ratio of the mixed salt and 2,2,6, 6-tetramethylpiperidine oxide is 4: 1.
Further, the mixed salt is any ratio mixture of nitrite and halide salt, preferably, the mixing molar ratio of nitrite and halide salt is 1: 1.
Further, the nitrite is one or a mixture of several of lithium nitrite, sodium nitrite, potassium nitrite, copper nitrite, ferric nitrite and ammonium nitrite mixed in any ratio, and is preferably sodium nitrite.
Further, the halide salt is one or a mixture of several of lithium chloride, sodium chloride, potassium chloride, ferric chloride, cupric chloride, lithium bromide, sodium bromide, potassium bromide, ferric bromide, cupric bromide, lithium iodide, sodium iodide and potassium iodide mixed in any ratio, and is preferably sodium chloride.
Further, the solvent is one or a mixture of several of dichloromethane, ethyl acetate, toluene and acetonitrile in any ratio, and dichloromethane is preferred.
Further, the temperature of the reaction is 0 to 40 ℃, preferably 25 to 30 ℃.
Further, the oxidant for the reaction is air.
Further, the amount ratio of the 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol to the catalyst to the solvent is 1moL:0.03-0.3moL: 200-.
The invention has the beneficial effects that:
1. the invention uses mixed salt and 2,2,6, 6-tetramethyl piperidine oxide as mixed catalyst, uses air as oxidant, and oxidizes 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol to form rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde, wherein the mixed salt is common nitrate and halide, the nitrate and halide are cheap, the oxidant is air, the source is convenient and safe, and the production cost is greatly reduced; meanwhile, the method has the advantages of less three wastes, environmental friendliness and convenient and simple post treatment.
2. The oxidant used in the method is air, the oxidation selectivity is high, the side reaction is less, the alcohol can be effectively oxidized into aldehyde, the yield of the obtained product can reach more than 90%, and the purity can reach more than 99%.
3. The method has mild and controllable reaction conditions, is convenient to popularize and is suitable for industrial production.
In conclusion, the synthetic method of the rosuvastatin calcium intermediate provided by the invention is convenient, simple and safe to operate, convenient to popularize and suitable for industrial production, side reactions and byproducts are few in the reaction process, the yield of the produced product is high, the purity is high, the method is environment-friendly, and the production cost is greatly reduced.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
a synthetic method of a rosuvastatin calcium intermediate comprises the following steps:
uniformly mixing 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol, a catalyst and a solvent, keeping a reaction system open, providing a simple air environment, stirring at the stirring speed of 200r/min at the temperature of 0 ℃, stirring for reaction for 20 hours, then adding distilled water into the reaction liquid, standing for layering, taking an organic phase A, extracting a water phase with a solvent to obtain an organic phase B, mixing the organic phase A and the organic phase B, adding anhydrous sodium sulfate into the mixed organic phase, drying and concentrating to obtain the rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde.
The catalyst is a mixture of mixed salt and 2,2,6, 6-tetramethylpiperidine oxide in a molar mass ratio of 3:1, the mixed salt is a mixture of nitrite and halide in a molar mass ratio of 1:2, the nitrite is potassium nitrite, the halide is potassium chloride, the solvent is ethyl acetate, and the adding amount ratio of the 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol to the catalyst to the solvent is 1moL:0.03moL:200 mL.
The melting point, yield and purity of the obtained product were calculated, and the calculated result was 98.46% purity, 98.1% yield, and the measured melting point was 179.2 ℃.
Example 2:
a synthetic method of a rosuvastatin calcium intermediate comprises the following steps:
uniformly mixing 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol, a catalyst and a solvent, keeping a reaction system open, providing a simple air environment, stirring at the stirring speed of 200r/min at the temperature of 10 ℃, stirring for reaction for 20 hours, then adding distilled water into the reaction liquid, standing for layering, taking an organic phase A, extracting a water phase with a solvent to obtain an organic phase B, mixing the organic phase A and the organic phase B, adding anhydrous sodium sulfate into the mixed organic phase, drying and concentrating to obtain the rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde.
The catalyst is a mixture of mixed salt and 2,2,6, 6-tetramethylpiperidine oxide in a molar mass ratio of 4:1, the mixed salt is a mixture of nitrite and halide in a molar mass ratio of 1:1, the nitrite is sodium nitrite, the halide is sodium chloride, the solvent is dichloromethane, and the adding amount ratio of the 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol to the catalyst to the solvent is 1moL:0.25moL:250 ml.
The melting point, yield and purity of the obtained product were calculated, and the calculated result was 98.86% purity, 98.2% yield, and the measured melting point was 180 ℃.
Example 3:
a synthetic method of a rosuvastatin calcium intermediate comprises the following steps:
uniformly mixing 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol, a catalyst and a solvent, keeping a reaction system open, providing a simple air environment, stirring at 40 ℃ and a stirring speed of 200r/min, stirring for reaction for 22h, then adding distilled water into the reaction liquid, standing for layering, taking an organic phase A, extracting a water phase with a solvent to obtain an organic phase B, mixing the organic phase A and the organic phase B, adding anhydrous sodium sulfate into the mixed organic phase, drying and concentrating to obtain the rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde.
The method comprises the following steps of mixing a salt catalyst and 2,2,6, 6-tetramethylpiperidine oxide according to a molar mass ratio of 1:3, wherein the salt catalyst is a mixture of nitrite and halide according to a molar mass ratio of 2:1, the nitrite is potassium nitrite, the halide is lithium iodide, a solvent is acetonitrile, the reaction temperature is 40 ℃, and the adding amount ratio of the salt catalyst to the solvent is 1moL:0.3moL:300 mL.
The melting point, yield and purity of the obtained product were calculated, and the calculated result was 98.71% purity, 98.0% yield, and the measured melting point was 179.6 ℃.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (7)
1. A synthetic method of a rosuvastatin calcium intermediate is characterized by comprising the following steps:
4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-methanol and an oxidant generate rosuvastatin calcium intermediate 4- (4-fluorophenyl) -6-isopropyl-2- [ (N-methyl-N-methylsulfonyl) amino ] pyrimidine-5-formaldehyde under the action of a catalyst.
2. The method for synthesizing the rosuvastatin calcium intermediate according to claim 1, wherein the catalyst is a mixture of a mixed salt and 2,2,6, 6-tetramethylpiperidine oxide in any ratio.
3. The method for synthesizing the rosuvastatin calcium intermediate according to claim 2, wherein the mixed salt is a mixture of nitrite and halide in any ratio.
4. The method for synthesizing the rosuvastatin calcium intermediate according to claim 3, wherein the nitrite is one or a mixture of more of lithium nitrite, sodium nitrite, potassium nitrite, copper nitrite, ferric nitrite and ammonium nitrite in any ratio.
5. The method for synthesizing rosuvastatin calcium intermediate according to claim 3, wherein the halide salt is one or a mixture of more of lithium chloride, sodium chloride, potassium chloride, ferric chloride, cupric chloride, lithium bromide, sodium bromide, potassium bromide, ferric bromide, cupric bromide, lithium iodide, sodium iodide and potassium iodide.
6. The method for synthesizing the rosuvastatin calcium intermediate according to claim 1, wherein the solvent is one or a mixture of several of dichloromethane, ethyl acetate, toluene and acetonitrile.
7. The method for synthesizing rosuvastatin calcium intermediate according to claim 1, wherein the oxidizing agent is air.
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