CN115417824A - High-purity preparation method of rosuvastatin intermediate - Google Patents
High-purity preparation method of rosuvastatin intermediate Download PDFInfo
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- CN115417824A CN115417824A CN202211152990.1A CN202211152990A CN115417824A CN 115417824 A CN115417824 A CN 115417824A CN 202211152990 A CN202211152990 A CN 202211152990A CN 115417824 A CN115417824 A CN 115417824A
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- C07—ORGANIC CHEMISTRY
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention discloses a high-purity preparation method of a rosuvastatin intermediate, which belongs to the technical field of chemical industry, wherein rosuvastatin methyl ester is mixed with ethanol, the pH value is adjusted, and the heat preservation reaction is carried out until the residual quantity of the rosuvastatin methyl ester is less than or equal to 1.0%; diluting with water, concentrating under reduced pressure, extracting, combining organic phases, washing, drying to obtain an intermediate solution, adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine and a seed crystal dispersion solution for reaction, centrifuging, drying, detecting the purity, judging the product to be qualified when the purity is more than 99.9%, and crushing to obtain a rosuvastatin intermediate; when the purity is less than or equal to 99.9 percent, judging that the product is unqualified, and refining the unqualified product to obtain a rosuvastatin intermediate; the purity of the finally prepared rosuvastatin intermediate is more than 99.9 percent, the quality control in the synthesis process of rosuvastatin calcium is met, and the quality and the curative effect of the medicine are ensured.
Description
Technical Field
The invention belongs to the technical field of chemical industry, and particularly relates to a high-purity preparation method of a rosuvastatin intermediate.
Background
Rosuvastatin calcium is a selective HMG-CoA reductase inhibitor, the main site of action of which is the liver. Rosuvastatin calcium can increase the number of hepatic LDL cell surface receptors, promote LDL absorption and catabolism, inhibit hepatic synthesis of VLDL, and thereby reduce the total number of VLDL and LDL particles.
Rosuvastatin methyl ester is called rosuvastatin intermediate calcium H-3, the purity of the rosuvastatin methyl ester in the industrial preparation process is generally more than or equal to 90%, the product quality is not high, the quality control is not facilitated in the rosuvastatin calcium medicament synthesis process, and more impurities are easily introduced. Therefore, the rosuvastatin methyl ester is taken as a raw material to synthesize a new rosuvastatin intermediate, and the new rosuvastatin intermediate can meet the requirement of high purity.
Disclosure of Invention
The invention aims to provide a high-purity preparation method of a rosuvastatin intermediate, so as to solve the problems in the background art.
The purpose of the invention can be realized by the following technical scheme:
a high-purity preparation method of a rosuvastatin intermediate comprises the following steps:
the method comprises the following steps: adding rosuvastatin methyl ester and ethanol into a reaction kettle, stirring and mixing, dropwise adding alkali liquor at 5 +/-3 ℃, preserving heat for 30min, adjusting the pH value to 11.0-13.5, then heating to 18-22 ℃, preserving heat for reaction, and sampling and detecting the residual quantity of rosuvastatin methyl ester according to the frequency of 2-3 h/time until the residual quantity of rosuvastatin methyl ester is less than or equal to 1.0%; adding water into the reaction kettle, stirring and mixing, and then dropwise adding dilute hydrochloric acid to adjust the pH value to 7.0-8.0 to obtain a diluent;
step two: concentrating the diluted solution under reduced pressure to remove ethanol to obtain concentrated solution; extracting the concentrated solution with isopropyl acetate at 5 + -3 deg.C to obtain an organic layer as the upper layer and an aqueous layer as the lower layer, and collecting the organic layer; stirring and mixing the water layer and isopropyl acetate to obtain a mixed solution, dropwise adding dilute hydrochloric acid into the mixed solution to adjust the pH value to 1.7-2.5, stirring for 30 +/-5 min, standing for layering, and collecting an organic layer; repeating the steps for 2 times, and combining the organic layers extracted for 3 times to obtain an organic phase;
step three: adding a sodium chloride solution into the organic phase, stirring for 30 +/-5 min, standing for layering and removing a water layer, adding anhydrous magnesium sulfate into the organic layer, stirring and drying for 1h, filtering to obtain a filter cake and a filtrate, washing the filter cake with isopropyl acetate with the mass of 5-6 times that of the anhydrous magnesium sulfate, and combining a washing solution and the filtrate to obtain an intermediate solution;
step four: adding the intermediate solution into a reaction kettle, dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at 45-50 ℃, standing for 15 +/-5 min, adding a seed crystal dispersion, continuously dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at 45-50 ℃, stopping the reaction after the dropwise adding is finished within 5 +/-1 h, and then cooling to 20-25 ℃ within 1-2 h; transferring the reaction solution into a centrifuge for centrifugal drying to obtain a wet product; drying the wet product under the protection of nitrogen until the drying weight loss is less than or equal to 1%, discharging, performing purity detection, judging to be qualified when the purity is more than 99.9%, and crushing to obtain a rosuvastatin intermediate; and when the purity is less than or equal to 99.9%, judging to be unqualified, obtaining an unqualified product, weighing, recording the weight, and then performing refining treatment to obtain the rosuvastatin intermediate.
The reaction process is as follows:
further, the dosage ratio of rosuvastatin methyl ester, ethanol and water in the first step is 100g:220g: 78. + -.5 g.
Further, the total dosage of the isopropyl acetate in the second step is 3/4 of the mass of the ethanol in the first step.
Further, the dosage ratio of the organic phase, the sodium chloride solution and the anhydrous magnesium sulfate in the third step is 60g:13g:1g of the total weight of the composition.
Further, the ratio of the amount of the intermediate solution in step four, the isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine and the seed crystal dispersion was 300kg:110kg:70g.
Further, the refining treatment comprises the following steps:
step S1: adding 10 times of water and 15 times of isopropyl acetate into a reaction kettle, continuously stirring and adding the unqualified product, and stirring for 30 +/-10 min at the temperature of 5 +/-3 ℃ to obtain a remixed solution; dropwise adding dilute hydrochloric acid into the heavy mixed solution to adjust the pH value to 1.0-1.6, stirring for 30 +/-5 min, standing for layering, removing a lower water layer, and collecting an organic layer;
step S2: adding 6 times of quality isopropyl acetate of an unqualified product into the organic layer obtained in the step S1, adjusting the pH value to 1.3 +/-0.3 by using dilute hydrochloric acid, stirring for 30 +/-5 min, standing for layering, removing a lower water layer, and collecting the organic layer;
and step S3: combining the organic layers collected in the step S1 and the step S2, washing the combined organic layers for 2-3 times by using a sodium chloride solution, adding anhydrous magnesium sulfate with the mass being 0.25 times that of an unqualified product, and stirring for 1h; filtering, collecting filtrate, washing the filter cake for 2-3 times by using isopropyl acetate with the mass of 0.67 time that of an unqualified product, combining washing liquid and the filtrate, and transferring the mixture to a new reaction kettle; dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine with the mass being 5.5 times of that of an unqualified product and a proper amount of seed crystal dispersion liquid into a reaction kettle at 45-50 ℃, stopping the reaction after the dropwise adding is finished, cooling to 20-25 ℃, transferring the reaction liquid into a centrifugal machine, centrifugally spin-drying to obtain a wet product, drying the wet product under the protection of nitrogen until the loss on drying is less than or equal to 1%, cooling to 20-35 ℃, discharging, and crushing to finish the refining of the unqualified product.
Further, the amount ratio of the isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine and the seed crystal dispersion in step S3 was 110kg:70g.
Further, the alkali liquor is sodium hydroxide solution with the mass fraction of 2-2.5%.
Furthermore, the mass fraction of the dilute hydrochloric acid is 3.6-3.8%.
Further, the mass fraction of the sodium chloride solution was 20%.
Further, the amount ratio of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine to isopropyl acetate in the isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine was 51 ± 0.5kg:495 plus or minus 5kg.
Further, the seed crystal dispersion comprises seed crystals and isopropyl acetate, and the use ratio of the seed crystals to the isopropyl acetate is 1g:6g.
The invention has the beneficial effects that:
the method for preparing the rosuvastatin intermediate in high purity takes rosuvastatin methyl ester as a raw material, the rosuvastatin methyl ester finally reacts with (R) -1- [ (4-chlorophenyl) benzyl ] piperazine to prepare the rosuvastatin intermediate, the unqualified product is refined under the condition that the purity does not meet the requirement through quality control, the purity of the finally prepared rosuvastatin intermediate is more than 99.9%, the quality control in the rosuvastatin calcium synthesis process is met, and the quality and curative effect of a medicament are favorably ensured.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the 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 high-purity preparation method of a rosuvastatin intermediate comprises the following steps:
the method comprises the following steps: 505kg of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine and 1900kg of isopropyl acetate were prepared as a solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine in isopropyl acetate; 100g of seed crystals and 600g of isopropyl acetate were prepared as a seed crystal dispersion for use.
Adding 100kg of rosuvastatin methyl ester and 220kg of ethanol into a reaction kettle, stirring and mixing, dropwise adding a sodium hydroxide solution with the mass fraction of 2% at the temperature of 2 ℃, preserving heat for 30min, adjusting the pH value to 11.0, then heating to 18 ℃, preserving heat for reaction, and sampling and detecting the residual quantity of the rosuvastatin methyl ester according to the frequency of 2 h/time until the residual quantity of the rosuvastatin methyl ester is less than or equal to 1.0%; 730kg of water is added into the reaction kettle, and diluted hydrochloric acid with the mass fraction of 3.6 percent is added dropwise to adjust the pH value to 7.0 after stirring and mixing, so as to obtain a diluted solution.
Step two: concentrating the diluted solution under reduced pressure to remove ethanol to obtain concentrated solution; extracting the concentrated solution with isopropyl acetate at 2 deg.C, collecting the organic layer as the upper layer and the water layer as the lower layer; stirring and mixing the water layer and isopropyl acetate to obtain a mixed solution, dropwise adding dilute hydrochloric acid with the mass fraction of 3.6% into the mixed solution to adjust the pH value to 1.7, stirring for 25min, standing for layering, and collecting an organic layer; repeating the steps for 2 times, and combining the organic layers extracted for 3 times to obtain an organic phase; the total dosage of the isopropyl acetate is 3/4 of the mass of the ethanol in the step one.
Step three: adding 39kg of 20% sodium chloride solution by mass into 180kg of organic phase, stirring for 25min, standing for layering and removing a water layer, adding 3kg of anhydrous magnesium sulfate into the organic layer, stirring for 1h, filtering to obtain a filter cake and a filtrate, washing the filter cake with 15kg of isopropyl acetate, and combining the washing solution and the filtrate to obtain an intermediate solution.
Step four: adding 300kg of intermediate solution into a reaction kettle, dropwise adding 10kg of isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at the temperature of 45 ℃, standing for 10min, adding 70g of seed crystal dispersion, continuously dropwise adding 100kg of isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at the temperature of 45 ℃, stopping the reaction after dropwise adding is completed within 4h, and then cooling to 20 ℃ within 1h; transferring the reaction solution into a centrifuge for centrifugal drying to obtain a wet product; drying the wet product under the protection of nitrogen until the drying weight loss is less than or equal to 1%, then cooling to 20 ℃ under the protection of nitrogen, discharging, carrying out purity detection, judging to be qualified when the purity is more than 99.9%, and crushing to obtain the rosuvastatin intermediate.
Step five: when the purity is less than or equal to 99.9 percent, judging that the product is unqualified, obtaining an unqualified product, weighing and recording the weight, and then carrying out refining treatment; adding 10 times of water and 15 times of isopropyl acetate into a reaction kettle, continuously stirring and adding the unqualified product, and stirring for 20min at the temperature of 2 ℃ to obtain a remixed solution; dropwise adding dilute hydrochloric acid with the mass fraction of 3.6% into the heavy mixed solution to adjust the pH value to 1.0, stirring for 25min, standing for layering, removing a lower water layer, and collecting an organic layer; adding 6 times of quality isopropyl acetate into the organic layer, adjusting pH to 1.0 with 3.6% dilute hydrochloric acid, stirring for 25min, standing for layering, removing the lower water layer, and collecting the organic layer; combining the collected organic layers, washing the combined organic layers for 2 times by using a sodium chloride solution with the mass fraction of 20%, adding an unqualified product of anhydrous magnesium sulfate with the mass of 0.25 time, and stirring for 1h; filtering, collecting filtrate, washing a filter cake with unqualified isopropyl acetate with the mass of 0.67 time, combining washing liquid and the filtrate, and transferring to a new reaction kettle.
Step six: dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine into a reaction kettle at 45 ℃, adding a seed crystal dispersion liquid with the quality of unqualified products being 0.0035 times after 10min, continuously dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine, and stopping the reaction after the dropwise adding is finished within 4h, wherein the total dropwise adding amount of the isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine is 5.5 times of the quality of unqualified products; cooling to 20 ℃ within 1h, transferring the reaction liquid into a centrifuge, centrifuging and drying to obtain a wet product, drying the wet product under the protection of nitrogen until the drying weight loss is less than or equal to 1%, then cooling to 20 ℃, discharging, crushing, finishing the refining of unqualified products, and obtaining the rosuvastatin intermediate with the purity of more than 99.9%.
Example 2
A high-purity preparation method of a rosuvastatin intermediate comprises the following steps:
the method comprises the following steps: 510kg of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine and 1950kg of isopropyl acetate were mixed to prepare a solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine in isopropyl acetate; 100g of seed crystals and 600g of isopropyl acetate were prepared as a seed crystal dispersion for use.
Adding 100kg of rosuvastatin methyl ester and 220kg of ethanol into a reaction kettle, stirring and mixing, dropwise adding a sodium hydroxide solution with the mass fraction of 2.2% at the temperature of 5 ℃, preserving heat for 30min, adjusting the pH value to 12.0, then heating to 20 ℃, preserving heat for reaction, and sampling and detecting the residual quantity of the rosuvastatin methyl ester according to the frequency of 2.5 h/time until the residual quantity of the rosuvastatin methyl ester is less than or equal to 1.0%; 780kg of water is added into the reaction kettle, and diluted hydrochloric acid with the mass fraction of 3.7% is added dropwise to adjust the pH value to 7.5 after stirring and mixing, so as to obtain a diluted solution.
Step two: concentrating the diluted solution under reduced pressure to remove ethanol to obtain concentrated solution; extracting the concentrated solution with isopropyl acetate at 5 deg.C to obtain an organic layer as the upper layer and an aqueous layer as the lower layer, and collecting the organic layer; stirring and mixing the water layer and isopropyl acetate to obtain a mixed solution, dripping dilute hydrochloric acid with the mass fraction of 3.7% into the mixed solution to adjust the pH value to 2.0, stirring for 30min, standing for layering, and collecting an organic layer; repeating the steps for 2 times, and combining the organic layers extracted for 3 times to obtain an organic phase; the total dosage of the isopropyl acetate is 3/4 of the mass of the ethanol in the step one.
Step three: adding 39kg of 20% sodium chloride solution in mass fraction into 180kg of organic phase, stirring for 30min, standing for layering, removing a water layer, adding 3kg of anhydrous magnesium sulfate into the organic layer, stirring for 1h, filtering to obtain a filter cake and a filtrate, washing the filter cake with 16kg of isopropyl acetate, and combining the washing solution and the filtrate to obtain an intermediate solution.
Step four: adding 300kg of intermediate solution into a reaction kettle, dropwise adding 10kg of isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at 48 ℃, standing for 15min, adding 70g of seed crystal dispersion, continuously dropwise adding 100kg of isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at 48 ℃, stopping the reaction after dropwise adding is completed within 5h, and then cooling to 22 ℃ within 1.5 h; transferring the reaction solution into a centrifuge for centrifugal drying to obtain a wet product; drying the wet product under the protection of nitrogen until the loss on drying is less than or equal to 1%, then cooling to 25 ℃ under the protection of nitrogen, discharging, carrying out purity detection, judging to be qualified when the purity is more than 99.9%, and crushing to obtain the rosuvastatin intermediate.
Step five: when the purity is less than or equal to 99.9 percent, judging that the product is unqualified, obtaining an unqualified product, weighing and recording the weight, and then carrying out refining treatment; adding 10 times of water and 15 times of isopropyl acetate into a reaction kettle, continuously stirring and adding the unqualified product, and stirring for 30min at 5 ℃ to obtain a remixed liquid; dropwise adding dilute hydrochloric acid with the mass fraction of 3.7% into the heavy mixed solution to adjust the pH value to 1.3, stirring for 30min, standing for layering, removing a lower water layer, and collecting an organic layer; adding 6 times of quality isopropyl acetate into the organic layer, adjusting pH to 1.3 with 3.7% diluted hydrochloric acid, stirring for 30min, standing for layering, removing the lower water layer, and collecting the organic layer; combining the collected organic layers, washing the combined organic layers for 2 times by using a sodium chloride solution with the mass fraction of 20%, adding an unqualified product of anhydrous magnesium sulfate with the mass of 0.25 time, and stirring for 1h; filtering, collecting filtrate, washing a filter cake for 2 times by using an unqualified product isopropyl acetate with the mass being 0.67 time, combining washing liquid and the filtrate, and transferring the mixture to a new reaction kettle.
Step six: dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine into the reaction kettle at 48 ℃, adding a seed crystal dispersion liquid with the quality of unqualified products being 0.0035 times of that of the isopropyl acetate solution after 15min, continuously dropwise adding the isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine, and stopping the reaction after dropwise adding is completed within 5h, wherein the total dropwise adding amount of the isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine is 5.5 times of that of the unqualified products; and cooling to 22 ℃ within 1.5h, transferring the reaction liquid into a centrifugal machine, centrifuging and drying to obtain a wet product, drying the wet product under the protection of nitrogen until the loss of drying is less than or equal to 1%, then cooling to 25 ℃, discharging, crushing, finishing the refining of unqualified products, and obtaining a rosuvastatin intermediate with the purity of more than 99.9%.
Example 3
A high-purity preparation method of a rosuvastatin intermediate comprises the following steps:
the method comprises the following steps: 515kg of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine and 2000kg of isopropyl acetate were prepared as a solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine in isopropyl acetate; 100g of seed crystals and 600g of isopropyl acetate were prepared as a seed crystal dispersion for use.
Adding 100kg of rosuvastatin methyl ester and 220kg of ethanol into a reaction kettle, stirring and mixing, dripping a sodium hydroxide solution with the mass fraction of 2.5% at the temperature of 8 ℃, preserving heat for 30min, adjusting the pH value to 13.5, then heating to 22 ℃, preserving heat for reaction, and sampling and detecting the residual quantity of rosuvastatin methyl ester according to the frequency of 3 h/time until the residual quantity of rosuvastatin methyl ester is less than or equal to 1.0%; adding 830kg of water into the reaction kettle, stirring and mixing, and then dropwise adding dilute hydrochloric acid with the mass fraction of 3.8% to adjust the pH value to 8.0 to obtain a diluent.
Step two: concentrating the diluted solution under reduced pressure to remove ethanol to obtain concentrated solution; extracting the concentrated solution with isopropyl acetate at 8 deg.C to obtain an organic layer as the upper layer and an aqueous layer as the lower layer, and collecting the organic layer; stirring and mixing the water layer and isopropyl acetate to obtain a mixed solution, dropwise adding dilute hydrochloric acid with the mass fraction of 3.8% into the mixed solution to adjust the pH value to 2.5, stirring for 35min, standing for layering, and collecting an organic layer; repeating the steps for 2 times, and combining the organic layers extracted for 3 times to obtain an organic phase; the total dosage of the isopropyl acetate is 3/4 of the mass of the ethanol in the step one.
Step three: adding 39kg of 20% sodium chloride solution by mass into 180kg of organic phase, stirring for 35min, standing for layering and removing a water layer, adding 3kg of anhydrous magnesium sulfate into the organic layer, stirring for 1h, filtering to obtain a filter cake and a filtrate, washing the filter cake with 18kg of isopropyl acetate, and combining the washing solution and the filtrate to obtain an intermediate solution.
Step four: adding 300kg of intermediate solution into a reaction kettle, dropwise adding 10kg of isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at 50 ℃, standing for 20min, adding 70g of seed crystal dispersion, continuously dropwise adding 100kg of isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at 50 ℃, stopping the reaction after the dropwise adding is finished within 6h, and then cooling to 25 ℃ within 2 h; transferring the reaction solution into a centrifuge for centrifugal drying to obtain a wet product; drying the wet product under the protection of nitrogen until the loss on drying is less than or equal to 1%, then cooling to 35 ℃ under the protection of nitrogen, discharging, carrying out purity detection, judging to be qualified when the purity is more than 99.9%, and crushing to obtain the rosuvastatin intermediate.
Step five: when the purity is less than or equal to 99.9 percent, judging to be unqualified, obtaining an unqualified product, weighing, recording the weight, and then refining; adding 10 times of water and 15 times of isopropyl acetate into a reaction kettle, continuously stirring and adding the unqualified product, and stirring for 40min at the temperature of 8 ℃ to obtain a remixed liquid; dropwise adding dilute hydrochloric acid with the mass fraction of 3.8% into the heavy mixed solution to adjust the pH value to 1.6, stirring for 35min, standing for layering, removing a lower water layer, and collecting an organic layer; adding 6 times of quality isopropyl acetate into the organic layer, adjusting pH to 1.6 with 3.8% dilute hydrochloric acid, stirring for 35min, standing for layering, removing lower water layer, and collecting organic layer; combining the collected organic layers, washing the combined organic layers for 3 times by using a sodium chloride solution with the mass fraction of 20%, adding an unqualified product of anhydrous magnesium sulfate with the mass of 0.25 time, and stirring for 1h; filtering, collecting filtrate, washing a filter cake for 3 times by using an unqualified product isopropyl acetate with the mass being 0.67 time, combining washing liquid and the filtrate, and transferring the mixture to a new reaction kettle.
Step six: dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine into a reaction kettle at 50 ℃, adding a seed crystal dispersion liquid with the quality of unqualified products being 0.0035 times after 20min, continuously dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine, and stopping the reaction after the dropwise adding is finished within 6h, wherein the total dropwise adding amount of the isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine is 5.5 times of the quality of unqualified products; and cooling to 25 ℃ within 2h, transferring the reaction liquid into a centrifugal machine, centrifuging and drying to obtain a wet product, drying the wet product under the protection of nitrogen until the loss on drying is less than or equal to 1%, then cooling to 35 ℃, discharging, crushing, finishing the refining of unqualified products, and obtaining a rosuvastatin intermediate with the purity of more than 99.9%.
It should be noted that, in this document, terms such as "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (9)
1. A high-purity preparation method of a rosuvastatin intermediate is characterized by comprising the following steps:
the method comprises the following steps: adding rosuvastatin methyl ester and ethanol into a reaction kettle, stirring and mixing, adjusting the pH value to 11.0-13.5 by using an alkali liquor under the condition of 5 +/-3 ℃, then heating to 18-22 ℃, and carrying out heat preservation reaction until the residual quantity of rosuvastatin methyl ester is less than or equal to 1.0%; adding water into the reaction kettle, and adjusting the pH value to 7.0-8.0 by using dilute hydrochloric acid to obtain a diluent;
step two: concentrating the diluted solution under reduced pressure to remove ethanol to obtain concentrated solution; extracting the concentrated solution with isopropyl acetate at 5 + -3 deg.C for 3 times, mixing the organic layers obtained by 3 times of extraction to obtain organic phase;
step three: washing the organic phase with a sodium chloride solution, drying with anhydrous magnesium sulfate, filtering to obtain a filter cake and a filtrate, washing the filter cake with isopropyl acetate with the mass of 5-6 times that of the anhydrous magnesium sulfate, and combining the washing solution and the filtrate to obtain an intermediate solution;
step four: adding the intermediate solution into a reaction kettle, dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at 45-50 ℃, standing for 15 +/-5 min, adding a seed crystal dispersion liquid, continuously dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine at 45-50 ℃, cooling to 20-25 ℃ after dropwise adding, centrifugally drying to obtain a wet product, drying, detecting the purity, judging to be qualified when the purity is more than 99.9%, and crushing to obtain a rosuvastatin intermediate; and when the purity is less than or equal to 99.9 percent, judging that the product is unqualified, and refining the unqualified product to obtain the rosuvastatin intermediate.
2. The process for preparing rosuvastatin intermediate of claim 1, wherein the ratio of rosuvastatin methyl ester, ethanol and water in step one is 100g:220g:78 + -5 g.
3. The method for preparing rosuvastatin intermediate of claim 1, wherein the ratio of the organic phase, sodium chloride solution and anhydrous magnesium sulfate in step three is 60g:13g:1g.
4. The process for preparing a rosuvastatin intermediate of claim 1, wherein the ratio of the intermediate solution in step four, isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine and seed crystal dispersion is 300kg:110kg:70g.
5. The method for preparing a rosuvastatin intermediate of high purity according to claim 1, wherein the refining process comprises the steps of:
extracting the unqualified product with isopropyl acetate to obtain an organic layer, washing the organic layer with sodium chloride solution for 2-3 times, then drying with anhydrous magnesium sulfate, filtering, collecting filtrate, washing the filter cake with isopropyl acetate for 2-3 times, combining the washing solution and the filtrate, and transferring to a new reaction kettle; dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine into a reaction kettle at 45-50 ℃, then adding a seed crystal dispersion, continuously dropwise adding an isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine, stopping the reaction after the dropwise adding is finished, cooling to 20-25 ℃, centrifugally drying the reaction solution to obtain a wet product, drying the wet product until the loss on drying is less than or equal to 1%, discharging, and crushing to finish the refining of unqualified products.
6. The method for preparing a rosuvastatin intermediate at high purity according to claim 5, wherein the method for extracting rejected products comprises the following steps: adding 10 times of water and 15 times of isopropyl acetate into a reaction kettle, continuously stirring and adding an unqualified product, stirring and mixing at 5 +/-3 ℃ to obtain a heavy mixed solution, dropwise adding dilute hydrochloric acid to adjust the pH value of the heavy mixed solution to 1.0-1.6, stirring for 30 +/-5 min, standing for layering, removing a lower water layer, and collecting an organic layer; adding 6 times of quality isopropyl acetate of an unqualified product into the organic layer obtained in the step S1, adjusting the pH value to 1.3 +/-0.3 by using dilute hydrochloric acid, stirring for 30 +/-5 min, standing for layering, removing a lower water layer, and collecting the organic layer; the organic layers were combined.
7. The method for preparing a rosuvastatin intermediate of high purity according to claim 1, wherein the alkali solution is a sodium hydroxide solution with a mass fraction of 2-2.5%.
8. The process for preparing rosuvastatin intermediate of claim 5, wherein the ratio of isopropyl acetate to (R) -1- [ (4-chlorophenyl) benzyl ] piperazine in the isopropyl acetate solution of (R) -1- [ (4-chlorophenyl) benzyl ] piperazine is 51 ± 0.5kg:495 plus or minus 5kg.
9. The method for preparing a rosuvastatin intermediate in high purity according to claim 5, wherein the seed crystal dispersion comprises seed crystal and isopropyl acetate, and the use ratio of the seed crystal to the isopropyl acetate is 1g:6g.
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