CN111518073A - Preparation method of rosuvastatin side chain intermediate - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and particularly provides a preparation method of a rosuvastatin side chain intermediate. The method comprises the following steps: (1) dissolving a compound I, an oxidation catalyst and a phase transfer catalyst in an organic solvent A, and respectively adding an alkaline buffer solution and an oxidant to react to obtain a compound II; (2) dissolving the crude compound II in an organic solvent B, heating for dissolving, adding purified water, separating out a solid, filtering, and drying to obtain a refined compound II product. The yield of the rosuvastatin side chain intermediate prepared by the technology of the invention is higher than 95%, the HPLC purity is higher than 99.70%, and the generated carboxylic acid impurity is lower than 0.2%. The process has mild reaction conditions, does not need harsh reaction conditions such as ultralow temperature, no water and the like, does not generate malodorous gas in the reaction process, is environment-friendly, is easy to amplify and generate, has easy realization of reaction temperature, and is beneficial to industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of a rosuvastatin side chain intermediate.
Background
Rosuvastatin (rosuvastatin) was developed by astrazen, first approved in the netherlands in 2002 for 11 months, approved by FDA in the united states in 2003 for 8 months, approved and marketed in china in 2006, and currently marketed in many countries, and is one of the widely used statins.
The (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate (compound II) is a key intermediate for synthesizing statins such as rosuvastatin, pitavastatin and the like, and can be obtained by oxidizing (4R-cis) -6-hydroxymethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate (compound I). The reaction equation is as follows:
at present, literature reports of methods for preparing (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate by oxidizing (4R-cis) -6-hydroxymethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate mainly include a Swern oxidation method, a Dess-Martin oxidation, a TEMPO/NaBr/NaClO (or TCCA) oxidation, a pyridine sulfur trioxide complex oxidation (Parikh-Doering oxidation) and the like.
U.S. Pat. No. 4, 4970313A and Chinese patent No. 1876644A (application No. CN200610052219.1) report the Swern oxidation process, which uses oxalyl chloride as an activator, wherein oxalyl chloride is easily decomposed at room temperature to generate hydrogen chloride gas, and the hydrogen chloride gas has strong corrosivity to equipment. In addition, the reaction needs to be carried out at the ultralow temperature of-78 ℃, the energy consumption is high, and a malodorous dimethyl sulfide byproduct is generated to pollute the atmospheric environment.
Chinese patent CN102617540A (application No. CN201210117031.6) reports a method for preparing (4R-Cis) -6 aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate by using a sulfur trioxide pyridine complex as an oxidant, wherein the pyridine sulfur trioxide complex used in the method has high cost and strong corrosivity. Pyridine generated in the reaction process is difficult to completely remove, and the product quality is influenced.
U.S. Pat. No. 4R-Cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester is prepared by using NaClO as oxidant and TEMPO as catalyst as reported in U.S. Pat. No. 7161004B2 and European patent EP2351762B 1. The reaction is carried out in a two-phase system of an organic solvent and water, and if the system is strong in alkalinity, tert-butyl ester can be hydrolyzed, so that the yield is influenced. Therefore, the NaClO solution needs to be adjusted to a specific pH value in advance and is slowly dripped into the reaction system, so that the operation is complicated, and the method is not beneficial to industrial production.
Most of (4R-Cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate obtained by the method is oily, has poor stability and is difficult to store for a long time. In addition, the process is easy to generate carboxylic acid impurities (shown in a general formula below) which are excessively oxidized, and the carboxylic acid impurities are not easy to remove, so that the product quality is influenced.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of a rosuvastatin side chain intermediate ((4R-Cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate).
A method for preparing a rosuvastatin side chain intermediate specifically comprises the following steps:
(1) dissolving a compound I, an oxidation catalyst and a phase transfer catalyst in an organic solvent A, respectively adding an alkaline buffer solution and an oxidant, and reacting to obtain a crude compound II;
(2) dissolving the crude compound II in an organic solvent B, heating for dissolving, adding purified water, separating out a solid, filtering, and drying to obtain a refined compound II;
in the preparation method of the rosuvastatin side chain intermediate, an oxidant in the step (1) is N-chlorosuccinimide (NCS).
According to the preparation method of the rosuvastatin side chain intermediate, the molar ratio of the compound I to the oxidant in the step (1) is 1: 1.2 to 1.6.
In the method for preparing the rosuvastatin side chain intermediate, the phase transfer catalyst in the step (1) is selected from one of tetrabutylammonium bromide, dodecyl trimethyl ammonium chloride and benzyl triethyl ammonium chloride.
In the method for preparing the rosuvastatin side chain intermediate, the organic solvent A in the step (1) is selected from one or more of dichloromethane, ethyl acetate, toluene, methyl acetate, chloroform and 1, 2-dichloroethane.
In the method for preparing the rosuvastatin side chain intermediate, the base in the step (1) is selected from one group of potassium carbonate/sodium bicarbonate, sodium carbonate/potassium bicarbonate, sodium carbonate/sodium bicarbonate and potassium carbonate/potassium bicarbonate.
According to the preparation method of the rosuvastatin side chain intermediate, the pH value of a buffer solution of alkali in the step (1) is 7.5-8.5.
In the preparation method of the rosuvastatin side chain intermediate, in the step (1), the oxidation catalyst is selected from TEMPO,
4-MeO-TEMPO, 4-AcHN-TEMPO, 4-NC-TEMPO and 4-BzO-TEMPO.
In the preparation method of the rosuvastatin side chain intermediate, the organic solvent B in the step (2) is selected from one or more of acetone, acetonitrile, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol and dioxane; the mass-to-volume ratio of the crude compound II to the organic solvent B is 1: 1-3, wherein the mass is in g and the volume is in mL.
According to the preparation method of the rosuvastatin side chain intermediate, the mass volume ratio of the crude compound II to the purified water in the step (2) is 1: 3-7, wherein the mass is g, and the volume is mL.
The preparation scheme of the present invention is further detailed below:
(1) adding the compound I, an oxidation catalyst and a phase transfer catalyst into an organic solvent A, adding a buffer solution with the pH value of 7.5-8.5, adding N-chlorosuccinimide (NCS), stirring for reaction, standing for liquid separation after the reaction is finished, extracting a water phase by using dichloromethane, combining organic phases, washing the organic phases by using saturated salt solution, and drying the organic phases by using anhydrous sodium sulfate. Filtering and concentrating to obtain a crude product of (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, namely a crude product of a compound II.
(2) Dissolving the crude product of the compound II in an organic solvent B, heating, stirring and dissolving, slowly dropwise adding purified water to separate out a white solid, filtering and drying to obtain a refined product of (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, namely a refined product of the compound II.
Preferably, the amount of the oxidation catalyst used in step (1) is 0.5 to 1.5% by mole of compound I.
Further preferably, the amount of the oxidation catalyst used in step (1) is 1.0% by mole of the compound I.
Preferably, the amount of the phase transfer catalyst used in step (1) is 1 to 8% by mole based on the compound I.
Further preferably, in step (1), the amount of the phase transfer catalyst is 5% by mole based on the amount of the compound I.
Preferably, the mass-to-volume ratio of the buffer solution of compound I and the base in step (1) is 1: 6-15, wherein the mass is in g, and the volume is in mL.
Further preferably, the mass-to-volume ratio of the buffer solution of the compound I and the base in the step (1) is 1:10, wherein the mass is in g and the volume is in mL.
Preferably, the mass-to-volume ratio of the compound I to the organic solvent A in the step (1) is 1: 6-15, wherein the mass is g, and the volume is mL.
Further preferably, the mass-to-volume ratio of the compound I to the organic solvent a in step (1) is 1:10, wherein the mass is in g and the volume is in mL.
In the preparation method of the rosuvastatin side chain intermediate, the organic solvent B in the step (2) is selected from one or more of acetone, acetonitrile, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol and dioxane.
According to the preparation method of the rosuvastatin side chain intermediate, the mass volume ratio of the crude compound II to the purified water in the step (2) is 1: 3-7, wherein the mass is g, and the volume is mL.
According to the preparation method of the rosuvastatin side chain intermediate, the heating temperature in the step (2) is 35-50 ℃.
In the preparation method of the rosuvastatin side chain intermediate, the cooling temperature in the step (2) is 0-15 ℃.
Preferably, the mass-to-volume ratio of the crude compound II to the organic solvent B in the step (2) is 1: 1-3, wherein the mass is in g and the volume is in mL.
Compared with the prior art, the invention has the following beneficial effects:
(1) the reaction condition is mild, harsh reaction conditions such as ultralow temperature, no water and the like are not needed, the reaction is easy to realize, no malodorous gas is generated in the reaction process, the environment is friendly, the large scale generation is easy, and the industrial production is facilitated.
(2) High yield and high purity. The yield of tert-butyl (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-acetate was higher than 95%, the HPLC purity was more than 99.70%, and the carboxylic acid impurity ((4R,6S) -6- (2- (tert-butoxy) -2-oxoethyl) -2, 2-dimethyl-1, 3-dioxane-4-carboxylic acid) was less than 0.2%.
(3) The (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate in a high-purity solid form can be obtained by the refining method of the technology, the stability is obviously improved, and after stability tests such as illumination, high temperature, high humidity and the like, the HPLC purity of the (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate in a solid form prepared by the method is still higher than 99.5 percent, and the carboxylic acid impurities are lower than 0.35 percent.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.
Example 1: preparation of (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate
(1) 260.3g of Compound I, 1.6g of TEMPO1 and 16.1g of tetrabutylammonium bromide were dissolved in 2600mL of methylene chloride, 2600mL of a buffer solution of potassium carbonate/sodium bicarbonate having a pH of 7.5 was added, 186.9g N-chlorosuccinimide (NCS) was added at 10 ℃ and the reaction was stirred for 5 hours. The mixture was allowed to stand for liquid separation, the aqueous phase was extracted with 300mL of dichloromethane, the organic phases were combined, 200mL of a saturated saline solution was added to the organic phase, and the mixture was stirred and washed, and then allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtering and concentrating to obtain 256.9g of light yellow oily matter, namely crude (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, wherein the HPLC purity is as follows: 97.4%, carboxylic acid impurities: 0.76 percent.
(2) 540mL of ethanol was added to the flask containing the crude compound II, heated to 40 ℃ and dissolved with stirring. Then controlling the temperature to be 40-45 ℃, dropwise adding 1300mL of purified water, separating out a large amount of white solid after adding, cooling to 10 ℃, and carrying out suction filtration. The filter cake was dried under vacuum at 40 ℃ to give 253.6g of a white powdery solid, 98.2% overall yield in two steps, 99.90% HPLC purity, carboxylic acid impurity: 0.10 percent.
Example 2: preparation of (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate
(1) 260.3g of compound I, 3.9g of 4-BzO-TEMPO and 3.2g of tetrabutylammonium bromide are dissolved in 1600mL of ethyl acetate, 1600mL of sodium carbonate/potassium bicarbonate buffer solution with pH of 8.0 are added, 160.2g N-chlorosuccinimide (NCS) is added at 15 ℃, and the reaction is stirred for 5 hours. The mixture was allowed to stand for liquid separation, the aqueous phase was extracted with 300mL of dichloromethane, the organic phases were combined, 200mL of a saturated saline solution was added to the organic phase, and the mixture was stirred and washed, and then allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtering and concentrating to obtain 255.8g of light yellow oily matter, namely crude (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, wherein the HPLC purity is as follows: 97.12%, carboxylic acid impurities: 0.87 percent.
(2) 270mL of acetone was added to the flask containing the crude compound II, heated to 50 ℃ and dissolved with stirring. Then controlling the temperature to be 20-25 ℃, and dripping 780mL of purified water. After addition, a large amount of white solid precipitated. Cooling to 15 deg.C, and vacuum filtering. The filter cake was dried under vacuum at 40 ℃ to give 253.1g of a white powdery solid, 98.0% overall yield in two steps, 99.85% HPLC purity, carboxylic acid impurity: 0.12 percent.
Example 3: preparation of (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate
(1) 260.3g of compound I, 1.1g of 4-AcNH-TEMPO and 18.2g of benzyltriethylammonium chloride were dissolved in 3900mL of toluene, 3900mL of a sodium carbonate/sodium bicarbonate buffer solution having a pH of 8.5 was added, 213.6g N-chlorosuccinimide (NCS) was added at 20 ℃ and the reaction was stirred for 5 hours. The mixture was allowed to stand for liquid separation, the aqueous phase was extracted with 300mL of dichloromethane, the organic phases were combined, 200mL of a saturated saline solution was added to the organic phase, and the mixture was stirred and washed, and then allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtering and concentrating to obtain 257.4g of light yellow oily matter, namely crude (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, wherein the HPLC purity is as follows: 96.80%, carboxylic acid impurities: 0.93 percent.
(2) 540mL of methanol was added to the flask containing the crude compound II, heated to 35 ℃ and dissolved with stirring. Then, the temperature is controlled to be 30-35 ℃, and 1800mL of purified water is dripped. After addition, a large amount of white solid precipitated. Cooling to 0 deg.C, and vacuum filtering. The filter cake was dried under vacuum at 40 ℃ to give 252.6g of a white powdery solid, 97.8% overall yield in two steps, 99.80% HPLC purity, carboxylic acid impurity: 0.15 percent.
Example 4: preparation of (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate
(1) 260.3g of compound I, 2.2g of 4-AcNH-TEMPO and 10.6g of dodecyltrimethylammonium chloride were dissolved in 3900mL of 1, 2-dichloroethane, 3900mL of a sodium carbonate/sodium bicarbonate buffer solution having a pH of 8.2 was added, 200.3g N-chlorosuccinimide (NCS) was added at 20 ℃ and the reaction was stirred for 5 hours. The mixture was allowed to stand for liquid separation, the aqueous phase was extracted with 300mL of dichloromethane, the organic phases were combined, 200mL of a saturated saline solution was added to the organic phase, and the mixture was stirred and washed, and then allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtering and concentrating to obtain 258.3g of light yellow oily matter which is crude (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, wherein the HPLC purity is as follows: 96.85%, carboxylic acid impurities: 0.90 percent.
(2) 540mL of methanol was added to the flask containing the crude compound II, heated to 37 ℃ and dissolved with stirring. Then, the temperature is controlled to be 30-35 ℃, and 1800mL of purified water is dripped. After addition, a large amount of white solid precipitated. Cooling to 5 deg.C, and vacuum filtering. The filter cake was dried under vacuum at 40 ℃ to give 252.6g of a white powdery solid, 97.8% overall yield in two steps, 99.83% HPLC purity, carboxylic acid impurity: 0.12 percent.
Example 5: preparation of (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate
(1) 260.3g of compound I, 0.5g of 4-NC-TEMPO and 1.6g of tetrabutylammonium bromide were dissolved in 5000mL of methyl acetate, 2600mL of a potassium carbonate/potassium bicarbonate buffer solution having a pH of 7.0 were added, 240.3g N-chlorosuccinimide (NCS) was added at-5 ℃ and the reaction was stirred for 5 hours. The mixture was allowed to stand for liquid separation, the aqueous phase was extracted with 300mL of dichloromethane, the organic phases were combined, 200mL of a saturated saline solution was added to the organic phase, and the mixture was stirred and washed, and then allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtering and concentrating to obtain 254.4g of light yellow oily matter, namely crude (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, wherein the HPLC purity is as follows: 96.53%, carboxylic acid impurities: 0.99 percent.
(2) 540mL of ethanol was added to the flask containing the crude compound II, heated to 30 ℃ and dissolved with stirring. Then controlling the temperature to be 25-30 ℃, and dropwise adding 1300mL of purified water. After addition, a large amount of white solid precipitated. Cooling to 10 deg.C, and vacuum filtering. The filter cake was dried under vacuum at 40 ℃ to give 249.8g of a white powdery solid in 96.7% overall yield in two steps, 99.70% HPLC purity, carboxylic acid impurity: 0.18 percent.
Example 6: preparation of (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate
(1) 260.3g of compound I, 5.6g of 4-MeO-TEMPO and 39.6g of dodecyltrimethylammonium chloride were dissolved in 5000mL of chloroform, 1000mL of a buffer solution of potassium carbonate/sodium bicarbonate having a pH of 9.5 was added, 133.5g N-chlorosuccinimide (NCS) was added at 45 ℃ and the reaction was stirred for 5 hours. The mixture was allowed to stand for liquid separation, the aqueous phase was extracted with 300mL of dichloromethane, the organic phases were combined, 200mL of a saturated saline solution was added to the organic phase, and the mixture was stirred and washed, and then allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate. Filtering and concentrating to obtain 253.9g of light yellow oily matter which is crude (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, wherein the HPLC purity is as follows: 96.25%, carboxylic acid impurities: 1.16 percent.
(2) 540mL of ethanol was added to the flask containing the crude compound II, heated to 60 ℃ and dissolved with stirring. Then controlling the temperature to be 35-40 ℃, and dropwise adding 1300mL of purified water. After addition, a large amount of white solid precipitated. Cooling to 10 deg.C, and vacuum filtering. The filter cake was dried under vacuum at 40 ℃ to give 246.9g of a white powdery solid with a two step overall yield of 95.6%, HPLC purity 99.72%, carboxylic acid impurity: 0.20 percent.
Comparative example 1: preparation of 2- [ (4R,6S) -6-formyl-2, 2-dimethyl- [1,3] dioxan-4-yl ] -N-methoxy-N-methyl-acetamide
2- [ (4R,6S) -6-hydroxymethyl-2, 2-dimethyl- [1,3] dioxan-4-yl ] -N-methoxy-N-methyl-acetamide (30.0g), ethyl acetate (240.0mL), sodium bicarbonate (28.5g), potassium bromide (3.0g) and TEMPO (0.06g) were added to the reactor. The temperature of the reaction mixture is adjusted to 0-5 ℃. A10% sodium hypochlorite solution (96.0mL) was slowly added to the reaction mixture and stirred at 0-5 ℃ for 2 h. A 5% sodium sulfite solution (150.0mL) was added to the reaction mixture. The separated organic layer was washed with 10% sodium chloride solution (150.0 mL). The organic layer was concentrated under reduced pressure to obtain 2- [ (4R,6S) -6-aldehyde-2, 2-dimethyl- [1,3] dioxan-4-yl ] -N-methoxy-N-methyl-acetamide as a light brown solid (27.1g, 91% yield), HPLC purity: 84.50%, carboxylic acid impurities: 2.93 percent.
Comparative example 2: preparation of 2- [ (4R,6S) -6-formyl-2, 2-dimethyl- [1,3] dioxan-4-yl ] -N-methoxy-N-methyl-acetamide
Under a nitrogen atmosphere, 2- [ (4R,6S) -6-hydroxymethyl-2, 2-dimethyl- [1,3] dioxan-4-yl ] -N-methoxy-N-methyl-acetamide (5.0g), dichloromethane (30.0mL) and dess-martin oxidant (11.2g) were added to the reactor. Stirring the reaction mixture at 20-30 ℃ for more than 5 h. Water (30.0mL) was added to the reaction mixture. The separated organic layer was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (ethyl acetate/N-hexane ═ 1:3) to obtain 2- [ (4R,6S) -6-formyl-2, 2-dimethyl- [1,3] dioxan-4-yl ] -N-methoxy-N-methyl-acetamide as a white solid (4.1g, yield 83%), HPLC purity: 92.42%, carboxylic acid impurities: 2.31 percent.
Comparative example 3: preparation of methyl 2- ((4R,6S) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-yl) acetate
Trichloroisocyanuric acid (852g, 90% purity, 3.3mol) was added portionwise to a 0 ℃ solution containing methyl 2- ((4R,6S) -6- (hydroxymethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetate (654g,3mol), 2,2,6, 6-tetramethylpiperidine nitroxide (5g,0.03mol), sodium bicarbonate (2.0Kg,24mol) in 15L of dichloromethane and 15L of water with stirring. The reaction mixture was stirred at 0 ℃ for 1 hour and extracted with 350L of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 2- ((4R,6S) -6-formyl-2, 2-dimethyl-1, 3-dioxan-4-yl) acetate as a yellow oil (460.0g, yield 71%). HPLC purity: 89.70%, carboxylic acid impurities: 2.26 percent.
The flask containing the crude compound prepared in the above step was charged with 500mL of acetone, heated to 50 deg.C, and dissolved with stirring. Then controlling the temperature to be 20-25 ℃, and dripping 1100mL of purified water. After addition, a large amount of white solid precipitated. Cooling to 15 deg.C, and vacuum filtering. The filter cake was dried under vacuum at 40 ℃ to give 421.2g of a white powdery solid, 65.0% overall yield in two steps, 99.35% HPLC purity, carboxylic acid impurity: 0.32 percent.
Comparative example 4: preparation of (4R-cis) -6-formyl-2, 2-dimethyl-1, 3-dioxane-4-ethyl acetate
Adding 250mL of dichloromethane and 10mL of oxalyl chloride into a 500mL reaction bottle under the protection of nitrogen, stirring and cooling to-75-65 ℃, dropwise adding 11.5mL of dimethyl sulfoxide for about 10 minutes, keeping the temperature for 5-10 minutes, dropwise adding 20mL of dichloromethane solution containing 13.5g of (4R-cis) -6-hydroxy-2, 2-dimethyl-1, 3-dioxane-4-ethyl acetate at the temperature, keeping the temperature for about 10 minutes, pouring the reaction solution into a 1L beaker containing 100mL of water, stirring for 5 minutes, standing and separating an oil layer, extracting the water layer once with 70mL of dichloromethane, combining organic layers, sequentially using 80mL of 1N hydrochloric acid 80mL of 5% sodium bicarbonate and 80mL of water, stirring and drying with 15g of anhydrous sodium sulfate for more than 2 hours, filtering, concentrating under reduced pressure to dryness at an external temperature of within 45 ℃ below zero and under a pressure of-0.09 MPa to-0.1 MPa to obtain 12.6g of colorless oily substance, namely (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-ethyl acetate, wherein the yield is 94.2 percent, and the HPLC purity is as follows: 93.62%, carboxylic acid impurities: 1.54 percent.
Comparative example 5: preparation of 2- (6-formyl-2, 2-dimethyl- [1,3] -dioxane-4-yl) -N- (1-phenyl-ethyl) -acetamide
To 20mL of a dichloromethane solution containing 2- (6-hydroxymethyl-2, 2-dimethyl- [1,3] -dioxane-4-yl) -N- (1-phenyl-ethyl) -acetamide (1g) was added 2,2,6, 6-tetramethylpiperidine oxide (10mg), sodium bromide (0.03g) and sodium hydrogen carbonate (0.45g) in this order at 0 to 5 ℃, and then a sodium hypochlorite solution (8 to 10%, 4.65mL) was slowly added at 0 to 5 ℃ to stir the reaction mixture for 2.0 hours. After the reaction was complete, 5% aqueous sodium thiosulfate (10mL) was added, the layers were separated, the organic phase was washed with brine and concentrated under reduced pressure to give 0.82g of the product in 82.5% yield, HPLC purity: 93.7%, carboxylic acid impurities: 1.85 percent.
Comparative example 6: preparation of 2- (6-formyl-2, 2-dimethyl- [1,3] -dioxane-4-yl) -N- (1-phenyl-ethyl) -acetamide
2- (6-hydroxymethyl-2, 2-dimethyl- [1,3] -dioxan-4-yl) -N- (1-phenyl-ethyl) -acetamide (300.0g) was dissolved in dichloromethane (4.5L) and cooled to-10 ℃ 2,2,6, 6-tetramethylpiperidine oxide (7.80g) and potassium bromide (87g) were added followed by sodium bicarbonate (123 g). Thereafter, sodium hypochlorite (8-10%, 972mL) was added slowly at-10 ℃. After completion of the reaction, 10% aqueous sodium thiosulfate (3L) was added to the reaction mass, and the layers were separated. The organic layer was washed with brine (1.5L) and concentrated under vacuum. The product was isolated from n-hexane (225 g). HPLC purity: 95.31 percent.
The above product (10g) was purified with isopropyl ether to obtain 8.7g of a purified product, yield: 87.0%, HPLC purity: 97.26%, carboxylic acid impurities: 1.56 percent.
Comparative example 7: preparation of tert-butyl 2- ((4R,6S) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-yl) acetate
2,2,6, 6-tetramethylpiperidine oxide (TEMPO) (0.2g), potassium bromide (9.6g) and sodium bicarbonate (90g) were dissolved in dichloromethane (600mL), stirred uniformly at 0-5 ℃, a dichloromethane solution (400mL) of (4R-cis) -6-hydroxymethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate (100g) was added to the above solution at 0-5 ℃, a sodium hypochlorite solution (159mL) was added to the reaction mixture at 0-5 ℃, and then sodium bicarbonate (96g) and a 10% sodium hypochlorite solution were sequentially added to the reaction mixture. Keeping the reactant at 0-5 ℃ for 1-2 hours, and filtering. The organic phase was separated and washed successively with 10% sodium thiosulfate solution (250mL), water (250mL) and saturated sodium chloride solution. The organic phase was distilled at less than 40 ℃ under reduced pressure to give 93g of the target product in 93.7% yield, HPLC purity: 92.13%, carboxylic acid impurities: 2.51 percent.
Comparative example 8: preparation of tert-butyl 2- ((4R,6S) -6-formyl-2, 2-dimethyl-1, 3-dioxan-4-yl) acetate
To 30mL of a dichloromethane reaction mixture solution (AZADO 0.002g, potassium bromide 0.22g) precooled at-15 ℃ to-5 ℃ was added 5g of tert-butyl 2- ((4R,6S) -6-hydroxymethyl-2, 2-dimethyl-1, 3-dioxan-4-yl) acetate. After stirring the reaction mixture at-15 ℃ to-5 ℃ for 15min, 19mL of sodium hypochlorite solution was added at this temperature. The reaction was stirred for 15 min. The reaction was quenched with 10% sodium thiosulfate solution. A further 20mL of water were added and the solution and organic phase were separated. The organic phase was washed successively with water and brine solution. Complete distillation of the solvent gave the title compound as a solid (4.1 g), yield: 78.8%, HPLC purity: 90.34%, carboxylic acid impurities: 3.21 percent.
Stability test
The products prepared in examples 1-6 and comparative examples 1-8 were weighed, respectively, and stability test was performed according to the guidance method for stability study in the fourth part of the pharmacopoeia 2015 edition, and purity test was performed by HPLC method, and the specific test results are shown in table 1.
TABLE 1 stability test results of the examples and comparative examples under light, high temperature and high humidity conditions
The monohetero compounds described in table 1 are the carboxylic acid impurities described in the present invention.
Experiments show that all the (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate prepared by the scheme of the invention can achieve the same stability effect as the examples 1-6. As can be seen from Table 1, the purity and appearance of the (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate prepared by the invention are not obviously changed under the conditions of illumination, high temperature and high humidity, while the purity of the products of comparative examples 1 to 8 is greatly reduced under the same experimental conditions, the content of carboxylic acid impurities and the total impurities are obviously increased, namely, the products are deteriorated, and the (4R-cis) -6-aldehyde-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate prepared by the invention has better chemical stability compared with the existing intermediate.
Claims (10)
1. A preparation method of a rosuvastatin side chain intermediate is characterized by comprising the following steps:
(1) dissolving a compound I, an oxidation catalyst and a phase transfer catalyst in an organic solvent A, respectively adding an alkaline buffer solution and an oxidant, and reacting to obtain a crude compound II;
(2) dissolving the crude compound II in an organic solvent B, heating for dissolving, adding purified water, separating out a solid, filtering, and drying to obtain a refined compound II;
2. the process according to claim 1, wherein the oxidizing agent in the step (1) is N-chlorosuccinimide; the molar ratio of compound I to oxidant is 1: 1.2 to 1.6.
3. The method according to claim 1, wherein the phase transfer catalyst in step (1) is one selected from tetrabutylammonium bromide, dodecyltrimethylammonium chloride and benzyltriethylammonium chloride; the dosage of the phase transfer catalyst is 1 to 8 percent of the molar weight of the compound I.
4. The preparation method according to claim 1, wherein the organic solvent A in the step (1) is one or more selected from dichloromethane, ethyl acetate, toluene, methyl acetate, chloroform and 1, 2-dichloroethane; the mass-to-volume ratio of the compound I to the organic solvent A is 1: 6-15, wherein the mass is g, and the volume is mL.
5. The method according to claim 1, wherein the base in the buffer solution of the base in the step (1) is selected from the group consisting of potassium carbonate/sodium bicarbonate, sodium carbonate/potassium bicarbonate, sodium carbonate/sodium bicarbonate, potassium carbonate/potassium bicarbonate combinations; the pH value of the buffer solution of the alkali is 7.5-8.5; the mass-to-volume ratio of the buffer solution of the compound I and the alkali is 1: 6-15, wherein the mass is in g, and the volume is in mL.
6. The method according to claim 1, wherein the oxidation catalyst in the step (1) is one selected from the group consisting of TEMPO, 4-MeO-TEMPO, 4-AcHN-TEMPO, 4-NC-TEMPO and 4-BzO-TEMPO.
7. The method according to claim 1, wherein the oxidation catalyst is used in an amount of 0.5 to 1.5% by mole based on the compound I in step (1).
8. The method according to claim 1, wherein the reaction temperature of the reaction in the step (1) is 0 to 40 ℃, preferably 10 to 20 ℃.
9. The preparation method according to claim 1, wherein the organic solvent B in the step (2) is one or more selected from acetone, acetonitrile, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol and dioxane; the mass-to-volume ratio of the crude compound II to the organic solvent B is 1: 1-3, wherein the mass is in g and the volume is in mL.
10. The method according to claim 1, wherein the mass-to-volume ratio of the crude compound II to the purified water in step (2) is 1: 3-7, wherein the mass is g, and the volume is mL.
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