CN114874181A - Preparation method of rosuvastatin chiral side chain intermediate - Google Patents
Preparation method of rosuvastatin chiral side chain intermediate Download PDFInfo
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Abstract
The invention provides a preparation method of a rosuvastatin chiral side chain intermediate, which is characterized in that an enzyme engineering technology, a biological catalysis technology and a microchannel reactor production technology are organically combined, the chiral side chain intermediate is named as (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, the invention provides a green and efficient rosuvastatin chiral side chain intermediate production mode, expensive borane reagents and catalysts are avoided to be used, the transfer of materials in different reaction kettles is reduced, and the labor cost is reduced; the industrialization level and the product quality of rosuvastatin are improved, the problems of low yield, complicated working procedures, three-waste discharge and the like which restrict the industry are solved, and the method has higher market competitiveness.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical production, in particular to a method for producing rosuvastatin chiral side chain intermediate (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate by combining enzyme catalysis and a microchannel reactor.
Background
Rosuvastatin is a selective HMG-CoA reductase inhibitor, is used for treating hyperlipidemia and hypercholesterolemia, has high lipid-lowering property and safety compared with other statins, and is increasingly demanded by the market, but the production cost is high, and the price is high, so that the popularization of the rosuvastatin is limited. Rosuvastatin is prepared from a main ring and a chiral side chain, the synthesis process of the main ring is mature, related researchers mainly focus more attention on the synthesis of the chiral side chain, and a large amount of research is carried out on the rosuvastatin at home and abroad to obtain a certain effect, but a plurality of defects exist.
At present, the industrial synthesis of rosuvastatin chiral side chain intermediate mainly depends on the traditional full chemical synthesis process using expensive borane reagent, catalyst and the like, the conditions are harsh, the total yield is low, the steps are complicated, more manual intervention is needed to control the reaction, and the three wastes treatment capacity is large. Therefore, the method and the process for developing a practical, simple and high-yield rosuvastatin chiral side chain intermediate are hot points of great attention in the rosuvastatin preparation industry and bottlenecks restricting the development of the industry.
Compared with the chemical catalytic asymmetric reduction reaction, the enzymatic asymmetric catalysis has the advantages of mild reaction conditions, high conversion rate, good stereoselectivity and the like, and has become the first choice of a plurality of chiral synthesis methods. The microchannel reaction has the advantages of high specific surface area, capability of accurately controlling reaction conditions, easiness in amplification, no amplification effect, high safety, small amount of three wastes and the like, and is widely applied to the field of fine chemical preparation in recent years. Therefore, the invention adopts a microchannel continuous production device, uses carbonyl reductase and glucose dehydrogenase dual-enzyme coupling catalytic reduction carbonyl, wherein the carbonyl reductase catalyzes and reduces a target substrate, and the glucose dehydrogenase catalyzes and oxidizes glucose to generate reduced coenzyme NADH or NADPH, transfers hydrogen to the carbonyl, and efficiently prepares the rosuvastatin chiral side chain intermediate, thereby realizing an environment-friendly production process, reducing the risk, reducing the emission of three wastes, and improving the production efficiency and the product quality.
Disclosure of Invention
Aiming at the problems in the prior art, the invention combines enzyme engineering and biological catalysis technologies with a microchannel reactor, provides a green and efficient production technology of rosuvastatin chiral side chain intermediate (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, and the implementation of the technology is expected to improve the chemical yield and the optical yield of the rosuvastatin chiral side chain intermediate, reduce the dependence on manpower to the maximum extent, improve the production efficiency and the product quality, reduce the discharge of three wastes, greatly reduce the product cost and improve the market competitiveness.
The technical scheme adopted for solving the problems in the prior art is as follows:
the invention adopts enzyme catalysis and a microchannel reactor to combine to produce rosuvastatin chiral side chain intermediate, the name of the chiral side chain intermediate is (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, and the chemical structural formula is as follows:
a preparation method of rosuvastatin chiral side chain intermediate comprises the following steps:
step 1, taking S-4-chloro-3-trimethylsilyl butyronitrile and nano-zinc tetrahydrofuran solution as one strand, taking methanesulfonic acid tetrahydrofuran solution as one strand, taking tert-butyl bromoacetate as a third strand, respectively and simultaneously pumping the three strands into a first mixer connected with a first microchannel reactor, fully mixing the two strands, then feeding the mixture into the first microchannel reactor for reaction, and treating reaction effluent to obtain S-6-chloro-5-hydroxy-3-oxohexanoic acid tert-butyl ester, wherein the reaction equation is as follows:
and 2, pumping the S-6-chloro-5-hydroxy-3-oxohexanoate tert-butyl ester obtained in the step 1 into a reaction kettle, adding phosphate buffer solution into the reaction kettle, stirring uniformly, and then adding glucose in batches. Controlling the temperature to be 30-35 ℃, adding a sodium hydroxide solution to adjust the pH value to 7, adding an enzyme catalyst, slowly dropwise adding a sodium hydroxide solution to maintain the pH value to be 6.6-7.2, reacting for 6-8 h, extracting with ethyl acetate, washing with saturated saline solution, concentrating and drying to obtain (3R,5S) -6-chloro-3, 5-dihydroxy tert-butyl hexanoate, wherein the reaction equation is as follows:
step 3, taking the tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate obtained in the step 2 as a strand, 2, 2-dimethoxypropane as a strand, taking a tetrahydrofuran solution of methanesulfonic acid as a third strand, respectively and simultaneously pumping the tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate into a second mixer connected with a second microchannel reactor, fully mixing, entering the second microchannel reactor for reaction, and treating a reaction effluent to obtain tert-butyl (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetate, wherein the reaction equation is as follows:
in the step 1, the concentrations of tetrahydrofuran solutions of S-4-chloro-3-trimethylsilyl butyronitrile and nano-zinc are respectively 2-3 mol/L and 3.6-5.3 mol/L, the concentration of tetrahydrofuran solution of methanesulfonic acid is 0.05-0.08 mol/L, and the molar ratio of S-4-chloro-3-trimethylsilyl butyronitrile to nano-zinc, methanesulfonic acid and tert-butyl bromoacetate in the reaction effluent of the first microchannel reactor is 1: 1.5-1.8: 0.008-0.018: 1 to 1.3.
In the step 1, the flow rate of the tetrahydrofuran solution of S-4-chloro-3-trimethylsilyl butyronitrile and nano zinc as one strand is 1-3 mL/min, the flow rate of the tetrahydrofuran solution of methanesulfonic acid as one strand is 0.5-2 mL/min, and the flow rate of the tert-butyl bromoacetate as a third strand is 0.5-1.5 mL/min; the volume of the first microchannel reactor is 9.1-45.5 mL, the residence time of the reaction is 5-25 min, and the reaction temperature is 70-80 ℃.
The treatment method of the reaction effluent in the step 1 comprises the following steps: filtering the reaction effluent, adding 10% hydrochloric acid into the filtrate, adjusting pH to 3 + -0.5, separating layers, extracting the water layer with ethyl acetate, combining organic layers, adjusting pH to neutral with 10% sodium bicarbonate solution, filtering, evaporating the filtrate to remove the solvent, concentrating and drying.
The enzyme catalysts in the step 2 are carbonyl reductase and glucose dehydrogenase.
In the step 2, the concentration of the phosphate buffer solution is 0.05-0.1 mol/L, and the concentration of the sodium hydroxide solution is 3.0-6.0 mol/L; the mass ratio of S-6-chloro-5-hydroxy-3-oxohexanoate tert-butyl ester to glucose to enzyme catalyst glucose carbonyl reductase to glucose dehydrogenase is 1: 1.0-1.3: 0.05-0.1: 0.03 to 0.05.
In the step 3, the concentration of the tetrahydrofuran solution of the methanesulfonic acid is 0.05-0.1 mol/L, and the molar ratio of tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate to 2, 2-dimethoxypropane to methanesulfonic acid in the reaction effluent of the second microchannel reactor is 1: 2.0-3.0: 0.01 to 0.02.
In the step 3, the flow rate of the tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate serving as one strand is 1.5-4 mL/min, the flow rate of the 2, 2-dimethoxypropane serving as one strand is 1.5-4 mL/min, and the flow rate of the tetrahydrofuran solution of methanesulfonic acid serving as one strand is 0.5-2.5 mL/min; the volume of the second microchannel reactor is 9.1-45.5 mL, the residence time of the reaction is 3-15 min, and the reaction temperature is 20-30 ℃.
The treatment method of the reaction effluent liquid in the step 3 comprises the following steps: adding 10% sodium bicarbonate solution and n-hexane into the reaction solution, layering, draining a water layer, washing an organic layer with saturated saline solution, and evaporating the solvent to obtain a product (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate.
The first microchannel reactor and the second microchannel reactor are both of the type RMCS181003, are named as a Haemai microchannel reactor and belong to directly applicable products.
The invention has the following advantages:
the invention organically combines enzyme engineering, a biological catalysis technology and a microchannel reactor production technology, and provides a green and efficient rosuvastatin chiral side chain intermediate production mode. The carbonyl reductase and glucose dehydrogenase dual-enzyme coupling catalysis has the advantages of high-efficiency asymmetric reduction, mild reaction conditions, high conversion rate, good stereoselectivity, simple separation, relatively low cost, environmental friendliness and the like. The microchannel reactor can accurately control the reaction selectivity and yield, has stable process, low transmission, energy and material consumption, is easy to realize industrialization, scale and automatic control, reduces the production cost and improves the benefit. The new process for preparing the rosuvastatin chiral side chain intermediate (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate improves the industrialization level and the product quality of rosuvastatin, solves the problems of low yield, complicated working procedures, three-waste discharge and the like which restrict the industry, and has higher market competitiveness.
Drawings
FIG. 1 is a schematic diagram of the production route for producing rosuvastatin chiral side chain intermediates of the present invention.
FIG. 2 is a reaction equation of the present invention.
FIG. 3 is a schematic view of a microchannel reactor.
Wherein: 1-raw material inlet, 2-filter, 3-plunger pump, 4-one-way valve, 5-safety valve, 6-control panel, 7-heat exchange medium outlet and 8-heat exchange medium inlet.
Detailed Description
The technical scheme of the present invention is further specifically described below by way of examples and with reference to the accompanying drawings, wherein a reaction apparatus adopted in the following examples is shown in fig. 1, and comprises a first microchannel reaction apparatus, a reaction kettle and a second microchannel reaction apparatus which are connected in series in sequence. The first microchannel reactor comprises a pump A, a pump B, a pump C, a first mixer I and a first microchannel reactor I; the reaction kettle comprises various feeding valves and a reaction kettle II; the second microchannel reactor device comprises a pump D, a pump E, a pump F, a second mixer and a second microchannel reactor III. The reaction raw materials enter a mixer through an injection pump and then enter a microchannel reactor, wherein the first microchannel reactor and the second microchannel reactor are both pipeline reactors, the model is RMCS181003 and the name is a Haemai microchannel reactor.
Example 1
(1) 2.56kg (13.4mol) of S-4-chloro-3-trimethylsilyl butyronitrile and 5.6L of a tetrahydrofuran solution of 1.56kg (24.1mol) of nano zinc are pumped into a first mixer (I), the flow rate of a pump A is 2.56mL/min, 2.8L of a tetrahydrofuran solution of 23g (0.24mol) of methanesulfonic acid is pumped into the first mixer (I), the flow rate of a pump B is 1.28mL/min, 3.41kg (17.5mol) of tert-butyl bromoacetate is pumped into the first mixer (I), and the flow rate of a pump C is 1.18 mL/min. After fully mixing, the mixture enters a first microchannel reactor for reaction, the volume of the first microchannel reactor I is 45.5mL, the reaction residence time is 9min, and the reaction temperature is 80 ℃. Filtering the reaction effluent, adding 10% hydrochloric acid into the filtrate, adjusting the pH value to 3 +/-0.5, separating layers, extracting a water layer by using ethyl acetate 2.0L, combining organic layers, adjusting the pH value to be neutral by using a 10% sodium bicarbonate solution, filtering, evaporating the filtrate to remove the solvent, concentrating and drying to obtain a colorless liquid of 3.10kg of S-6-chloro-5-hydroxy-3-oxohexanoic acid tert-butyl ester, wherein the yield is 98%.
(2) Pumping 2.95kg (12.4mol) of S-6-chloro-5-hydroxy-3-oxohexanoic acid tert-butyl ester obtained in the step (1) into a reaction kettle, adding 4.66L of 0.1M phosphate buffer solution into the reaction kettle, and adding 3.54kg (19.7mol) of glucose in 3 batches after uniformly stirring to avoid agglomeration. Controlling the temperature to be 30-35 ℃, adding 3.0mol/L sodium hydroxide solution to adjust the pH value to be 7, adding 0.3kg of carbonyl reductase and 0.15kg of glucose dehydrogenase serving as three enzyme catalysts, slowly dropwise adding 3.0mol/L sodium hydroxide solution to maintain the pH value to be 6.6-7.2, and reacting for 8 hours. Extracting with ethyl acetate 7.8L for three times, separating layers, mixing ethyl acetate layers, washing with saturated saline 2.0L once, concentrating, and drying to obtain oily substance (3R,5S) -6-chloro-3, 5-dihydroxy tert-butyl hexanoate 2.94kg with yield of 99%.
(3) Pumping 2.83kg (11.85mol) of (3R,5S) -6-chloro-3, 5-dihydroxy caproic acid tert-butyl ester obtained in the step (2) into a second mixer (2) at a flow rate of 2.83mL/min, pumping 3.69kg (35.5mol) of 2, 2-dimethoxypropane into the second mixer (3.69 mL/min), and pumping 2.3L of a tetrahydrofuran solution containing 23g (0.24mol) of methanesulfonic acid into the second mixer (2.3 mL/min). After fully mixing, the mixture enters a second microchannel reactor for reaction, the volume of a second microchannel reactor II is 45.5mL, the reaction residence time is 5min, and the reaction temperature is 30 ℃. Adding 2.0L of 5% sodium bicarbonate solution and 4.5L of n-hexane into the reaction effluent, demixing, discharging a water layer, washing an organic layer by using 2.0L of saturated sodium chloride solution, and distilling off the solvent to obtain 3.1kg of brown liquid (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate with the yield of 95%.
Comparative example 1
The procedure is the same as in example 1, except that: the step (1) and the step (3) are both carried out in a reaction kettle.
Step (1): 5.6L of tetrahydrofuran was pumped into the reactor by nitrogen displacement, and 1.55kg (23.8mol) of zinc powder and 20g (0.21mol) of methanesulfonic acid were charged through a solid feeder. Heated to about 67 ℃ for refluxing for 1h, and 2.56kg (13.4mol) of S-4-chloro-3-trimethylsilylbutyronitrile was added. Controlling the temperature to be 68-70 ℃, then dropwise adding 3.41kg (17.5mol) of tert-butyl bromoacetate, controlling the temperature to be 70 +/-2 ℃ midway, 1/3 before dropwise adding for 2h, 2/3 after dropwise adding for 2h, and heating and refluxing for 1h after dropwise adding. The reaction solution was filtered, 10% hydrochloric acid was added to the filtrate to adjust pH to 3 ± 0.5, the layers were separated, the aqueous layer was extracted with 2.0L of ethyl acetate, the organic layers were combined, pH was adjusted to neutral with 10% sodium bicarbonate solution, the filtrate was filtered, the solvent was evaporated off, and the filtrate was concentrated and dried to obtain 2.75kg of colorless liquid tert-butyl S-6-chloro-5-hydroxy-3-oxohexanoate with a yield of 86%.
And (3): adding 2.43kg (10.1mol) of tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate obtained in the step (2) into a reaction kettle, pumping 2.62kg (25.2mol) of 2, 2-dimethoxypropane, adjusting the temperature to 15 ℃, adding 20g of methanesulfonic acid, adjusting the pH value to 2-3, heating to 20-25 ℃, and stirring for 4 hours. And (2) transferring the reaction solution into 2.0L of prepared 10% sodium bicarbonate aqueous solution and 4.5L of n-hexane at room temperature, adjusting the pH to 7-7.5, stirring for 30min, layering, extracting the water layer once with 4.0L of n-hexane, combining organic layers, washing the water layer once with 2.0L of saline solution, layering, concentrating and drying the organic phase to obtain 2.45kg of brown liquid (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate with the yield of 87%.
Comparative example 2
The procedure is the same as in example 1, except that: the step (2) is carried out by adopting the traditional chemical catalytic asymmetric reduction reaction.
Step (2): pumping 2.75kg (11.6mol) of S-6-chloro-5-hydroxy-3-oxohexanoic acid tert-butyl ester obtained in the step (1) into a reaction kettle, adding 12.5L of tetrahydrofuran and 6.0L of methanol into the reaction kettle, cooling to-78 ℃ under the protection of nitrogen, adding 12.5L of triethylboron (1mol/L tetrahydrofuran solution), stirring for reaction for 20min, adding 0.5kg of sodium borohydride, reacting for 3h at the temperature, adding 2.5L of acetone and 0.9L of 30% hydrogen peroxide, reacting at-30 ℃ for 30min, pouring the reaction system into 6L of water, layering, extracting a water layer by using 7.8L of ethyl acetate, combining an organic phase, washing by using 2.0L of saturated sodium chloride solution, drying by using anhydrous sodium sulfate, concentrating and drying to obtain 2.43kg of oily (3R,5S) -6-chloro-3, 5-dihydroxyhexanoic acid tert-butyl ester, the yield was 88%.
Example 2
The procedure is the same as in example 1, except that:
in the step (1), the concentration of the tetrahydrofuran solution of S-4-chloro-3-trimethylsilyl butyronitrile is 3mol/L, the concentration of the tetrahydrofuran solution of nano-zinc is 5.3mol/L, the concentration of the tetrahydrofuran solution of methanesulfonic acid is 0.08mol/L, and the molar ratio of the S-4-chloro-3-trimethylsilyl butyronitrile to the nano-zinc, the methanesulfonic acid and the tert-butyl bromoacetate is 1: 1.5: 0.008: 1. the flow rates of pump A, pump B and pump C were 1.0mL/min, respectively, the flow rate of pump B was 0.5mL/min and the flow rate of pump C was 0.5 mL/min. The volume of the first microchannel reactor I was 36.4mL, the reaction residence time was 20min, the reaction temperature was 70 ℃ and the yield was 92%.
In the step (2), the concentration of the phosphate buffer solution is 0.05mol/L, and the concentration of the sodium hydroxide solution is 6.0 mol/L; the mass ratio of S-6-chloro-5-hydroxy-3-oxohexanoate tert-butyl ester to glucose to enzyme catalyst glucose carbonyl reductase to glucose dehydrogenase is 1: 1.0: 0.05: 0.03, yield 90%.
In the step (3), the concentration of tetrahydrofuran solution of methanesulfonic acid is 0.05mol/L, and the molar ratio of tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate to 2, 2-dimethoxypropane and methanesulfonic acid is 1: 2.0: 0.01. the flow rates of the pump D, the pump E and the pump F are respectively 1.5mL/min, 1.5mL/min and 0.5mL/min, the volume of the second microchannel reactor II is 36.4mL, the reaction residence time is 12min, the reaction temperature is 20 ℃, and the yield is 93%.
Compared with the example 1, the comparative example 1 has the advantages that the step (1) and the step (3) are both carried out in reaction kettles, and the product intermediates are transferred among different reaction kettles, so that material waste is caused, the labor cost is increased, and the production efficiency is low; the reaction in the kettle is uneven, the reaction time is long, the energy consumption is high, and the reaction yield is lower than that of the example 1.
Compared with the example 1, the step (2) is carried out by adopting the traditional chemical catalytic asymmetric reduction reaction, expensive borane reagent and sodium borohydride are used for reduction, the reaction conditions are harsh, the steps are complicated, the three-waste treatment capacity is large, and the reaction yield is lower than that of the example 1.
Example 2 compared to example 1, the first microchannel reactor i and the second microchannel reactor ii were smaller in volume than in example 1, and the reaction residence time was short, resulting in a lower reaction yield than in example 1.
The invention organically combines enzyme engineering, a biological catalysis technology and a microchannel reactor production technology, and provides a green and efficient rosuvastatin chiral side chain intermediate production mode. Expensive borane reagent and catalyst are avoided, the transfer of materials in different reaction kettles is reduced, the labor cost is reduced, and the three-waste treatment capacity is small. The volume of the microchannel reactor can be selected according to actual conditions, the residence time of reaction liquid in the pipeline is adjusted, and ideal yield is obtained.
The protective scope of the present invention is not limited to the above-described embodiments, and it is apparent that various modifications and variations can be made to the present invention by those skilled in the art without departing from the scope and spirit of the present invention. It is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.
Claims (10)
1. A preparation method of rosuvastatin chiral side chain intermediate is characterized by comprising the following steps:
step 1, taking S-4-chloro-3-trimethylsilyl butyronitrile and nano-zinc tetrahydrofuran solution as one strand, taking methanesulfonic acid tetrahydrofuran solution as one strand, taking tert-butyl bromoacetate as a third strand, respectively and simultaneously pumping the three strands into a first mixer connected with a first microchannel reactor, fully mixing the two strands, then feeding the mixture into the first microchannel reactor for reaction, and treating reaction effluent to obtain S-6-chloro-5-hydroxy-3-oxohexanoic acid tert-butyl ester, wherein the reaction equation is as follows:
step 2, pumping the tert-butyl S-6-chloro-5-hydroxy-3-oxohexanoate obtained in the step 1 into a reaction kettle, adding a phosphate buffer solution into the reaction kettle, stirring uniformly, adding glucose in batches, controlling the temperature to be 30-35 ℃, adding a sodium hydroxide solution to adjust the pH to be 7, adding an enzyme catalyst, slowly adding a sodium hydroxide solution dropwise to maintain the pH to be 6.6-7.2, reacting for 6-8 hours, extracting with ethyl acetate, washing with saturated saline solution, concentrating and drying to obtain the tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate, wherein the reaction equation is as follows:
step 3, taking the tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate obtained in the step 2 as one strand, 2, 2-dimethoxypropane as one strand, taking a tetrahydrofuran solution of methanesulfonic acid as a third strand, respectively and simultaneously pumping the tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate into a second mixer connected with a second microchannel reactor, fully mixing, entering the second microchannel reactor for reaction, and treating reaction effluent liquid to obtain tert-butyl (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetate, wherein the reaction equation is as follows:
2. the process for the preparation of rosuvastatin chiral side chain intermediate according to claim 1, wherein: in the step 1, the concentrations of S-4-chloro-3-trimethylsilyl butyronitrile and tetrahydrofuran solution of nano zinc are respectively 2-3 mol/L and 3.6-5.3 mol/L, the concentration of tetrahydrofuran solution of methanesulfonic acid is 0.05-0.08 mol/L, the molar ratio of S-4-chloro-3-trimethylsilyl butyronitrile to nano zinc, methanesulfonic acid and tert-butyl bromoacetate in the reaction effluent of the first microchannel reactor is 1: 1.5-1.8: 0.008-0.018: 1 to 1.3.
3. The process for the preparation of rosuvastatin chiral side chain intermediate according to claim 1, wherein: in the step 1, the flow rate of the tetrahydrofuran solution of S-4-chloro-3-trimethylsilyl butyronitrile and nano zinc as one strand is 1-3 mL/min, the flow rate of the tetrahydrofuran solution of methanesulfonic acid as one strand is 0.5-2 mL/min, and the flow rate of tert-butyl bromoacetate as a third strand is 0.5-1.5 mL/min; the volume of the first microchannel reactor is 9.1-45.5 mL, the residence time of the reaction is 5-25 min, and the reaction temperature is 70-80 ℃.
4. The process for the preparation of rosuvastatin chiral side chain intermediate according to claim 1, wherein: the treatment method of the reaction effluent in the step 1 comprises the steps of filtering the reaction effluent, adding 10% hydrochloric acid into filtrate, adjusting the pH to 3 +/-0.5, layering, extracting a water layer with ethyl acetate, combining organic layers, adjusting the pH to be neutral with 10% sodium bicarbonate solution, filtering, evaporating the filtrate to remove the solvent, concentrating and drying.
5. The process for the preparation of rosuvastatin chiral side chain intermediate according to claim 1, wherein: the enzyme catalysts in the step 2 are carbonyl reductase and glucose dehydrogenase.
6. The process for the preparation of rosuvastatin chiral side chain intermediate according to claim 1, wherein: in the step 2, the concentration of the phosphate buffer solution is 0.05-0.1 mol/L, and the concentration of the sodium hydroxide solution is 3.0-6.0 mol/L; the mass ratio of S-6-chloro-5-hydroxy-3-oxohexanoate tert-butyl ester to glucose to enzyme catalyst glucose carbonyl reductase to glucose dehydrogenase is 1: 1.0-1.3: 0.05-0.1: 0.03 to 0.05.
7. The process for the preparation of rosuvastatin chiral side chain intermediate of claim 1, wherein: in the step 3, the concentration of the tetrahydrofuran solution of the methanesulfonic acid is 0.05-0.1 mol/L, and the molar ratio of tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate to 2, 2-dimethoxypropane to methanesulfonic acid in the reaction effluent of the second microchannel reactor is 1: 2.0-3.0: 0.01 to 0.02.
8. The process for the preparation of rosuvastatin chiral side chain intermediate according to claim 1, wherein: in the step 3, the flow rate of the tert-butyl (3R,5S) -6-chloro-3, 5-dihydroxyhexanoate serving as one strand is 1.5-4 mL/min, the flow rate of the 2, 2-dimethoxypropane serving as one strand is 1.5-4 mL/min, and the flow rate of the tetrahydrofuran solution of methanesulfonic acid serving as one strand is 0.5-2.5 mL/min; the volume of the second microchannel reactor is 9.1-45.5 mL, the residence time of the reaction is 3-15 min, and the reaction temperature is 20-30 ℃.
9. The process for the preparation of rosuvastatin chiral side chain intermediate according to claim 1, wherein: and 3. the treatment method of the reaction effluent liquid in the step 3 comprises the steps of adding 10 percent sodium bicarbonate solution and n-hexane into the reaction liquid, layering, draining a water layer, washing an organic layer with saturated saline solution, and distilling off the solvent to obtain the product (4R, cis) -6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate.
10. The process for the preparation of rosuvastatin chiral side chain intermediate according to claim 1, wherein: the first microchannel reactor and the second microchannel reactor are of the type RMCS181003 and are named as a Haemai microchannel reactor.
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