CN114213270B - Method for synthesizing atorvastatin calcium intermediate by using continuous flow micro-channel reactor - Google Patents
Method for synthesizing atorvastatin calcium intermediate by using continuous flow micro-channel reactor Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 21
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 title claims abstract description 19
- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 23
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 230000035484 reaction time Effects 0.000 claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 239000000463 material Substances 0.000 claims description 102
- 239000000243 solution Substances 0.000 claims description 73
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000011347 resin Substances 0.000 claims description 31
- 229920005989 resin Polymers 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 238000002791 soaking Methods 0.000 claims description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 22
- 239000003960 organic solvent Substances 0.000 claims description 17
- 239000008367 deionised water Substances 0.000 claims description 16
- 229910021641 deionized water Inorganic materials 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 229920001429 chelating resin Polymers 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000005086 pumping Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 13
- 239000003054 catalyst Substances 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 6
- 238000010924 continuous production Methods 0.000 abstract 1
- 239000010815 organic waste Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 239000002585 base Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ADHRFDCBLJVNFO-UHFFFAOYSA-N 4-methyl-3-oxo-n-phenylpentanamide Chemical compound CC(C)C(=O)CC(=O)NC1=CC=CC=C1 ADHRFDCBLJVNFO-UHFFFAOYSA-N 0.000 description 2
- 101710095342 Apolipoprotein B Proteins 0.000 description 2
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- BWFCZHDTTAYGNN-CNZCJKERSA-N calcium;(3r,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound [Ca].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 BWFCZHDTTAYGNN-CNZCJKERSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000001258 dyslipidemic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing atorvastatin calcium intermediate by using a continuous flow microchannel reactor, wherein a compound II and aniline are used as raw materials, a strong base anion exchange resin is used as a catalyst in the microchannel reactor, and an intermediate compound I is prepared under the conditions of 25-70 ℃ and 20-100 s of time, and the reaction flow is shown as follows. The method solves the problems of long reaction time, high reaction condition requirement, incapability of continuous production, high cost and the like of the traditional preparation method. Meanwhile, the preparation method can accurately control reaction conditions, reduce the emission of organic waste liquid, complete the preparation of the atorvastatin calcium intermediate in an extremely short time by adopting a continuous and safe production mode, and ensure that the yield of a target product is more than 98% and the purity is more than 99%. The catalyst adopted by the invention can be recycled for more than 8 times, has low cost, saves resources, has simple post-treatment of products and is environment-friendly.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for synthesizing an atorvastatin calcium intermediate by using a continuous flow micro-channel reactor.
Background
Atorvastatin calcium (Atorvastain calium), known as (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid calcium, is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In 1997, it was proposed by the american-type scion company as a third-generation statin lipid-regulating drug, and is widely used for preventing and treating hypercholesterolemia in clinical practice. This effect is exerted by lowering the Total Cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels in dyslipidemic patients. In addition, atorvastatin calcium has an anti-inflammatory effect in atherosclerotic plaques. Because of the characteristics of high efficiency, safety and the like. Is always one of the most popular drugs for treating hypercholesterolemia.
The compound N-phenylisobutyrylacetamide (compound I) is a key intermediate compound in the synthesis of atorvastatin calcium, and the preparation method mainly adopts the following route at present:
Patent CN101337906A and CN106397241A report that the method for preparing the target product compound I by taking the compound II and aniline as raw materials and taking 4-dimethylaminopyridine as a catalyst has higher yield, but the catalyst has higher price, nitrogen wastewater is easy to generate in industrial production, the preparation method is carried out in the existing kettle type reaction bottle, the feeding mode is multiple step feeding, the reaction time is several hours, isomer impurities are generated, the post-treatment process is complex, and the process cost is increased.
Disclosure of Invention
The invention aims to provide a method for synthesizing atorvastatin calcium intermediate by using a continuous flow microchannel reactor based on the prior art, which takes strong base anion exchange resin as a catalyst, has mild reaction conditions, extremely short time required in the whole reaction process, effectively avoids byproducts generated by overlong reaction time or overhigh reaction temperature, has high yield, high purity and low cost, is environment-friendly, and can be recycled as the resin of the catalyst, particularly does not generate nitrogen wastewater in the production process, has simple post-treatment, and is suitable for industrialized mass production.
The technical scheme of the invention is as follows:
A method for synthesizing atorvastatin calcium intermediate by using a continuous flow micro-channel reactor comprises the following synthesis routes:
The method specifically comprises the following steps:
(1) Preparing a material A solution: mixing the compound II with an organic solvent, and uniformly stirring for later use;
(2) Preparing a material B solution: mixing aniline and an organic solvent, and uniformly stirring for later use;
(3) Preparing a material C solution: adding strong alkali type anion exchange resin into sodium hydroxide aqueous solution at 25-35 ℃ for soaking, separating out soaked resin, washing the resin by deionized water until the pH value is 6.5-7.5, adding the washed resin into organic solvent for soaking again, and reserving after the soaking is finished;
(4) Pumping the solution A, the solution B and the solution C into a micro-channel reactor respectively, mixing uniformly, and carrying out chemical reaction at the reaction temperature of 25-70 ℃ for 20-100 s; after the reaction is finished, separating liquid, washing and drying to obtain the intermediate compound I.
The preparation method of the application can accurately control the feeding proportion of the reaction materials, greatly shorten the reaction time, have high safety, low cost and simple post-treatment, and the yield of the product is more than 98 percent, and the purity is more than 99 percent, thereby being particularly suitable for industrialized mass production.
The invention uses strong base anion exchange resin as catalyst, no nitrogen waste water is produced in the production process, the post treatment is simple, the production cost is low, and the invention is suitable for industrialized mass production. For the purposes of the present invention, the strong base anion exchange resin in step (3) is a strong base anion exchange resin commercially suitable for use in the present invention, in particular Amberlite IRA 402 strong base anion exchange resin (chloride type).
For the purposes of the present invention, in step (1), when preparing the solution of material A, the organic solvent chosen is one or more of toluene, benzene, ethyl acetate, cyclohexane or n-hexane; preferably, the organic solvent selected is toluene, ethyl acetate or n-hexane.
In the step (2), when preparing the solution of the material B, the selected organic solvent is one or more of toluene, benzene, ethyl acetate, cyclohexane or n-hexane; preferably, the organic solvent selected is toluene, ethyl acetate or n-hexane.
In the step (3), when preparing the solution of the material C, the selected organic solvent is one or more of toluene, benzene, ethyl acetate, cyclohexane or n-hexane; preferably, the organic solvent selected is toluene, ethyl acetate or n-hexane.
For the present invention, in the step (3), the strong base anion exchange resin is added into the sodium hydroxide aqueous solution at the temperature of 25 to 35 ℃ for soaking, wherein the soaking time in the sodium hydroxide aqueous solution is 20 to 30 hours, and can be, but not limited to, 20 hours, 22 hours, 24 hours, 26 hours or 30 hours, and the soaking time is 24 hours for obtaining a better effect.
Further, the solvent water in the aqueous sodium hydroxide solution is deionized water, and the concentration of the aqueous sodium hydroxide solution is 1-5 wt%, which may be but not limited to 1wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt% or 5wt%, for obtaining better effect, the concentration of the aqueous sodium hydroxide solution is 3wt%.
In the present invention, the washed resin is soaked again in the organic solvent for 2-6 hours, which may be, but not limited to, 2 hours, 4 hours, 5 hours or 6 hours, and the soaking time is 4 hours in order to obtain a better effect.
In a preferred embodiment, in step (3), a solution of material C is prepared: adding strong alkali type anion exchange resin into 3wt% sodium hydroxide aqueous solution (water is deionized water) at 25-35 ℃ for soaking for 24h, separating out soaked resin, washing the soaked resin with deionized water until the pH value is 6.5-7.5, adding the washed resin into an organic solvent for soaking for 4h again, and standing by after the soaking is completed.
In the step (4), the addition amount of the strong base anion exchange resin needs to be controlled, and the dosage of the resin is low, so that incomplete reaction is easy to cause; the resin is used in a relatively high amount, byproducts are easy to generate, the cost is increased, and the smooth reaction is not facilitated, so that the yield and purity of the product are relatively low. In the present invention, the mass ratio of the compound II to the strong base anion exchange resin (for example, amberlite IRA 402 strong base anion exchange resin) is 1:0.25 to 0.8, which may be, but is not limited to, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.7 or 1:0.8, and the mass ratio of the compound II to the strong base anion exchange resin is 1:0.3 to 0.6, and further preferably 1:0.55, for better effects and cost saving.
For the invention, the molar ratio of the compound II to the aniline has great influence on the yield and purity of the target product, and too low is unfavorable for the smooth reaction, and the yield and purity of the target compound I are low, so that excessive raw materials are easily caused by too high, and the cost is high. In the step (4), the molar ratio of the compound II to the aniline is 1:1 to 1.5, which may be, but is not limited to, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.4 or 1:1.5, and the molar ratio of the compound II to the aniline is preferably 1:1.1 to 1.3, and further preferably the molar ratio of the compound II to the aniline is 1:1.2.
In the present invention, when the microchannel reaction is carried out in the step (4), the reaction temperature is precisely controlled by an external device, for example, in a preferred embodiment, the temperature of the microchannel reaction is 25 to 70℃and may be, but not limited to, 25℃30℃35℃40℃45℃50℃55℃60℃or 70℃and, for obtaining a better effect, the reaction temperature is preferably 30 to 60℃and more preferably 55 ℃.
In a preferred embodiment, the reaction time of the micro channel is 20 to 100s, which may be, but not limited to, 20s, 30s, 35s, 40s, 45s, 50s, 55s, 60s, 65s, 70s, 75s, 80s, 85s, 90s or 100s, and the reaction time is preferably 30 to 80s, and more preferably 60s for obtaining a better effect.
Further, in the microchannel reaction in the step (4), the flow rate of the solution of the conveyed material A is 10-20 ml/min, preferably 11ml/min; the flow rate of the solution for conveying the material B is 12-24 ml/min, preferably 18ml/min; the flow rate of the solution of the material C to be conveyed is 15-30 ml/min, preferably 22ml/min.
For the continuous flow micro-channel reactor, the reaction module of the micro-channel reactor is a three-feed single-discharge module, the structure of the reaction module is a T-shaped structure, a spherical baffle plate, a water drop-shaped structure or a heart-shaped structure, and the hydraulic diameter of the channel is 0.5-10 mm.
By adopting the technical scheme of the invention, the advantages are as follows:
According to the invention, a continuous flow microchannel reactor is utilized to synthesize a target product of atorvastatin calcium intermediate N-phenylisobutyrylacetamide, and a strong base type anion exchange resin is used as a catalyst, so that the dosage of reaction materials and the reaction temperature and time are strictly controlled in the reaction process, the whole reaction process is extremely short in time, the reaction condition is mild, byproducts generated due to overlong reaction time or overhigh reaction temperature are effectively avoided, the yield of the target product is high, the yield is up to more than 98%, the purity is high, and the purity is up to more than 99%. The catalyst adopted by the invention can be recycled for more than 8 times, has low cost, saves resources, has simple post-treatment of products and is environment-friendly.
Drawings
FIG. 1 is a schematic diagram of a microchannel reactor used in the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
As shown in FIG. 1, the microchannel reactor comprises a preheating module, a mixing module and a cooler, wherein the speed of materials A, B and C entering the preheating module is controlled by a counting pump respectively, the materials A, B and C are preheated in the preheating module, when the required reaction temperature is reached, the materials enter the mixing module for chemical reaction, after the reaction is finished, the obtained reaction liquid enters the cooler for cooling, and after the cooling is finished, the materials A, B and C flow out of the microchannel reactor in a high-dispersion continuous flow state.
Example 1
(1) Preparing a material A solution: compound II (268 g,3.8 mol) was added to toluene, diluted to 800ml, stirred well, placed in a feed tank a (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(2) Preparing a material B solution: aniline (428 g,4.6 mol) was added to toluene, diluted to 1309ml, stirred well, placed in a feed tank B (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(3) Preparing a material C solution: adding 300g Amberlite IRA 402 strong base anion exchange resin (chlorine type) into 600g of 3wt% sodium hydroxide aqueous solution (water is deionized water) at 25-35 ℃ for soaking for 24h, separating out soaked resin, washing the resin with deionized water until the pH value is 6.5-7.5, adding the washed resin into toluene, diluting to 1600ml, soaking for 4h again, and placing the resin into a raw material tank C (the bottom of the raw material tank is connected with a corresponding feed pipeline of a microchannel reactor through a valve) for nitrogen protection for standby.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A solution in the material tank A, a material B solution in the material tank B and a material C solution in the material tank C through a feed pump, setting the flow rate of the material tank A to 11ml/min, the flow rate of the material tank B to 18ml/min and the flow rate of the material tank C to 22ml/min through a counting pump, preheating the material A solution, the material B solution and the material C solution, setting the temperature of a heat exchanger to 55 ℃, keeping the reaction time in a channel to 60s, and enabling a reaction product to flow out of the reactor in a high-dispersion continuous flow state after passing through an ice-water bath of a cooling coil channel. After the reaction, the filtrate is filtered, washed once with 150mL of 3N diluted hydrochloric acid, the organic phase is washed twice with 200mL of water, and the organic phase is evaporated to dryness below 60 ℃ to obtain 768.3g of compound I, the yield is 98.5%, and the purity is 99.6%.
(5) Recycling of resins
And (3) directly recycling the solid obtained by suction filtration in the post-treatment process of the step (4) (namely Amberlite IRA 402 strong base anion exchange resin) as a catalyst in the step (3) after drying, and recycling for 8 times, wherein the yield and purity of the target product are as follows:
Example 2
(1) Preparing a material A solution: compound II (268 g,3.8 mol) was added to n-hexane, diluted to 800ml, stirred well, placed in a feed tank a (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(2) Preparing a material B solution: aniline (457 g,4.9 mol) was added to n-hexane, diluted to 960ml, stirred well, placed in a feed tank B (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve), and nitrogen protected for use.
(3) Preparing a material C solution: 164.5g Amberlite IRA 402 strong base anion exchange resin (chlorine type) is added into 350g of 3wt% sodium hydroxide aqueous solution (water is deionized water) at 25-35 ℃ for soaking for 24 hours, the soaked resin is separated, the soaked resin is washed by deionized water until the pH value is 6.5-7.5, the washed resin is added into n-hexane, diluted to 1200ml, soaked for 4 hours again, and placed into a raw material tank C (the bottom of the raw material tank is connected with a corresponding feed pipeline of a microchannel reactor through a valve) for nitrogen protection for standby.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A solution in the material tank A, a material B solution in the material tank B and a material C solution in the material tank C through a feed pump, setting the flow speed of the material tank A to be 10ml/min, the flow speed of the material tank B to be 12ml/min and the flow speed of the material tank C to be 15ml/min through a counting pump, preheating the material A solution, the material B solution and the material C solution, setting the temperature of a heat exchanger to be 60 ℃, keeping the reaction time in a channel to be 30s, and enabling a reaction product to flow out of the reactor in a high-dispersion continuous flow state after passing through an ice-water bath of a cooling coil channel. After the reaction, the filtrate is filtered, washed once with 150mL of 3N diluted hydrochloric acid, the organic phase is washed twice with 200mL of water, and the organic phase is evaporated to dryness below 60 ℃ to obtain 765.9g of compound I, the yield is 98.2%, and the purity is 99.4%.
Example 3
(1) Preparing a material A solution: compound II (268 g,3.8 mol) was added to ethyl acetate, diluted to 800ml, stirred well, placed in a feed tank a (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(2) Preparing a material B solution: aniline (354 g,3.8 mol) was added to ethyl acetate, diluted to 960ml, stirred well, placed in a feed tank B (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(3) Preparing a material C solution: adding 328.8g Amberlite IRA 402 strong base anion exchange resin (chlorine type) into 600g of 3wt% sodium hydroxide aqueous solution (water is deionized water) at 25-35 ℃ for soaking for 24h, separating out soaked resin, washing the resin by adopting deionized water until the pH value is 6.5-7.5, adding the washed resin into ethyl acetate, diluting to 1200ml, soaking for 4h again, and placing the resin into a raw material tank C (the bottom of the raw material tank is connected with a corresponding feed pipeline of a microchannel reactor through a valve) for nitrogen protection for standby.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A solution in the material tank A, a material B solution in the material tank B and a material C solution in the material tank C through a feed pump, setting a flow speed of 20ml/min of the material tank A, a flow speed of 24ml/min of the material tank B and a flow speed of 30ml/min of the material tank C through a counting pump, preheating the material A solution, the material B solution and the material C solution, setting the temperature of a heat exchanger to be 30 ℃, keeping the reaction time in a channel to be 90 seconds, and enabling a reaction product to flow out of the reactor in a high-dispersion continuous flow state after passing through an ice-water bath of a cooling coil channel. After the reaction, the filtrate is filtered, washed once with 150mL of 3N diluted hydrochloric acid, the organic phase is washed twice with 200mL of water, and the organic phase is evaporated to dryness below 60 ℃ to obtain 765.2g of compound I, the yield is 98.1%, and the purity is 99.3%.
Comparative example 1
(1) Preparing a material A solution: compound II (268 g,3.8 mol) was added to toluene, diluted to 800ml, stirred well, placed in a feed tank a (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(2) Preparing a material B solution: aniline (428 g,4.6 mol) was added to toluene, diluted to 1309ml, stirred well, placed in a feed tank B (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(3) Preparing a material C solution: 110g Amberlite IRA 402 strong base anion exchange resin (chlorine type) is added into 200g of 3wt% sodium hydroxide aqueous solution (water is deionized water) at 25-35 ℃ for soaking for 24 hours, the soaked resin is separated, the soaked resin is washed by deionized water until the pH value is 6.5-7.5, the washed resin is added into toluene, diluted to 1600ml, soaked for 4 hours again, and placed into a raw material tank C (the bottom of the raw material tank is connected with a corresponding feed pipeline of a microchannel reactor through a valve) for nitrogen protection for standby.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A solution in the material tank A, a material B solution in the material tank B and a material C solution in the material tank C through a feed pump, setting the flow rate of the material tank A to 11ml/min, the flow rate of the material tank B to 18ml/min and the flow rate of the material tank C to 22ml/min through a counting pump, preheating the material A solution, the material B solution and the material C solution, setting the temperature of a heat exchanger to 55 ℃, keeping the reaction time in a channel to 60s, and enabling a reaction product to flow out of the reactor in a high-dispersion continuous flow state after passing through an ice-water bath of a cooling coil channel. After the reaction, the filtrate is filtered, washed once with 150mL of 3N diluted hydrochloric acid, the organic phase is washed twice with 200mL of water, and the organic phase is evaporated to dryness below 60 ℃ to obtain 595.9g of compound I, with the yield of 76.4% and the purity of 95.8%.
Comparative example 2
(1) Preparing a material A solution: compound II (268 g,3.8 mol) was added to toluene, diluted to 800ml, stirred well, placed in a feed tank a (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(2) Preparing a material B solution: aniline (428 g,4.6 mol) was added to toluene, diluted to 1309ml, stirred well, placed in a feed tank B (the bottom of which was connected to the corresponding feed line of the microchannel reactor via a valve) and nitrogen protected for use.
(3) Preparing a material C solution: adding 300g Amberlite IRA 402 strong base anion exchange resin (chlorine type) into 600g of 3wt% sodium hydroxide aqueous solution (water is deionized water) at 25-35 ℃ for soaking for 24h, separating out soaked resin, washing the resin with deionized water until the pH value is 6.5-7.5, adding the washed resin into toluene, diluting to 1600ml, soaking for 4h again, and placing the resin into a raw material tank C (the bottom of the raw material tank is connected with a corresponding feed pipeline of a microchannel reactor through a valve) for nitrogen protection for standby.
(4) And (3) opening a valve at the bottom of a material tank, respectively conveying a material A solution in the material tank A, a material B solution in the material tank B and a material C solution in the material tank C through a feed pump, setting the flow rate of the material tank A to 11ml/min, the flow rate of the material tank B to 18ml/min and the flow rate of the material tank C to 22ml/min through a counting pump, preheating the material A solution, the material B solution and the material C solution, setting the temperature of a heat exchanger to 20 ℃, keeping the reaction time in a channel to 60s, and enabling a reaction product to flow out of the reactor in a high-dispersion continuous flow state after passing through an ice-water bath of a cooling coil channel. After the reaction, the filtrate was collected by suction filtration, washed once with 150mL of 3N diluted hydrochloric acid, and the organic phase was washed twice with 200mL of water, and evaporated to dryness at 60℃to give 620.9g of Compound I in 79.6% yield and 96.8% purity.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments may be modified or some technical features may be replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.
Claims (8)
1. A method for synthesizing atorvastatin calcium intermediate by using a continuous flow micro-channel reactor is characterized in that the synthesis route is as follows,
The method specifically comprises the following steps:
(1) Preparing a material A solution: mixing the compound II with an organic solvent, and uniformly stirring for later use;
(2) Preparing a material B solution: mixing aniline and an organic solvent, and uniformly stirring for later use;
(3) Preparing a material C solution: adding Amberlite IRA402 strong base anion exchange resin into 1-5wt% sodium hydroxide aqueous solution at 25-35 ℃ for soaking for 20-30 h, separating out soaked resin, washing with deionized water until the pH value is 6.5-7.5, adding the washed resin into an organic solvent, soaking again for 2-6 h, and standing by after soaking is completed;
(4) Pumping the solution A, the solution B and the solution C into a micro-channel reactor respectively, mixing uniformly, and carrying out chemical reaction at the reaction temperature of 30-60 ℃ for 30-90 s; after the reaction is finished, separating liquid, washing and drying to obtain an intermediate compound I;
Wherein the mass ratio of the compound II to the strong base anion exchange resin is 1:0.3-0.6; the molar ratio of the compound II to the aniline is 1:1-1.3; the flow rate of the solution for conveying the material A is 10-20 ml/min; the flow rate of the solution for conveying the material B is 12-24 ml/min; the flow rate of the solution for conveying the material C is 15-30 ml/min; the reaction module of the microchannel reactor is a three-feed single-discharge module, the structure of the reaction module is a T-shaped structure, a spherical baffle plate, a water drop-shaped structure or a heart-shaped structure, and the hydraulic diameter of the channel is 0.5-10 mm.
2. The method for synthesizing atorvastatin calcium intermediate by use of a continuous flow microchannel reactor according to claim 1, wherein in step (4), the reaction temperature is 55 ℃.
3. The method for synthesizing atorvastatin calcium intermediate by use of a continuous flow microchannel reactor according to claim 1, wherein in the step (4), the reaction time is 60s.
4. The method for synthesizing atorvastatin calcium intermediate by a continuous flow microchannel reactor of claim 1 wherein in step (4), the mass ratio of the compound II to the strong base anion exchange resin is 1:0.55.
5. The method of synthesizing atorvastatin calcium intermediate using a continuous flow microchannel reactor of claim 1 wherein in step (4) the molar ratio of compound II to the aniline is 1:1.2.
6. The method for synthesizing atorvastatin calcium intermediate by use of a continuous flow microchannel reactor according to claim 1, wherein in step (3), the time of soaking in the aqueous sodium hydroxide solution is 24 hours; the concentration of the aqueous sodium hydroxide solution was 3wt%; the solvent water in the sodium hydroxide aqueous solution is deionized water; the soaking time in the organic solvent is 4h.
7. The method for synthesizing atorvastatin calcium using a continuous flow microchannel reactor according to claim 1, wherein in step (1), (2) or (3), the organic solvent is one or more of toluene, benzene, ethyl acetate, cyclohexane or n-hexane.
8. The method for synthesizing atorvastatin calcium using a continuous flow microchannel reactor according to claim 7 wherein in step (1), (2) or (3), the organic solvent is toluene, ethyl acetate or n-hexane.
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