CN115557940A - Method for continuously producing canagliflozin by using microchannel reactor - Google Patents
Method for continuously producing canagliflozin by using microchannel reactor Download PDFInfo
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Abstract
The invention provides a method for continuously producing canagliflozin by using a microchannel reactor, which is characterized by comprising a first reaction zone, a second reaction zone and a third reaction zone which are sequentially connected in series, wherein the first reaction zone, the second reaction zone and the third reaction zone are communicated with a preheating module; the reaction process is as follows: and after the compound A and the compound B generated in the first reaction zone complete the mixing reaction process, sequentially introducing the product into the second reaction zone and the third reaction zone to complete the mixing reaction, and extracting, recrystallizing, filtering and drying the obtained product to obtain the canagliflozin. The method for continuously producing canagliflozin by using the microchannel reactor strictly controls the reaction temperature and the residence time, improves the production efficiency of the canagliflozin and reduces reaction byproducts. Meanwhile, the post-treatment of the reaction is greatly simplified, and the loss caused by each step of post-treatment is reduced. Thereby effectively improving the synthesis efficiency.
Description
Technical Field
The invention relates to a method for continuously producing canagliflozin by using a microchannel reactor.
Background
Canagliflozin (canagliflozin) with chemical name of (1)S) -1, 5-dehydration-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl ] group]Methyl radical]-4-methylphenyl radical]-DGlucitol, which is developed by Mitsubishi corporation and Shinsheng corporation, and is approved by the US FDA to be marketed at 29.3.2013, is the first sodium glucose cotransporter 2 (SGLT 2) inhibitor approved by the FDA, and is approved by the European Commission (EC) at 25.11.2013 to be used for treating adult type 2 diabetes. The canagliflozin can inhibit SGLT2, so that glucose in renal tubules cannot be successfully reabsorbed into blood and is discharged along with urine, thereby reducing the blood glucose concentration.
The structure of canagliflozin is mainly composed of glycosyl and aromatic hydrophobic side chain, and the current synthetic strategy of canagliflozin is mainly to obtain a product by condensation coupling of the side chain and protected gluconolactone, wherein the side chain is 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene or 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene.
At present, the industrial production of canagliflozin still adopts a traditional kettle type mechanical stirring reactor, the heat transfer rate of the reactor is very low, the reaction temperature needs to be strictly controlled, the temperature runaway explosion is avoided, and the reaction efficiency is low. The key step in the preparation process of canagliflozin is to introduce glucosyl group at the methyl para position of a benzene ring by a carbon-glycoside bond, and the step generally needs extremely low temperature to control the reaction rate, and the poor control often causes the rapid temperature rise, possibly causing explosion or generating a large amount of byproducts. And the materials which are inevitably mixed by common stirring are not mixed uniformly, so that the conversion rate of the raw materials is low and the byproducts are high.
CN 101801371A and WO 2017046655 A1 disclose that a synthetic route realizes the preparation of canagliflozin, and a key intermediate 2- [ (5-bromo-2-methylphenyl) methyl]-5- (4-fluorophenyl) thiophene and 2,3,4,6-O-trimethylsilyl onCoupling reaction at-78 deg.c, deprotection with methanesulfonic acid and methanol, and triethyl silane (Et) 3 SiH) or Triisopropylsilane (TIPS) and boron trifluoride etherate to yield canagliflozin. The method has short synthetic route and cheap and easily-obtained raw materials, but the coupling reaction conditions are-70 ℃ and very harsh, thereby being not beneficial to industrial production.
Likewise, 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene may be used in place of 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene, and the coupling reaction may be carried out with n-butyllithium or an organometallic magnesium Grignard reagent. Then the canagliflozin is obtained through the reaction route.
CN 103467439B discloses that the synthetic route realizes the preparation of canagliflozin, and the key intermediate 2,3,4, 6-tetra-substituted-OAcetyl-DGluconolactone and 2- [ (5-iodo-2-methylphenyl) methyl]-5- (4-fluorophenyl) thiophene, and carrying out coupling reaction at the temperature of between 5 ℃ below zero and 0 ℃ under the action of sec-butyl magnesium chloride-lithium chloride. The method has the advantages of short synthetic route, mild reaction conditions, good stereoselectivity and high yield due to acetyl protection, but the organic metal reagent of sec-butyl magnesium chloride is not easy to obtain, has high price and is not easy to store.
Lemaire S,Houpis I N,Xiao T T,et al.Stereoselective C-glycosylation reaction with arylzinc reagents[J]Org Lett,2012,14 (6): 1480-1483, discloses that the synthetic route enables the preparation of canagliflozin, 2- [ (5-iodo-2-methylphenyl) methyl]The (E) -5- (4-fluorophenyl) thiophene firstly obtains aryl lithium reagent under the action of n-butyllithium, then metal exchange is carried out under the action of zinc bromide to obtain aryl zinc reagent, and then the aryl zinc reagent and 2,3,4,6-O-tet-pivaloyl-α-DThe coupling reaction of-bromo glucopyranose is carried out at 95 ℃, and finally, the coupling reaction is carried out in sodium methoxide methanolAnd under the action, removing the protecting group to obtain the canagliflozin. The method has high yield of a synthetic route, but the route is complicated, the post-treatment is also complicated, and the used aryl zinc needs to be prepared on site and cannot be stored; and the use of the bromoglucose derivatives with higher price increases the cost.
The micro-reactor is also called as a micro-channel reactor, and has excellent performances of efficient heat and mass transfer, accurate control of materials and reaction temperature and the like, so that the micro-reactor has unique advantages in the aspects of organic synthesis, polymer morphology control and the like compared with the traditional tank reactor, and the micro-reactor technology draws great attention in related fields once appearing.
In the synthesis process of canagliflozin, a coupling step is required to be carried out under the condition of low temperature (-78 ℃ to-10 ℃), and the reaction temperature needs to be strictly controlled in the step so as to prevent temperature runaway explosion caused by excessively high reaction speed. Moreover, the post-treatment process in the synthesis process of canagliflozin is very complicated and is very not beneficial to industrial continuous production. The invention provides a novel method for continuously producing canagliflozin by carrying out the reaction in a microchannel reactor according to the characteristics of large heat release, small mass transfer rate and explosive process.
Disclosure of Invention
The invention aims to solve the technical problems of overcoming the defects in the prior art, and provides a method for continuously producing canagliflozin by using a microchannel reactor, which has the structural characteristics of narrow reaction space and large specific surface area, can strengthen mass transfer and heat transfer, accurately control reaction temperature and reaction time, prevent the generation of a temperature runaway phenomenon and byproducts and improve conversion rate and yield; meanwhile, the microchannel reactor has the characteristics of small liquid holdup, short reaction retention time, strong mass transfer and heat transfer effects, no dead volume and the like, and improves the reaction safety.
In order to solve the technical problems, the invention adopts the technical scheme that: a method for continuously producing canagliflozin by utilizing a microchannel reactor, wherein the microchannel reactor comprises a first reaction zone, a second reaction zone and a third reaction zone which are sequentially connected in series, and preheating modules are communicated with the first reaction zone, the second reaction zone and the third reaction zone;
the process for producing canagliflozin is specifically shown as follows:
the reaction process is as follows: and after the compound A and the compound B generated in the first reaction zone complete a mixing reaction process, sequentially introducing the product into a second reaction zone and a third reaction zone to complete mixing reaction, and extracting, recrystallizing, filtering and drying the obtained product to obtain the canagliflozin.
Further, the compound A is obtained by mixing and reacting a material 1 and a material 2, wherein the molar ratio of the material 1 to the material 2 is 1;
dissolving 97.2-123g of solute in 225mL of solvent to obtain a material 1, wherein the solute is 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene and the solvent is tetrahydrofuran in the material 1;
dissolving isopropyl magnesium chloride and lithium chloride in tetrahydrofuran to obtain a material 2, wherein the molar ratio of the isopropyl magnesium chloride to the lithium chloride is 1; among said charge 2 was 14% by weight of isopropyl magnesium chloride.
Further, the preparation method of the material 3 is as follows: dissolving 90-135g of compound B in 100mL of tetrahydrofuran to obtain a material 3; and preheating the material 3 and introducing the preheated material into the first reaction zone to complete the mixing reaction.
Further, in the first reaction zone, the reaction residence time is 30-120s, the reaction temperature is-5-5 ℃, and the reaction pressure is 0-15bar.
Further, the molar ratio of the material 4 to the material 1 is 1-3, the material 4 is a mixture of boron trifluoride diethyl etherate and triethylsilane, and the volume ratio of the boron trifluoride diethyl etherate to the triethylsilane is 30; and preheating the material 4 and then introducing the preheated material into a second reaction zone to complete mixing reaction.
Further, in the second reaction zone, the reaction residence time is 30-120s, the reaction temperature is-5-0 ℃, and the reaction pressure is 0-10bar.
Further, the molar ratio of the material 5 to the material 1 is 1-2, and the preparation process of the material 5 specifically comprises the following steps: dissolving 62g of sodium methoxide in 300mL of methanol to obtain a material 5; and preheating the material 5 and introducing the preheated material into a third reaction zone to complete mixing reaction.
Further, in the third reaction zone, the reaction residence time is 30-120s, the reaction temperature is-5-0 ℃, and the reaction pressure is 0-10bar.
Further, the preheating temperature in the preheating module is-5-0 ℃, and heat exchange media are arranged in the first reaction zone, the second reaction zone, the third reaction zone and the preheating module, and the heat exchange media are ethanol water solution or heat conduction oil.
Compared with the prior art, the invention has the beneficial effects that:
1. by using the method for continuously producing canagliflozin by using the microchannel reactor, the reaction temperature and the retention time are strictly controlled, the production efficiency of canagliflozin is improved, and reaction byproducts are reduced. Meanwhile, the post-treatment of the reaction is greatly simplified, and the loss caused by each step of post-treatment is reduced. Thereby effectively improving the synthesis efficiency;
2. the invention adopts a continuous production method, the reaction time is shortened from traditional hours to dozens of seconds to several minutes, the production period is short, the reaction process is more stable, the reaction efficiency is obviously improved, and byproducts caused by unstable reaction temperature and overlong reaction time are reduced;
3. the mass transfer and heat transfer performance can be enhanced in the selected microchannel reactor, the reaction temperature is kept constant, the temperature runaway phenomenon is avoided, the generation of by-products is reduced, and the safety of the reaction process is improved;
4. the selected microchannel reactor has strong mass transfer effect, so that liquid-solid heterogeneous reaction liquid is fully mixed, and the reaction efficiency is improved;
5. the continuous production method adopted by the invention simplifies the complex post-treatment condition of the canagliflozin in the production process, obviously reduces the production period, reduces the loss caused by the complex post-treatment and obviously improves the reaction yield.
Drawings
The disclosure of the present invention is illustrated with reference to the accompanying drawings. It is to be understood that the drawings are designed solely for the purposes of illustration and not as a definition of the limits of the invention. In the drawings, like reference numerals are used to refer to like elements throughout. Wherein:
FIG. 1 is a process flow diagram for the continuous synthesis of canagliflozin of the present invention.
FIG. 2 is a diagram of a continuous flow microchannel reactor apparatus used in the present invention: 1 to 5 are raw material pumps, 6 to 10 are preheating zones, 11 to 13 are micro channels, and 14 is a quenching zone.
Fig. 3 is a channel structure diagram of a microchannel used in the present invention, where a is a straight-flow channel, B is a rectangular flat pipeline microchannel, C is a pancake type pulse diameter-variable rectangular flat pipeline, D is an oblique pancake type pulse diameter-variable rectangular flat pipeline, E is an enhanced hybrid pancake type rectangular flat pipeline, F is an enhanced hybrid oblique pancake type rectangular flat pipeline, and G is a heart-shaped microchannel.
FIG. 4 shows how canagliflozin produced by the continuous production method of canagliflozin using a microchannel reactor according to the invention 1 HNMR spectrogram.
FIG. 5 is a 13C NMR spectrum of canagliflozin produced by the continuous production method of canagliflozin using a microchannel reactor according to the present invention.
Detailed Description
It is easily understood that, according to the technical solution of the present invention, a person skilled in the art can propose various alternative structural modes and implementation modes without changing the spirit of the present invention. Therefore, the following detailed description and the accompanying drawings are merely illustrative of the technical aspects of the present invention, and should not be construed as all of the present invention or as limitations or limitations on the technical aspects of the present invention.
As shown in fig. 1-2, a method for continuously producing canagliflozin by using a microchannel reactor, the microchannel reactor used in the present invention is of a continuous structure, and comprises a first reaction zone, a second reaction zone and a third reaction zone which are sequentially connected in series, wherein an output end of the third reaction zone is communicated with a quenching zone, the first reaction zone is a reaction zone 1 shown in fig. 1, the second reaction zone is a reaction zone 2 shown in fig. 1, and the third reaction zone is a reaction zone 3 shown in fig. 1. As shown in fig. 1, the reaction zone 1 is connected to 3 preheating zones, which are a preheating zone 1, a preheating zone 2 and a preheating zone 3, respectively, the preheating zone 4 is connected to the reaction zone 2, the preheating zone 5 is connected to the reaction zone 3, and a metering pump is disposed at the input end of the preheating zone to meter the amount of the material fed into the preheating zone.
And a plurality of forms of micro-channel structures are arranged in the preheating zone and the reaction zone, as shown in fig. 3, A is a straight-flow channel, B is a rectangular flat pipeline micro-channel, C is a round cake type pulse diameter-changing rectangular flat pipeline, D is an oblique square cake type pulse diameter-changing rectangular flat pipeline, E is an enhanced mixed round cake type rectangular flat pipeline, F is an enhanced mixed oblique square cake type rectangular flat pipeline, and G is a heart-shaped structure micro-channel.
The technical effects of the present application will be further described with reference to the following examples. The following examples were carried out in a microchannel reactor according to the requirements of the process of the present invention.
Example 1
1) The device comprises the following steps: the continuous flow micro-channel reaction device (A + A + A) determines the connection mode of the micro-channel reactor by referring to FIG. 2, the length of the micro-channel is determined according to the flow velocity and the reaction residence time, and the heat exchange medium is heat conduction oil.
2) Preparation of canagliflozin: adjusting the microchannel reaction device into a preheating zone, a reaction zone and a quenching zone according to the needs of the reaction process. The reaction residence time is controlled to be 60s by adjusting the flow of the pump and the length of the micro-channel, the preheating temperature and the reaction temperature are set to be minus 5 ℃, and the reaction pressure is 5bar. Under the protection of inert gas, 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (123 g) was dissolved in 225mL of tetrahydrofuran, fed into preheating zone 1 of the apparatus through metering pump 1, and isopropyl magnesium chloride and lithium chloride (molar ratio 1.1) were dissolved in tetrahydrofuran to give a solution (14 wt% isopropyl magnesium chloride), fed into preheating zone 2 of the apparatus through metering pump 2, and after both materials were sufficiently preheated, they were fed into reaction zone 1 for mixing reaction. The compound of structure B (135 g) was dissolved in 100mL tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, sufficiently preheated, and then fed into the reaction zone 1 for a mixing reaction. The reaction is carried out without treatment and directly enters a reaction zone 2, and simultaneously boron trifluoride diethyl etherate (150 mL) and triethylsilane (185 mL) are input into a preheating zone 4 of a device through a metering pump 4, are fully preheated and then enter the reaction zone 2 for mixed reaction, and the reaction is carried out without treatment. Sodium methoxide (62 g) and 300mL of methanol are input into a preheating zone 5 of the device through a metering pump 5, and after the sodium methoxide and the methanol are fully preheated, the two materials are conveyed into a reaction zone 3 for mixing reaction. And continuously discharging the canagliflozin product from an outlet, collecting the canagliflozin product into a product collector, and extracting, recrystallizing, filtering and drying to obtain 109g of canagliflozin with the purity of 97 percent and the yield of 85 percent.
Example 2
1) The device comprises the following steps: the continuous flow micro-channel reaction device (D + D + D) determines the connection mode of the micro-channel reactor by referring to FIG. 2, the length of the micro-channel is determined according to the flow velocity and the reaction residence time, and the heat exchange medium is heat conduction oil.
2) Preparation of canagliflozin: adjusting the microchannel reaction device into a preheating zone, a reaction zone and a quenching zone according to the needs of the reaction process. The reaction residence time is controlled to be 45s by adjusting the flow of the pump and the length of the micro-channel, the preheating temperature and the reaction temperature are set to be-5 ℃, and the reaction pressure is 10bar. Under the protection of inert gas, 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (123 g) was dissolved in 225mL of tetrahydrofuran, introduced into a preheating zone 1 of a device through a metering pump 1, and isopropyl magnesium chloride and lithium chloride (molar ratio 1. A compound (135 g) of the structure B is dissolved in 100mL of tetrahydrofuran, is conveyed into a preheating zone 3 of a device through a metering pump 3, and enters a reaction zone 1 for mixing reaction after being sufficiently preheated. The reaction is carried out without treatment and directly enters the reaction zone 2, and simultaneously boron trifluoride diethyl etherate (150 mL) and triethylsilane (185 mL) are input into a preheating zone 4 of the device through a metering pump 4, and after being sufficiently preheated, the boron trifluoride diethyl etherate and triethylsilane enter the reaction zone 2 for mixed reaction without treatment. Sodium methoxide (62 g) and 300mL of methanol are conveyed into a preheating zone 5 of the device through a metering pump 5, and after the sodium methoxide and the methanol are sufficiently preheated, two materials are conveyed into a reaction zone 3 for mixing reaction. Continuously discharging the canagliflozin product from an outlet, collecting the canagliflozin product into a product collector, and obtaining 112g of canagliflozin through extraction, recrystallization, suction filtration and drying, wherein the purity is 97 percent, and the yield is 89 percent.
Example 3
1) The device comprises the following steps: the continuous flow microchannel reaction device (G + G + G) determines the connection mode of the microchannel reactor by referring to FIG. 2, the length of the microchannel is determined according to the flow velocity and the reaction residence time, and the heat exchange medium is heat conduction oil.
2) Preparation of canagliflozin: adjusting the microchannel reaction device into a preheating zone, a reaction zone and a quenching zone according to the needs of the reaction process. The reaction residence time is controlled to be 30s by adjusting the flow of the pump and the length of the micro-channel, the preheating temperature and the reaction temperature are set to be-5 ℃, and the reaction pressure is 15bar. Under the protection of inert gas, 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (123 g) was dissolved in 225mL of tetrahydrofuran, fed into preheating zone 1 of the apparatus through metering pump 1, and isopropyl magnesium chloride and lithium chloride (molar ratio 1.1) were dissolved in tetrahydrofuran to give a solution (14 wt% isopropyl magnesium chloride), fed into preheating zone 2 of the apparatus through metering pump 2, and after both materials were sufficiently preheated, they were fed into reaction zone 1 for mixing reaction. The compound of structure B (135 g) was dissolved in 100mL tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, sufficiently preheated, and then fed into the reaction zone 1 for a mixing reaction. The reaction is carried out without treatment and directly enters a reaction zone 2, and simultaneously boron trifluoride diethyl etherate (150 mL) and triethylsilane (185 mL) are input into a preheating zone 4 of a device through a metering pump 4, are fully preheated and then enter the reaction zone 2 for mixed reaction, and the reaction is carried out without treatment. Sodium methoxide (62 g) and 300mL of methanol are input into a preheating zone 5 of the device through a metering pump 5, and after the sodium methoxide and the methanol are fully preheated, the two materials are conveyed into a reaction zone 3 for mixing reaction. Continuously discharging the canagliflozin product from an outlet, collecting the canagliflozin product into a product collector, and obtaining 121g of canagliflozin through extraction, recrystallization, suction filtration and drying, wherein the purity is 98 percent and the yield is 95 percent.
Example 4
1) The device comprises the following steps: the continuous flow micro-channel reaction device (G + C + C) determines the connection mode of the micro-channel reactor by referring to fig. 2, the length of the micro-channel is determined according to the flow velocity and the reaction residence time, and the heat exchange medium is heat conduction oil.
2) Preparation of canagliflozin: adjusting the microchannel reaction device into a preheating zone, a reaction zone and a quenching zone according to the needs of the reaction process. The reaction residence time is controlled to be 30s by adjusting the flow of the pump and the length of the micro-channel, the preheating temperature and the reaction temperature are set to be-5 ℃, and the reaction pressure is 10bar. Under the protection of inert gas, 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (216 g) is dissolved in 500 mL of tetrahydrofuran, introduced into a preheating zone 1 of a device through a metering pump 1, and isopropyl magnesium chloride and lithium chloride (molar ratio 1. The compound of structure B (270 g) was dissolved in 300mL tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, sufficiently preheated, and then fed into the reaction zone 1 for a mixing reaction. The reaction is carried out without treatment and directly enters a reaction zone 2, meanwhile, boron trifluoride diethyl etherate (300 mL) and triethylsilane (370 mL) are input into a preheating zone 4 of a device through a metering pump 4, and after being fully preheated, the boron trifluoride diethyl etherate and triethylsilane enter the reaction zone 2 for mixed reaction, and the reaction is carried out without treatment. Sodium methoxide (124 g) and 600mL of methanol are input into a preheating zone 5 of a device through a metering pump 5, and after the sodium methoxide and the methanol are fully preheated, the two materials are conveyed into a reaction zone 3 for mixing reaction. The canagliflozin product is continuously discharged from an outlet, collected in a product collector, extracted, recrystallized, filtered and dried to obtain 235g of canagliflozin with the purity of 97 percent and the yield of 92 percent.
Example 5
1) The device comprises the following steps: the continuous flow microchannel reaction device (G + E + G) determines the connection mode of the microchannel reactor by referring to FIG. 2, the length of the microchannel is determined according to the flow velocity and the reaction residence time, and the heat exchange medium is heat conduction oil.
2) Preparation of canagliflozin: adjusting the microchannel reaction device into a preheating zone, a reaction zone and a quenching zone according to the needs of the reaction process. The reaction residence time is controlled to be 45s by adjusting the flow of the pump and the length of the micro-channel, the preheating temperature and the reaction temperature are set to be-5 ℃, and the reaction pressure is 10bar. Under the protection of inert gas, 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (108 g) is dissolved in 225mL of tetrahydrofuran, introduced into a preheating zone 1 of a device through a metering pump 1, isopropyl magnesium chloride and lithium chloride (molar ratio 1. The compound of structure B (135 g) was dissolved in 100mL tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, sufficiently preheated, and then fed into the reaction zone 1 for a mixing reaction. The reaction is carried out without treatment and directly enters a reaction zone 2, and simultaneously boron trifluoride diethyl etherate (150 mL) and triethylsilane (185 mL) are input into a preheating zone 4 of a device through a metering pump 4, are fully preheated and then enter the reaction zone 2 for mixed reaction, and the reaction is carried out without treatment. Sodium methoxide (62 g) and 300mL of methanol are conveyed into a preheating zone 5 of the device through a metering pump 5, and after the sodium methoxide and the methanol are sufficiently preheated, two materials are conveyed into a reaction zone 3 for mixing reaction. Continuously discharging the canagliflozin product from an outlet, collecting the canagliflozin product into a product collector, and obtaining 116g of canagliflozin through extraction, recrystallization, suction filtration and drying, wherein the purity is 99 percent, and the yield is 91 percent.
Canagliflozin produced in examples 1 to 5 1 The HNMR spectrum is shown in FIG. 4, and the 13C NMR spectrum is shown in FIG. 5.
The technical scope of the present invention is not limited to the above description, and those skilled in the art can make various changes and modifications to the above-described embodiments without departing from the technical spirit of the present invention, and such changes and modifications should fall within the protective scope of the present invention.
Claims (9)
1. A method for continuously producing canagliflozin by using a microchannel reactor is characterized in that the microchannel reactor comprises a first reaction zone, a second reaction zone and a third reaction zone which are sequentially connected in series, and preheating modules are communicated with the first reaction zone, the second reaction zone and the third reaction zone;
the process for producing canagliflozin is specifically shown as follows:
the reaction process is as follows: and after the compound A and the compound B generated in the first reaction zone complete a mixing reaction process, sequentially introducing the product into the second reaction zone and the third reaction zone to complete mixing reaction, and extracting, recrystallizing, filtering and drying the obtained product to obtain the canagliflozin.
2. The method for continuously producing canagliflozin by using the microchannel reactor as claimed in claim 1, wherein the compound A is obtained by mixing and reacting a material 1 and a material 2, and the molar ratio of the material 1 to the material 2 is 1:1-2;
dissolving 97.2-123g of solute in 225ml of solvent to obtain a material 1, wherein the solute is 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene and the solvent is tetrahydrofuran in the material 1;
dissolving isopropyl magnesium chloride and lithium chloride in tetrahydrofuran to obtain a material 2, wherein the molar ratio of the isopropyl magnesium chloride to the lithium chloride is 1; among said charge 2 was 14% by weight of isopropyl magnesium chloride.
3. The method for continuously producing canagliflozin by using the microchannel reactor as claimed in claim 2, wherein the preparation method of the material 3 is as follows: dissolving 90-135g of compound B in 100mL of tetrahydrofuran to obtain a material 3; and preheating the material 3 and introducing the preheated material into the first reaction zone to complete the mixing reaction.
4. The method for continuously producing canagliflozin by using the microchannel reactor as claimed in claim 3, wherein in the first reaction zone, the reaction residence time is 30 to 120s, the reaction temperature is-5 to 5 ℃, and the reaction pressure is 0 to 15bar.
5. The method for continuously producing canagliflozin by using the microchannel reactor, according to claim 1, wherein the molar ratio of the material 4 to the material 1 is 1-3, the material 4 is a mixture of boron trifluoride diethyl etherate and triethylsilane, and the volume ratio of the boron trifluoride diethyl etherate to the triethylsilane is 30; and preheating the material 4 and introducing the preheated material into a second reaction zone to complete mixing reaction.
6. The continuous production method of canagliflozin by using the microchannel reactor as claimed in claim 5, wherein in the second reaction zone, the reaction residence time is 30 to 120s, the reaction temperature is-5 to 0 ℃, and the reaction pressure is 0 to 10bar.
7. The method for continuously producing canagliflozin by using the microchannel reactor as claimed in claim 1, wherein the molar ratio of the material 5 to the material 1 is 1-2, and the preparation process of the material 5 is as follows: dissolving 62g of sodium methoxide in 300mL of methanol to obtain a material 5; and preheating the material 5 and introducing the preheated material into a third reaction zone to complete mixing reaction.
8. The continuous production method of canagliflozin by using the microchannel reactor as claimed in claim 7, wherein in the third reaction zone, the reaction residence time is 30 to 120s, the reaction temperature is-5 to 0 ℃, and the reaction pressure is 0 to 10bar.
9. The method for continuously producing canagliflozin by using the microchannel reactor as claimed in any one of claims 1 to 8, wherein the preheating temperature in the preheating module is-5 ℃ to 0 ℃, and heat exchange media are arranged in the first reaction zone, the second reaction zone, the third reaction zone and the preheating module, and the heat exchange media are ethanol aqueous solution or heat transfer oil.
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