CN115557940B - Method for continuously producing canagliflozin by utilizing microchannel reactor - Google Patents
Method for continuously producing canagliflozin by utilizing microchannel reactor Download PDFInfo
- Publication number
- CN115557940B CN115557940B CN202211554828.2A CN202211554828A CN115557940B CN 115557940 B CN115557940 B CN 115557940B CN 202211554828 A CN202211554828 A CN 202211554828A CN 115557940 B CN115557940 B CN 115557940B
- Authority
- CN
- China
- Prior art keywords
- reaction
- reaction zone
- canagliflozin
- zone
- microchannel reactor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a method for continuously producing canagliflozin by utilizing 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 a preheating module is communicated with each of the first reaction zone, the second reaction zone and the third reaction zone; the reaction process is specifically as follows: after the compound A and the compound B generated in the first reaction zone complete the mixing reaction process, the product is sequentially introduced into the second reaction zone and the third reaction zone to complete the mixing reaction, and the obtained product is extracted, recrystallized, filtered and dried to obtain the canagliflozin. The method for continuously producing the canagliflozin by utilizing the microchannel reactor strictly controls the reaction temperature and the residence time, improves the production efficiency of the canagliflozin and reduces the 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 utilizing a microchannel reactor.
Background
Canagliflozin (Canagliflozin), chemical name (1)S) 1, 5-dehydration-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl ]]Methyl group]-4-methylphenyl]-D-glucitol, which was co-developed by mitsubishi and qisheng, and was approved by the us FDA for marketing in 3 months 29 of 2013, was the first sodium glucose co-transporter 2 (SGLT 2) inhibitor approved by the FDA, and was approved by the european union committee (EC) in 11 months 25 of 2013 for the treatment of adult type 2 diabetes. Canagliflozin reduces blood glucose concentration by inhibiting SGLT2, so that glucose in the kidney tubule cannot be successfully reabsorbed into blood and discharged with urine.
The structure of the canagliflozin mainly comprises a glycosyl group and an aromatic hydrophobic side chain, and the existing synthetic strategy of the canagliflozin mainly comprises the step of obtaining a product through condensation coupling of a 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 slow, the reaction temperature needs to be strictly controlled, the fly-temperature explosion is avoided, and the reaction efficiency is low. The key step in the preparation process of canagliflozin is to introduce a glucose group into the para position of a methyl group of a benzene ring through a carbon glycoside bond, and the step generally needs extremely low temperature to control the reaction rate, and the temperature is often increased rapidly due to poor control, so that explosion can be initiated or a large amount of byproducts can be generated. And the common stirring inevitably causes uneven material mixing, so that the raw material conversion rate is low and the byproducts are high.
The synthetic routes disclosed in CN 101801371a and WO 2017046655 A1 enable the preparation of canagliflozin, a key intermediate 2- [ (5-bromo-2-methylphenyl) methyl]5- (4-fluorophenyl) thiophenes and 2,3,4, 6-)OCoupling of trimethylsilyl groups at-78deg.C, deprotection with methanesulfonic acid and methanol, and triethylsilane (Et) 3 SiH) or Triisopropylsilane (TIPS) and boron trifluoride diethyl etherate to give canagliflozin. The method has the advantages of short synthetic route, low cost and easy obtainment of raw materials, but severe coupling reaction conditions of-70 ℃ and no contribution to industrial production.
Alternatively, 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene may be used instead of 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene, and the coupling reaction may be performed under the action of n-butyllithium or an organometallic magnesium grignard reagent. Then the canagliflozin is obtained through the reaction route.
CN 103467439B discloses a synthetic route for preparing canagliflozin, a key intermediate 2,3,4, 6-tetrakawakamiumOAcetyl-D-gluconolactone and 2- [ (5-iodo-2-methyl)Phenyl) methyl]-5- (4-fluorophenyl) thiophene, and coupling reaction is carried out by sec-butyl magnesium chloride-lithium chloride at-5~0 ℃. The method has the advantages of short synthetic route, mild reaction condition, good stereoselectivity when acetyl is used for protection, and high yield, but the organometallic reagent 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. Synthetic routes are disclosed to effect preparation of canagliflozin, 2- [ (5-iodo-2-methylphenyl) methyl]The method comprises the steps of firstly obtaining an aryl lithium reagent from 5- (4-fluorophenyl) thiophene under the action of n-butyllithium, then carrying out metal exchange under the action of zinc bromide to obtain an aryl zinc reagent, and then carrying out reaction with 2,3,4,6-OTetrapivaloyl radicalα-DCoupling reaction of bromopyranose at 95 deg.c, and final deprotection to obtain canagliflozin under the action of sodium methoxide and methanol. The method has higher yield of the 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 bromine glucose derivative with higher price is used, so that the cost is increased.
The micro-reactor is also called as a micro-channel reactor, and has the advantages of high-efficiency heat and mass transfer, accurate control of materials and reaction temperature and the like, and has unique advantages in aspects of organic synthesis, polymer morphology control and the like compared with the traditional kettle-type reactor, so that great attention is paid to the related field as soon as the micro-reactor technology appears.
In the synthesis process of canagliflozin, the coupling step is carried out under the condition of low temperature (-78 ℃ to-10 ℃), and the reaction temperature is strictly controlled in the step so as to prevent the reaction speed from being too high to cause the explosion at the flying temperature. And the patent also shows that the post-treatment process in the synthesis process of the canagliflozin is very complicated, which is very unfavorable for industrial continuous production. According to the characteristics of large heat release quantity, small mass transfer rate and explosive process, the invention provides a novel method for continuously producing canagliflozin by carrying out the reaction in a microchannel reactor.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a method for continuously producing canagliflozin by utilizing a microchannel reactor, which has the structural characteristics of narrow reaction space and huge specific surface area, can strengthen mass transfer and heat transfer, accurately control reaction temperature and reaction time, prevent the occurrence of 'flying temperature' phenomenon and the generation of byproducts, and improve the conversion rate and yield; meanwhile, the micro-channel reactor has the characteristics of small liquid holdup, short reaction residence time, strong mass transfer and heat transfer effects, no dead volume and the like, and the safety of the reaction is improved.
In order to solve the technical problems, the invention adopts the following technical scheme: a method for continuously producing canagliflozin by utilizing a micro-channel reactor comprises a first reaction zone, a second reaction zone and a third reaction zone which are sequentially connected in series, wherein a preheating module is communicated with each of the first reaction zone, the second reaction zone and the third reaction zone;
the process for producing the canagliflozin is specifically shown as the following formula:
the reaction process is specifically as follows: after the compound A and the compound B generated in the first reaction zone complete the mixing reaction process, the product is sequentially introduced into the second reaction zone and the third reaction zone to complete the mixing reaction, and the obtained product is extracted, recrystallized, filtered and dried 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 1:1-2;
in the material 1, the solute is 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene, the solvent is tetrahydrofuran, and 97.2-123g of the solute is dissolved in 225mL of solvent to obtain the material 1;
dissolving isopropyl magnesium chloride and lithium chloride in tetrahydrofuran to obtain a material 2, wherein the mol ratio of the isopropyl magnesium chloride to the lithium chloride is 1:1.1; included in the material 2 was 14wt% isopropyl magnesium chloride.
Further, the preparation method of the material 3 specifically comprises the following steps: dissolving 90-135g of compound B in 100mL of tetrahydrofuran to obtain a material 3; the material 3 is preheated and then introduced into a first reaction zone to complete the mixed 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 1-3:1, 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 30:37; the material 4 is preheated and then is introduced into a second reaction zone to complete the mixed 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 1-2:1, and the preparation process of the material 5 specifically comprises the following steps: 62g of sodium methoxide is dissolved in 300mL of methanol to obtain a material 5; the material 5 is preheated and then is introduced into a third reaction zone to complete the mixed 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, in the preheating module, the preheating temperature 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, wherein 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 utilizing the method for continuously producing the canagliflozin by the microchannel reactor, the reaction temperature and the residence time are strictly controlled, the production efficiency of the canagliflozin is improved, and the 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 a traditional few hours to tens of seconds to a few 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 selected micro-channel reactor can strengthen mass transfer and heat transfer performance, keep the reaction temperature constant, avoid the phenomenon of temperature runaway, reduce the generation of byproducts and improve the safety of the reaction process;
4. the strong mass transfer effect in the selected micro-channel reactor ensures that the liquid-solid heterogeneous reaction liquid is fully mixed, thereby improving the reaction efficiency;
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 generated by the complex post-treatment and obviously improves the reaction yield.
Drawings
The disclosure of the present invention is described 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 parts. Wherein:
FIG. 1 is a flow chart of the continuous synthesis of canagliflozin according to the present invention.
FIG. 2 is a schematic diagram of a continuous flow microchannel reactor apparatus used in the present invention: 1-5 of a raw material pump, 6-10 of a preheating zone, 11-13 of a micro-channel and 14 of a quenching zone.
Fig. 3 is a channel structure diagram of a microchannel used in the present invention, wherein a is a direct current type channel, B is a rectangular flat channel, C is a round cake type pulse variable diameter rectangular flat channel, D is an inclined cake type pulse variable diameter rectangular flat channel, E is an enhanced hybrid round cake type rectangular flat channel, F is an enhanced hybrid inclined cake type rectangular flat channel, and G is a heart-shaped structure microchannel.
FIG. 4 shows a continuous process for producing canagliflozin using a microchannel reactor in accordance with the present invention 1 HNMR spectra.
FIG. 5 is a 13C NMR spectrum of canagliflozin produced by the process of the present invention using a microchannel reactor to continuously produce canagliflozin.
Detailed Description
It is to be understood that, according to the technical solution of the present invention, those skilled in the art may propose various alternative structural modes and implementation modes without changing the true spirit of the present invention. Accordingly, the following detailed description and drawings are merely illustrative of the invention and are not intended to be exhaustive or to limit the invention to the precise form disclosed.
As shown in fig. 1-2, a method for continuously producing canagliflozin by using a microchannel reactor is provided, wherein the microchannel reactor used in the invention is 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 the 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. According to the illustration in FIG. 1, the reaction zone 1 is connected with 3 preheating zones, namely a preheating zone 1, a preheating zone 2 and a preheating zone 3, the preheating zone 4 is connected with the reaction zone 2, the preheating zone 5 is connected with the reaction zone 3, and metering pumps are arranged on the input ends of the preheating zones for metering the amount of materials input into the preheating zones.
The preheating zone and the reaction zone are provided with various micro-channel structures, as shown in fig. 3, wherein A is a direct current type channel, B is a rectangular flat pipeline micro-channel, C is a round cake type pulse variable diameter rectangular flat pipeline, D is an inclined cake type pulse variable diameter rectangular flat pipeline, E is an enhanced mixed round cake type rectangular flat pipeline, F is an enhanced mixed inclined cake type rectangular flat pipeline, and G is a heart-shaped structure micro-channel.
The technical effects of the present application are further described below with reference to examples. The following examples were carried out in a microchannel reactor according to the requirements of the process of the invention.
Example 1
1) The device comprises: continuous flow microchannel reaction the device (A+A+A), the microchannel reactor connection mode is determined with reference to figure 2, the length of the micro-channel is determined according to the flow rate and the reaction residence time, and the heat exchange medium is heat conduction oil.
2) Preparation of canagliflozin: the micro-channel reaction device is adjusted to be a preheating zone, a reaction zone and a quenching zone according to the reaction process requirement. The reaction residence time is controlled to be 60s by adjusting the flow of the pump and the channel length of the micro channel, the preheating temperature and the reaction temperature are set to be-5 ℃, and the reaction pressure is 5bar. 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (123 g) was dissolved in 225mL tetrahydrofuran under the protection of inert gas, and isopropyl magnesium chloride and lithium chloride (molar ratio 1:1.1) were dissolved in tetrahydrofuran to obtain a solution (14 wt% isopropyl magnesium chloride) by the preheating zone 1 of the feeding device of the metering pump 1, and after the two materials were sufficiently preheated, they were fed into the reaction zone 1 to undergo a mixing reaction by the preheating zone 2 of the feeding device of the metering pump 2. The compound of structure B (135 g) was dissolved in 100mL of tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, and after sufficient preheating, fed into the reaction zone 1 to carry out a mixing reaction. The reaction is directly carried out in the reaction zone 2 without treatment, meanwhile, 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, fully preheated, then carried out in the reaction zone 2 for mixed reaction, and the reaction is not treated. Sodium methoxide (62 g) and 300mL of methanol are fed into a preheating zone 5 of the device through a metering pump 5, and after being fully preheated, the two materials are conveyed into a reaction zone 3 for mixed reaction. The canagliflozin product is continuously discharged from the outlet, is collected in a product collector, and is subjected to extraction, recrystallization, suction filtration and drying to obtain 109g of canagliflozin with the purity of 97% and the yield of 85%.
Example 2
1) The device comprises: continuous flow microchannel reaction the device (D+D+D), the microchannel reactor connection mode is determined with reference to figure 2, the length of the micro-channel is determined according to the flow rate and the reaction residence time, and the heat exchange medium is heat conduction oil.
2) Preparation of canagliflozin: the micro-channel reaction device is adjusted to be a preheating zone, a reaction zone and a quenching zone according to the reaction process requirement. The reaction residence time is controlled to be 45s by adjusting the flow of the pump and the channel length of the micro channel, the preheating temperature and the reaction temperature are set to be-5 ℃, and the reaction pressure is 10bar. 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (123 g) was dissolved in 225mL tetrahydrofuran under the protection of inert gas, and isopropyl magnesium chloride and lithium chloride (molar ratio 1:1.1) were dissolved in tetrahydrofuran to obtain a solution (14 wt% isopropyl magnesium chloride) by the preheating zone 1 of the feeding device of the metering pump 1, and after the two materials were sufficiently preheated, they were fed into the reaction zone 1 to undergo a mixing reaction by the preheating zone 2 of the feeding device of the metering pump 2. The compound of structure B (135 g) was dissolved in 100mL of tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, and after sufficient preheating, fed into the reaction zone 1 to carry out a mixing reaction. The reaction is directly carried out in the reaction zone 2 without treatment, meanwhile, 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, fully preheated, then carried out in the reaction zone 2 for mixed reaction, and the reaction is not treated. Sodium methoxide (62 g) and 300mL of methanol are fed into a preheating zone 5 of the device through a metering pump 5, and after being fully preheated, the two materials are conveyed into a reaction zone 3 for mixed reaction. The canagliflozin product is continuously discharged from the outlet, is collected in a product collector, 112g of canagliflozin is obtained through extraction, recrystallization, suction filtration and drying, the purity is 97%, and the yield is 89%.
Example 3
1) The device comprises: continuous flow microchannel reaction the device (G+G+G), the microchannel reactor connection mode is determined with reference to figure 2, the length of the micro-channel is determined according to the flow rate and the reaction residence time, and the heat exchange medium is heat conduction oil.
2) Preparation of canagliflozin: the micro-channel reaction device is adjusted to be a preheating zone, a reaction zone and a quenching zone according to the reaction process requirement. The reaction residence time is controlled to be 30s by adjusting the flow of the pump and the channel length of the micro-channel, the preheating temperature and the reaction temperature are set to be-5 ℃, and the reaction pressure is 15bar. 2- [ (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (123 g) was dissolved in 225mL tetrahydrofuran under the protection of inert gas, and isopropyl magnesium chloride and lithium chloride (molar ratio 1:1.1) were dissolved in tetrahydrofuran to obtain a solution (14 wt% isopropyl magnesium chloride) by the preheating zone 1 of the feeding device of the metering pump 1, and after the two materials were sufficiently preheated, they were fed into the reaction zone 1 to undergo a mixing reaction by the preheating zone 2 of the feeding device of the metering pump 2. The compound of structure B (135 g) was dissolved in 100mL of tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, and after sufficient preheating, fed into the reaction zone 1 to carry out a mixing reaction. The reaction is directly carried out in the reaction zone 2 without treatment, meanwhile, 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, fully preheated, then carried out in the reaction zone 2 for mixed reaction, and the reaction is not treated. Sodium methoxide (62 g) and 300mL of methanol are fed into a preheating zone 5 of the device through a metering pump 5, and after being fully preheated, the two materials are conveyed into a reaction zone 3 for mixed reaction. The canagliflozin product is continuously discharged from the outlet, is collected in a product collector, and is subjected to extraction, recrystallization, suction filtration and drying to obtain 121g of canagliflozin with the purity of 98% and the yield of 95%.
Example 4
1) The device comprises: a continuous flow microchannel reactor (G+C+C) is described, with reference to FIG. 2, in which the microchannel reactor connection mode is determined, the microchannel length is determined based on the flow rate and the reaction residence time, and the heat exchange medium is heat transfer oil.
2) Preparation of canagliflozin: the micro-channel reaction device is adjusted to be a preheating zone, a reaction zone and a quenching zone according to the reaction process requirement. The reaction residence time was controlled to 30s by adjusting the flow rate of the pump and the channel length of the micro-channel, the preheating temperature and the reaction temperature were set to-5℃and the reaction pressure was 10bar. 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (216 g) is dissolved in 500 mL tetrahydrofuran under the protection of inert gas, isopropyl magnesium chloride and lithium chloride (molar ratio 1:1.1) are dissolved in tetrahydrofuran to obtain a solution (14 wt% isopropyl magnesium chloride) through a preheating zone 1 of a metering pump 1 input device, and after two materials are fully preheated respectively, the two materials enter a reaction zone 1 to carry out a mixing reaction. The compound of structure B (270 g) was dissolved in 300mL of tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, and after sufficient preheating, fed into the reaction zone 1 to carry out a mixing reaction. The reaction is directly carried out in the reaction zone 2 without treatment, meanwhile, boron trifluoride diethyl etherate (300 mL) and triethylsilane (370 mL) are input into a preheating zone 4 of the device through a metering pump 4, fully preheated, then carried out in the reaction zone 2 for mixed reaction, and the reaction is carried out without treatment. Sodium methoxide (124 g) and 600mL of methanol are fed into a preheating zone 5 of the device through a metering pump 5, and after being fully preheated, the two materials are conveyed into a reaction zone 3 for mixed reaction. The canagliflozin product is continuously discharged from the outlet, is collected in a product collector, and is subjected to extraction, recrystallization, suction filtration and drying to obtain 235g of canagliflozin with the purity of 97% and the yield of 92%.
Example 5
1) The device comprises: a continuous flow microchannel reactor (G+E+G) is described, with reference to FIG. 2, in which the microchannel reactor connection mode is determined, the microchannel length is determined based on the flow rate and the reaction residence time, and the heat exchange medium is heat transfer oil.
2) Preparation of canagliflozin: the micro-channel reaction device is adjusted to be a preheating zone, a reaction zone and a quenching zone according to the reaction process requirement. The reaction residence time is controlled to be 45s by adjusting the flow of the pump and the channel length of the micro channel, the preheating temperature and the reaction temperature are set to be-5 ℃, and the reaction pressure is 10bar. 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene (108 g) is dissolved in 225mL tetrahydrofuran under the protection of inert gas, isopropyl magnesium chloride and lithium chloride (molar ratio 1:1.1) are dissolved in tetrahydrofuran to obtain a solution (14 wt% isopropyl magnesium chloride) through a preheating zone 1 of a metering pump 1 input device, and after two materials are fully preheated respectively, the two materials enter a reaction zone 1 to carry out a mixing reaction. The compound of structure B (135 g) was dissolved in 100mL of tetrahydrofuran, fed into the preheating zone 3 of the apparatus through the metering pump 3, and after sufficient preheating, fed into the reaction zone 1 to carry out a mixing reaction. The reaction is directly carried out in the reaction zone 2 without treatment, meanwhile, 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, fully preheated, then carried out in the reaction zone 2 for mixed reaction, and the reaction is not treated. Sodium methoxide (62 g) and 300mL of methanol are fed into a preheating zone 5 of the device through a metering pump 5, and after being fully preheated, the two materials are conveyed into a reaction zone 3 for mixed reaction. The canagliflozin product is continuously discharged from the outlet, is collected in a product collector, 116g of canagliflozin is obtained through extraction, recrystallization, suction filtration and drying, and the purity is 99 percent and the yield is 91 percent.
Canagliflozin prepared in examples 1 to 5 1 The HNMR pattern is shown in FIG. 4, and the 13C NMR pattern 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 may make various changes and modifications to the above-described embodiments without departing from the technical spirit of the present invention, and these changes and modifications should be included in the scope of the present invention.
Claims (9)
1. The method for continuously producing the canagliflozin by utilizing the microchannel reactor is characterized by comprising a first reaction zone, a second reaction zone and a third reaction zone which are sequentially connected in series, wherein a preheating module is communicated with each of the first reaction zone, the second reaction zone and the third reaction zone;
the process for producing the canagliflozin is specifically shown as the following formula:
the reaction process is specifically as follows: 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, the third reaction zone and completing the mixing reaction, and extracting, recrystallizing, suction filtering and drying the obtained product to obtain the canagliflozin.
2. The method for continuously producing canagliflozin by utilizing the microchannel reactor according to claim 1, wherein the compound A is obtained by mixing and reacting a material 1 and a material 2;
in the material 1, the solute is 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene, the solvent is tetrahydrofuran, and 97.2-123g of the solute is dissolved in 225ml of solvent to obtain the material 1;
dissolving isopropyl magnesium chloride and lithium chloride in tetrahydrofuran to obtain a material 2, wherein the mol ratio of the isopropyl magnesium chloride to the lithium chloride is 1:1.1; included in the material 2 was 14wt% isopropyl magnesium chloride.
3. The method for continuously producing canagliflozin by utilizing the microchannel reactor according to claim 2, wherein the preparation method of the material 3 is specifically as follows: dissolving 90-135g of compound B in 100mL of tetrahydrofuran to obtain a material 3; the material 3 is preheated and then introduced into a first reaction zone to complete the mixed reaction.
4. The method for continuously producing canagliflozin using the microchannel reactor according to claim 3, wherein the reaction residence time in the first reaction zone 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 utilizing the microchannel reactor according to claim 1, wherein the material 4 is a mixture of 150mL of boron trifluoride diethyl etherate solution and 185mL of triethylsilane; the material 4 is preheated and then is introduced into a second reaction zone to complete the mixed reaction.
6. The continuous process for producing canagliflozin using a microchannel reactor according to claim 5, wherein the reaction residence time in the second reaction zone is 30-120s, the reaction temperature is-5-0 ℃, and the reaction pressure is 0-10bar.
7. The method for continuously producing canagliflozin by utilizing the microchannel reactor according to claim 1, wherein the preparation process of the material 5 is specifically as follows: 62g of sodium methoxide is dissolved in 300mL of methanol to obtain a material 5; the material 5 is preheated and then is introduced into a third reaction zone to complete the mixed reaction.
8. The method for continuously producing canagliflozin using the microchannel reactor according to claim 7, wherein the reaction residence time in the third reaction zone 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 utilizing the microchannel reactor according to 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 water solution or heat transfer oil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211554828.2A CN115557940B (en) | 2022-12-06 | 2022-12-06 | Method for continuously producing canagliflozin by utilizing microchannel reactor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211554828.2A CN115557940B (en) | 2022-12-06 | 2022-12-06 | Method for continuously producing canagliflozin by utilizing microchannel reactor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115557940A CN115557940A (en) | 2023-01-03 |
| CN115557940B true CN115557940B (en) | 2023-06-20 |
Family
ID=84770427
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211554828.2A Active CN115557940B (en) | 2022-12-06 | 2022-12-06 | Method for continuously producing canagliflozin by utilizing microchannel reactor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115557940B (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY162628A (en) * | 2007-09-10 | 2017-06-30 | Janssen Pharmaceutica Nv | Process for the preparation of compounds useful as inhibitors of sglt |
| US9056850B2 (en) * | 2008-10-17 | 2015-06-16 | Janssen Pharmaceutica N.V. | Process for the preparation of compounds useful as inhibitors of SGLT |
| WO2016016852A1 (en) * | 2014-07-31 | 2016-02-04 | Sun Pharmaceutical Industries Limited | Process for the purification of canagliflozin |
| CN106866645B (en) * | 2017-02-14 | 2019-07-23 | 齐鲁天和惠世制药有限公司 | A method of Kan Gelie piperazine is prepared using microreactor one kettle way continuous flow |
| CN113549042B (en) * | 2021-07-23 | 2022-09-27 | 安庆奇创药业有限公司 | Preparation method of dapagliflozin |
| CN114570303A (en) * | 2022-03-02 | 2022-06-03 | 南京市计量监督检测院 | Microchannel reactor and method for preparing dapagliflozin intermediate based on reactor |
-
2022
- 2022-12-06 CN CN202211554828.2A patent/CN115557940B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN115557940A (en) | 2023-01-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103113326A (en) | Preparation method of 5-hydroxymethylfurfural | |
| CN115557940B (en) | Method for continuously producing canagliflozin by utilizing microchannel reactor | |
| CN111100088A (en) | Method for continuously synthesizing ethyl dithiaoximate | |
| CN111205225B (en) | Method for continuously synthesizing acridone | |
| CN110627754A (en) | Method for preparing 2-oxo-2-furyl acetic acid by using continuous flow microchannel reactor | |
| CN104109182A (en) | Preparation method of gemcitabine hydrochloride | |
| CN101492413B (en) | Fine purification method for carprofen | |
| CN114380694A (en) | Synthetic method for preparing indobufen intermediate by continuous flow | |
| CN113149973A (en) | Synthesis method of engagliflozin | |
| CN110563627B (en) | Preparation method of (S) -1- (2-chloroacetyl) pyrrolidine-2-carbonitrile | |
| CN104693157A (en) | Preparation method of 2-C-methyl-D-ribotide-1,4-lactone | |
| CN115716821A (en) | Method for continuously producing englezin by using microchannel reactor | |
| CN113861246B (en) | Stereoselective synthesis method of beta-D-arabinofuranoside bond | |
| CN101462934B (en) | Method for preparing p-hydroxybenzene formaldehyde by diazo salt hydrolysis of p-aminobenzaldehyde | |
| CN201351148Y (en) | Device for preparation of parahydroxyben-zaldehyde by hydrolyzing diazonium salt of para aminotenzaldehyde | |
| CN116063363B (en) | Process for synthesizing emamectin benzoate intermediate by using intermittent microchannel reactor | |
| CN111269282A (en) | Method for preparing sofosbuvir intermediate by using continuous flow microchannel reactor | |
| CN114478663B (en) | Preparation method of fondaparinux sodium impurity | |
| CN115611954A (en) | Preparation method of 5'-O- (4, 4' -dimethoxytrityl) -nucleoside | |
| CN116239583A (en) | Synthetic method of enggliflozin | |
| CN117263887A (en) | Preparation method of nucleoside compound | |
| CN117362170A (en) | Preparation method of cable Ma Lutai intermediate | |
| CN114853691A (en) | Method for continuously preparing (Z) -2- (2-amino-4 thiazole) acetic acid by using microchannel reactor | |
| CN117624265A (en) | Ai Tuoge column purification impurity synthesis method | |
| CN116178250A (en) | Method for preparing 2-amino-5-nitropyridine by utilizing microchannel reactor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |