CN112961135A

CN112961135A - Method for continuously synthesizing benzyl substituted gluconolactone by adopting microchannel reaction device

Info

Publication number: CN112961135A
Application number: CN202110162417.8A
Authority: CN
Inventors: 吴学平; 时珠勇
Original assignee: Anqing Chico Pharmaceutical Co ltd
Current assignee: Anqing Chico Pharmaceutical Co ltd
Priority date: 2021-02-05
Filing date: 2021-02-05
Publication date: 2021-06-15
Anticipated expiration: 2041-02-05
Also published as: CN112961135B

Abstract

The invention discloses a method for continuously synthesizing benzyl substituted glucolactone by adopting a microchannel reaction device, which uses methyl-alpha-D-mannopyranoside as a starting material to prepare an old organic solvent solution and react with an organic solvent solution of benzyl chloride in a first microreactor to generate methyl glucose with hydroxyl protected by benzyl; the reaction solution of benzyl substituted gluconic acid and a small amount of hydrochloric acid solution are mixed to form a homogeneous solution, and the homogeneous solution is reacted in a second microreactor to generate hydroxybenzyl substituted glucose; and finally, reacting the reaction solution with an aqueous solution of hydrogen peroxide and sodium hydroxide and an organic solvent solution of tetramethylpiperidine oxynitride in a third microreactor to generate a high-purity hypoglycemic drug Dapagliflozin intermediate benzyl substituted gluconolactone. The method has the advantages of higher heat and mass transfer efficiency, easy industrial amplification, simple, cheap and easily-obtained starting materials, simple process, high purity of the obtained intermediate, high yield, capability of effectively reducing the production cost and suitability for industrial production.

Description

Method for continuously synthesizing benzyl substituted gluconolactone by adopting microchannel reaction device

Technical Field

The invention belongs to the field of medicinal chemistry and continuous flow, and particularly relates to a method for continuously synthesizing a hypoglycemic Dapagliflozin intermediate benzyl substituted gluconolactone by adopting a microchannel reaction device.

Background

In recent years, diabetes poses a serious threat to the people, and the SGLT2 inhibitor introduces the people to the root of the diabetes, and can continuously and stably reduce the blood sugar of the patients by using the reabsorption of glucose in renal tubules as an action target, thereby opening up a new chapter of the treatment history of the diabetes.

Dapagliflozin (Dapagliflozin) is the first medically important sodium-dependent glucose transporter (SGLT2) inhibitor developed by the united states of centella asiatica and eastern americana and is the first drug of choice for the treatment of type ii diabetes at present. As a representative medicine of SGLT2 inhibitor, dapagliflozin has more obvious effect compared with the traditional medicine for treating diabetes, and has the advantages of good tolerance, high safety, continuous and stable sugar reduction, less side reaction and the like. Dapagliflozin is approved by the European Medicines Administration (EMA) to be marketed at 12/3/2012 under the trade name Forxiga, and is currently mainly used for assisting dietary control and exercise, thereby improving the blood glucose level of adult type II diabetes. In addition, dapagliflozin can not cause serious gastrointestinal reaction, does not need injection administration, improves the medication compliance of patients and has wide application prospect. Therefore, the research and the improvement of the synthesis method are of great significance.

In the domestic and foreign literature, the reports on the total synthetic route of dapagliflozin mostly use 5-bromo-2-chloro-4' -methoxydiphenylmethane and TMS protected gluconolactone as two important intermediates, and then the hypoglycemic drug dapagliflozin is obtained through a series of reactions such as condensation, etherification, deprotection, purification and the like of the two intermediates (as shown in figure 1). Wherein the protecting group of the gluconolactone intermediate can be acetyl, trimethylsilane, tert-butyldimethylsilane, tert-butyldiphenylsilane, benzyl, 4-methoxybenzyl, etc. (see fig. 2 and fig. 3). The variously protected anomeric sugar lactones are key building blocks for the synthesis of important biologically active compounds and natural products, as well as the primary intermediates for the synthesis of various carbon glycosides and carbon and imino sugars. In addition, the gluconolactone intermediates can be reduced into polyhydroxy bio-based small molecules, and can be widely applied to the fields of chemical industry, medicine, food manufacturing and the like. However, due to the unique lactone structure, hydrolysis and ring-opening reactions are easy to occur in the reaction process, so that the purity of the subsequently synthesized hypoglycemic drug dapagliflozin is not high, and the yield is low. The high purity of the intermediate is very important for synthesizing the hypoglycemic drug Dapagliflozin, otherwise, the quality of the drug is greatly influenced, and more complicated operation and material loss are brought by post-treatment; meanwhile, the purity requirement of the currently specified medicine development of the country is higher, the limited amount of single impurity is very low, and the purity of the intermediate is also very high. Therefore, the synthesis research and production of the D-gluconolactone have wide development prospect and great practical significance.

Traditional isotacticonolactones are prepared by oxidizing the isocephalic hydroxide using aqueous bromine/barium carbonate under classical mild conditions. Due to the toxicity of bromine and the risks involved in handling, several transformation methods were subsequently reported, including classical oxidation reactions such as Swern oxidation and Corey-Kim oxidation and the use of DMSO/Ac₂And oxidizing O. Several transition metal based oxidant systems have also been reported, including hexavalent chromium based oxidants (PCC and PDC, etc.), manganese dioxide, silver carbonate-diatomaceous earth, and N-methylmorpholine-N-oxide/tetra-N-propyl ammonium perrhenate, among others. In addition, a palladium (II) catalyzed process using PhBr as a hydrogen acceptor has also been reported for the conversion of anomeric hydroxides to lactones. Of course, there are also some non-metal based oxidants used for the conversion of anomeric hydroxides, such as Dess-Martin periodate (DMP) in pyridine, diiodo monochloride, molecular iodine and DAIB/TEMPO, etc. These methods all have some disadvantages, in that Swern oxidation and Corey-Kim oxidation reagents are sensitive to water, the reaction temperature is-78 ℃, and toxic malodorous Me is released in the route₂And (5) an S substance. Likewise, DMSO/Ac₂The O method uses a large excess of Ac₂O and release the malodorous mercaptans. Transition metal systems, in addition to being costly, require toxic chromium or ruthenium oxidants and are complex and cumbersome in post-treatment and purification techniques. These disadvantages make them unsuitable for large-scale synthesis and industrial applications. Also, conventional methods require large excesses of reagents, toxic solvents with pungent taste.

The first important Trimethylsilyl (TMS) -protected gluconolactone intermediate was obtained by the former Miner, Calif. S.Shi Guibao company, directly using D-gluconolactone as a raw material in the synthetic routes reported in patents CN101628905A and Journal of Medicinal Chemistry,2008, vol.51,1145-1149, and adding N-methylmorpholine (NMM) in THF and trimethylchlorosilane (TMSCl) under argon atmosphere. However, 2, 3, 4, 6-tetra-O-trimethylsilyl-D-gluconolactone is in syrup form, poor in quality control and operability, not favorable for industrial production operation, and furan ring isomer impurities are generated in the steps of anomeric hydroxyl etherification and trimethyl silane protecting group removal, so that the impurities are effectively removed by repeated recrystallization in the subsequent steps, thereby affecting the product yield. Meanwhile, the route needs splitting and purifying operation, and is not beneficial to industrial production.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the defects of the existing synthesis of Dapagliflozin intermediate, the method for continuously synthesizing the benzyl substituted gluconolactone of the intermediate Dapagliflozin of the hypoglycemic drug by adopting the microchannel reaction device is provided, and by means of the novel microchannel reaction device, the problems of higher cost, complex reaction conditions, overlong reaction time, fussy post-treatment, difficult purification of reaction products, low purity and the like in the prior art are solved by means of solvent unification, online post-treatment, coordination of flow field parameters and the like, so that continuous flow preparation is realized, the reaction efficiency is improved, and industrial production is further realized. The invention also optimizes the process route, has no dangerous and complex process in the reaction, simple equipment, simple and convenient operation, cheap and easily obtained raw materials, high purity of the obtained final product and suitability for industrial production.

The method for continuously synthesizing the benzyl substituted gluconolactone serving as the intermediate of the high-purity hypoglycemic drug Dapagliflozin by adopting the microchannel reaction device comprises the following steps:

step (1): respectively and simultaneously pumping the organic solvent solution of methyl-alpha-D-mannopyranoside and the organic solvent solution of benzyl chloride into a first micro-structure mixer in a first section of microchannel reaction device, fully mixing, pumping into a first micro-reactor in the first section of microchannel reaction device for reaction, and directly carrying out the next reaction without carrying out post-treatment on the reaction solution;

step (2): the reaction solution in the step (1) flows into a second micro-structure mixer of a second section of microchannel reaction device, meanwhile, an organic solvent solution of hydrochloric acid is pumped into the second micro-structure mixer, and after the solution is fully mixed, the solution is pumped into a second micro-reactor of the second section of microchannel reaction device for reaction, so as to obtain a homogeneous mixed

solution

2, 3, 4, 6 tetra-O-benzyl-D-gluconic acid (compound III) solution;

and (3): and (3) allowing the homogeneous mixed solution obtained in the step (2) to flow into a third micro-structure mixer of a third-section microchannel reaction device, simultaneously pumping an aqueous solution of hydrogen peroxide and sodium hydroxide and an organic solvent solution of Tempo (2,2,6, 6-tetramethylpiperidine oxide) into the third micro-structure mixer respectively, fully mixing, pumping into a third micro-reactor of the third-section continuous microchannel reaction device for reaction, and performing post-treatment on reaction effluent to obtain a

midbody

2, 3, 4, 6 tetra-O-benzyl-D-gluconolactone (compound IV) of the hypoglycemic drug dapagliflozin.

In the step (1), the concentration of the organic solvent solution of the methyl-alpha-D-mannopyranoside is 0.1-1.0 mol/L, preferably 0.5-0.8 mol/L; the solution concentration of the benzyl chloride organic solvent solution is 0.5-5.0 mol/L, preferably 1.5-3.0 mol/L; and benzyl chloride in a molar ratio of 1:2 to 10, preferably 1: 5.

in the step (1), the flow rate of the organic solvent solution of methyl-alpha-D-mannopyranoside pumped into the first micro-structure mixer is 0.17-0.33 mL/min, preferably 0.21-0.29 mL/min; the flow rate of the benzyl chloride organic solvent solution pumped into the first micro-structure mixer is 0.83-1.67 mL/min, preferably 1.11-1.53 mL/min; the volume of the first microreactor is 10-50 mL, and preferably 20-30 mL; the residence time of the reaction is 10-25 min, preferably 18-22 min; the reaction temperature in the first microreactor is 20-100 ℃, and preferably 50-75 ℃.

In the step (2), the flow rate of the reaction liquid obtained in the step (1) is 1.0-2.0 ml/min; the concentration of the tetrahydrofuran solution of the hydrochloric acid is 1.0-1.6 mol/L, preferably 1.2-1.5 mol/L; the molar ratio of the benzyl substituted gluconic acid to the hydrochloric acid is 1:1 to 1.25, preferably 1: 1.05 to 1.15.

In the step (2), the flow rate of the tetrahydrofuran solution of hydrochloric acid pumped into the second micro-structure mixer is 0.25-0.5 mL/min, preferably 0.31-0.42 mL/min; the volume of the second microreactor is 10-50 mL, and preferably 20-30 mL; the residence time of the reaction is 8-20 min, preferably 12-16 min; the reaction temperature in the second microreactor is-10-50 ℃, and preferably 0-25 ℃.

Preferably, the organic solvent is one or a mixture of acetonitrile, toluene, N-dimethylformamide, tetrahydrofuran and dichloromethane. More preferably, the organic solvent is tetrahydrofuran.

In the step (3), the concentration of the aqueous solution of sodium hydroxide and hydrogen peroxide is 1.25-2 mol/L, preferably 1.55-1.75 mol/L; the molar ratio of the sodium hydroxide to the hydrogen peroxide is 1: 1.2-1.5, preferably 1: 1.33-1.45; the temperature of the aqueous solution of sodium hydroxide and hydrogen peroxide and the effluent liquid in the step (2) is-10-60 ℃, preferably 0-35 ℃; the concentration of the tetrahydrofuran solution of Tempo is 0.5-0.8mol/L, preferably 0.65-0.75 mol/L; the molar ratio of the sodium hydroxide to the Tempo is 1: 0.5-1.0, preferably 1: 0.65-0.85; the post-treatment is to cool the reaction effluent to room temperature, and then inject water and ethyl acetate, preferably, the volume ratio of water to ethyl acetate is 1:2, combining the organic extracts and adding Na₂SO₄Drying, filtering and vacuum concentrating, flash column chromatography to obtain pure product.

In the step (3), the flow rate of pumping the aqueous solution of hydrogen peroxide and sodium hydroxide into the third micro-structure mixer is 0.625-0.71 mL/min, preferably 0.675-0.70 mL/min; pumping the tetrahydrofuran solution of the Tempo into the third micro-structure mixer at the flow rate of 0.04-0.125 mL/min, preferably 0.08-0.105 mL/min; the volume of the third microreactor is 10-50 mL, and preferably 20-30 mL; the residence time of the reaction is 5-15 min, preferably 9-14 min; the reaction temperature in the third microreactor is 20-100 ℃, and preferably 50-75 ℃.

The first-section microchannel reaction device comprises a pump A, a pump B, a first micro-structure mixer and a first microreactor, wherein the pump A and the pump B are connected with the first micro-structure mixer in a parallel mode through a connecting pipe, and the first micro-structure mixer and the first microreactor are connected in a series mode through the connecting pipe; the second section of continuous microchannel reaction device comprises a pump C, a second micro-structure mixer and a second microreactor, wherein the pump C is connected with the second micro-structure mixer in series through a connecting pipe, and the second micro-structure mixer is connected with the second microreactor in series through the connecting pipe; in the step (3), the third-stage continuous microchannel reaction device comprises a pump D, a pump E, a third microstructure mixer, a third microreactor and a first receiving device, wherein the pump D and the pump E are connected in parallel through a connecting pipe and the third microstructure mixer, the third microreactor and the first receiving device are connected in series through a connecting pipe.

The device can realize the input into a micro mixer and subsequent equipment by a precise and low-pulsation pump (such as an HPLC pump or an injection pump), thereby realizing the continuous passing of materials through the microchannel modular reaction device and simultaneously controlling the residence time of the materials. The raw material storage tank and the product collecting bottle can be respectively connected at the head and the tail according to requirements to realize continuous operation.

The pump described in the present invention is preferably an HPLC pump.

The models of the first microstructure mixer, the second microstructure mixer and the third microstructure mixer are T type, Y type and inverted Y type, and the Y type is preferred; the first, second and third microreactors are in the form of channel reactors, core-structured reactors, preferably channel reactors.

The diameter of the connecting pipe is 0.5-2 mm, the connecting pipe comprises a liquid inlet pipe, a connecting pipe between the microstructure mixer and the micro-reaction device, and a liquid outlet pipe between the micro-reaction device and the receiving device, and the length of each section of the connecting pipe is 5-15 cm, preferably 10-13 cm; the diameters of the pipelines of the first, second and third microreactors are 0.5-4 mm, and preferably 0.5-2 mm; the material connecting pipe used in the present invention is controlled in the above preferable range, although the thin pipe diameter can effectively increase the specific surface area, it may cause the liquid flow pressure to rise, which may cause the problems of blockage, pipe burst, etc.

Has the advantages that: compared with the prior art, the invention has the following technical effects:

1) according to the invention, the intermediate benzyl glucolactone of the hypoglycemic drug dapagliflozin is continuously prepared from 2-methyl glucoside by adopting a microchannel reaction device for the first time, the product obtained in each step is not required to be purified, and is directly put into the next step for reaction, so that the yield is not reduced, but the operation is greatly simplified, the consumption of the intermediate in each step is reduced, and the yield is improved;

2) the known process for synthesizing the hypoglycemic drug dapagliflozin is optimized, after the synthesis process of removing methyl to form hemiacetal by adding a tetrahydrofuran solution of hydrochloric acid in the step (2), the HCl is firstly removed by alkalization in the traditional method, and then the oxidation is carried out by using oxidants such as sodium hypochlorite and the like under an alkaline condition, but the continuous alkalization operation is realized by accurately controlling the sampling rate by utilizing the continuous flow characteristic of a microreactor, and then the sodium hypochlorite is replaced by hydrogen peroxide, and the final product is obtained by composite oxidation with Tempo, wherein in the process, the HCl byproduct generated in the step (1) is just the reactant in the step (2), so that the use amount of the hydrochloric acid can be reduced; a large amount of chloride ions are generated in the step (2), and are oxidized into chlorine by hydrogen peroxide and a catalytic amount of Tempo in the alkaline condition of sodium hydroxide after entering the step (3), so that the circulation from the chloride ions to the chlorine and then to the chloride ions is realized, the waste acid in the reaction solution is fully used, and the pollution emission is reduced;

3) the whole process has short reaction time and simple and convenient post-treatment, can simplify the complex multistep synthesis process, realizes simple and convenient production of the intermediate benzylgluconolactone of the hypoglycemic drug dapagliflozin, and avoids the long time consumption and complex operation of the traditional process;

4) the invention has the advantages of low toxicity and pollution, low production cost, good product quality, high profit, environmental protection, energy conservation and high efficiency, and has the potential of industrial amplification.

Drawings

FIG. 1 is a classical synthetic route to Dapagliflozin;

FIG. 2 shows a first novel synthetic route for Dapagliflozin intermediate 1;

FIG. 3 is a second scheme of the novel synthesis of intermediate 1 of Dapagliflozin;

FIG. 4 is a schematic diagram of the synthesis route of the microchannel reactor apparatus used in the present invention.

FIG. 5 is a reaction equation of the present invention;

FIG. 6 is a hydrogen spectrum of a final product, benzyl substituted gluconolactone (solvent is deuterated DMSO);

fig. 7 is a carbon spectrum of the final product benzyl substituted gluconolactone (solvent is deuterated DMSO).

Detailed Description

The present invention will be described in further detail with reference to specific examples. The examples will help to understand the present invention given the detailed embodiments and the specific operation procedures, but the scope of the present invention is not limited to the examples described below.

The invention will be better understood from the following examples.

The microchannel reactor apparatus described in the following examples, as shown in fig. 4, comprises a first stage microchannel reactor apparatus comprising a pump a1, a pump B2, a first micro-structured mixer 3, a first microreactor 4; the second-stage continuous microchannel reaction device comprises a pump C5, a second micro-structure mixer 6 and a first microreactor 7; the third-stage continuous micro-reaction channel device comprises a pump D8, a pump E9, a third micro-structure mixer 10, a third microreactor 11 and a third receiving device 12. The pump A1 and the pump B2 are connected with the first micro-structure mixer 3 through a connecting pipe in a parallel mode, and the first micro-structure mixer 3 and the first micro-reactor 4 are connected with each other through a connecting pipe in a series mode; the pump C is connected with the second micro-structure mixer in a series connection mode through a connecting pipe, and the second micro-structure mixer is connected with the second micro-reactor in a series connection mode through the connecting pipe; the pump D and the pump E are connected in parallel by a connecting tube and a third micro-structured mixer, which is connected in series with the first receiving means 12 by a connecting tube.

The reaction raw materials enter the micro-structure mixer through an HPLC pump or an injection pump and then enter the micro-reactor. The first, second and third micro-structure mixers are Y-shaped. The first micro reactor, the second micro reactor and the third micro reactor are channel reactors. In the following examples, a Bayer Y-type mixer was used as the micro-mixer, and a microreactor type Vaporurtec Ltd was used.

Example 1

(1) In a microchannel reactor, a solution of methyl- α -D-mannopyranoside (0.025mol) in tetrahydrofuran (50mL) and a solution of benzyl chloride (0.125mol) in tetrahydrofuran (50mL) were pumped from pumps A1, B2, respectively, into first micro-structured mixer 3 at a flow rate of 0.25mL/min for pump A1 and 1.25mL/min for pump B2. After fully mixing, the mixture enters a first microreactor 4, the volume of the first microreactor 4 is 25mL, and the reaction residence time is 20 min. The reaction temperature was 55 ℃ and the yield was 93.2%.

(2) Pumping a tetrahydrofuran solution (25mL) of hydrochloric acid (0.025mol) from a pump C5 in the second stage of continuous microchannel reaction device into the second micro-structure mixer 6 with the reaction liquid obtained in the step (1) flowing into the second micro-structure mixer, wherein the flow rate of the pump C5 is 0.39 mL/min; and after fully mixing, pumping the mixture into a second microreactor 7 in a second-stage continuous microchannel reaction device for reaction, wherein the volume of the second microreactor 7 is 25mL, the retention time is 15min, the heating temperature is 20 ℃, and the obtained reaction liquid is benzylgluconic acid, and the yield is 89.7%.

(3) After the homogeneous mixed solution obtained in the step (2) flows into a third micro-structure mixer 10, sodium hydroxide (0.025mol), an aqueous solution (40mL) of hydrogen peroxide (0.032mol) and a tetrahydrofuran (25mL) solution of Tempo (0.0125mol) are respectively pumped into the third micro-structure mixer 11 from a pump D8 and a pump E9, the flow rate of the pump D8 is 0.875mL/min, the flow rate of the pump E9 is 0.105mL/min, after full mixing, the mixture is pumped into a third microreactor 11 in a third section of continuous microchannel reaction device for reaction, the volume of the third microreactor 11 is 25mL, the reaction temperature is 65 ℃, the residence time is 10min, a first receiving device 12 collects the reaction effluent, the reaction effluent is cooled to room temperature and then injected into water (50mL) and ethyl acetate (50mL), extraction liquid separation, filtration, washing and drying are carried out, so as to obtain the hypoglycemic drug Dagliflozin intermediate benzyl substituted glucolactone, the yield is 88.1%, the product purity is 99.0%, and the hydrogen spectrum and the carbon spectrum of the obtained product benzyl substituted gluconolactone are shown in fig. 6 and 7.

Comparative example 1

The comparative example was carried out in a round bottom flask.

(1) 5.0g (0.025mol) methyl-alpha-D-mannopyranoside, 16.3g (0.129mol) benzyl chloride, and 50ml tetrahydrofuran solution were added to a three-necked flask and reacted at 50 ℃ for 8 hours under nitrogen. Cooling to room temperature, and carrying out post-treatment to obtain the product, namely benzyl-substituted methyl-alpha-D-mannopyranoside, with the yield of 74.2%.

(2) 3.71g (6.8mmol) of benzyl-substituted methyl-alpha-D-mannopyranoside is dissolved in anhydrous tetrahydrofuran solution (50mL), cooled to 0 ℃, 0.21mL (6.8mmol) of hydrochloric acid is slowly added dropwise, the temperature is kept not to exceed 15 ℃, and the temperature is raised to room temperature after the addition is finished for reaction for 18 h. Distilling under reduced pressure to remove solvent tetrahydrofuran, adding 25mL of water and ethyl acetate for extraction, and performing post-treatment to obtain benzyl substituted gluconic acid compound with yield of 71.3%

(3) 2.65g (4.9mmol) of benzyl substituted gluconic acid compound was added to anhydrous tetrahydrofuran solution (25mL), 0.32mL (5.2mmol) of sodium hypochlorite and Tempo (0.38g,2.44mmol) were added, the temperature was raised to 50 ℃ and the reaction was maintained at this temperature for 1 h. Cooling to room temperature, extracting with water (100ml) and ethyl acetate (100ml x 2), mixing organic phases, drying, concentrating to obtain crude product with purity of 73.5%, separating with silica gel column to obtain final product benzyl substituted gluconolactone gluconate with yield of 65.5% and purity of 98.6%.

Example 2

The procedure is the same as in example 1, except that:

(1) in step (1), the flow rate of pump A1 was 0.21mL/min and the flow rate of pump B2 was 1.11 mL/min. The first microreactor 4 had a volume of 20mL and a reaction residence time of 18 min. The reaction temperature was 50 ℃ and the yield was 86.2%.

(2) The flow rate of the pump C5 was 0.31mL/min, the volume of the second microreactor 7 was 20mL, the residence time was 12min, the heating temperature was 0 ℃ and the yield was 84.9%.

(3) The flow rate of the pump D8 was 0.675mL/min, the flow rate of the pump E9 was 0.04mL/min, the volume of the third microreactor 11 was 20mL, the reaction temperature was 50 ℃, the residence time was 9min, the yield was 81.8%, and the purity was 97.5%.

Example 3

The procedure is the same as in example 1, except that:

(1) in step (1), the flow rate of pump A1 was 0.29mL/min and the flow rate of pump B2 was 1.53 mL/min. The first microreactor 4 had a volume of 30mL and a reaction residence time of 22 min. The reaction temperature was 75 ℃ and the yield was 87.5%.

(2) The flow rate of the pump C5 was 0.42mL/min, the volume of the second microreactor 7 was 30mL, the residence time was 16min, the heating temperature was 25 ℃ and the yield was 85.8%.

(3) The flow rate of the pump D8 was 0.70mL/min, the flow rate of the pump E9 was 0.105mL/min, the volume of the third microreactor 11 was 30mL, the reaction temperature was 75 ℃, the residence time was 14min, the yield was 82.4%, and the purity was 96.8%.

Based on the difficulty of synthesizing the intermediate benzylglucolactone by the traditional route, the method introduces a micro-reaction technology for the first time through reaction kinetics research and side reaction apparent kinetics data investigation, coordinates various flow field parameters, enables the reaction to have series potential through an integrated form, and lays a foundation for the continuous preparation of the compound in the whole process. The micro-reaction technology brings the advantages of high mass and heat transfer efficiency, safety, environmental protection, strong operability, high product purity, easy industrial amplification and the like.

The invention makes process innovation and optimization from the purposes of solvent recovery, three-waste reduction and economy and practicality, particularly creatively uses a micro-channel continuous flow system for the first time, and more safely and efficiently realizes the continuous and efficient synthesis of the benzyl-protected glucolactone. According to the invention, the reaction solution is alkalized by using a method of micro-channel sodium hydroxide immobilization, so that the complicated steps of removing acid and alkalizing in the traditional method are avoided, and the method is more efficient and safer. In addition, the hydrogen peroxide is directly used for replacing the traditional sodium hypochlorite, and the recycling of the sodium hypochlorite is realized by adding the catalytic amount of Tempo, so that the recovery rate of the solvent is realized, the discharge of waste liquid is reduced, meanwhile, the post-treatment process of each step is optimized, and the benzyl-protected glucolactone as the intermediate of the hypoglycemic drug dapagliflozin is synthesized efficiently and high-quality.

Claims

1. A method for continuously synthesizing benzyl substituted gluconolactone by adopting a microchannel reaction device is characterized by comprising the following steps:

step (1): respectively and simultaneously pumping the organic solvent solution of methyl-alpha-D-mannopyranoside and the organic solvent solution of benzyl chloride into a first micro-structure mixer of a first section of microchannel reaction device, fully mixing, pumping into a first micro-reactor in the first section of microchannel reaction device for reaction, and directly carrying out the next reaction without carrying out post-treatment on the reaction solution;

step (2): the reaction solution in the step (1) flows into a second micro-structure mixer of a second-section microchannel reaction device, meanwhile, a solvent solution of hydrochloric acid is pumped into the second micro-structure mixer, and after the solution is fully mixed, the solution is pumped into a second micro-reactor of the second-section microchannel reaction device for reaction, so that a homogeneous mixed solution 2, 3, 4, 6 tetra-O-benzyl-D-gluconic acid solution is obtained;

and (3): and (3) allowing the homogeneous mixed solution obtained in the step (2) to flow into a third micro-structure mixer of a third-section microchannel reaction device, simultaneously pumping the aqueous solution of hydrogen peroxide and sodium hydroxide and the organic solvent solution of Tempo into the third micro-structure mixer respectively, fully mixing, pumping into a third microreactor in a third-section continuous microchannel reaction device for reaction, and performing aftertreatment on reaction effluent liquid to obtain an intermediate 2, 3, 4, 6 tetra-O-benzyl-D-gluconolactone of the hypoglycemic drug dapagliflozin.

2. The method according to claim 1, wherein in the step (1), the concentration of the organic solvent solution of methyl-alpha-D-mannopyranoside is 0.1-1.0 mol/L; the concentration of the organic solvent solution of the benzyl chloride is 0.5-5.0 mol/L; the molar ratio of the methyl-alpha-D-mannopyranoside to the benzyl chloride is 1: 2-10.

3. The method according to claim 1, wherein in step (1), the flow rate of the organic solvent solution of methyl- α -D-mannopyranoside pumped into the first micro-structured mixer is 0.17 to 0.33mL/min, and the flow rate of the organic solvent solution of benzyl chloride pumped into the first micro-structured mixer is 0.83 to 1.67 mL/min; the volume of the first microreactor is 10-50 mL, the reaction residence time is 10-25 min, and the reaction temperature in the first microreactor is 20-100 ℃.

4. The method according to claim 1, wherein in the step (2), the flow rate of the reaction solution obtained in the step (1) is 1.0-2.0 ml/min; the concentration of the organic solvent solution of the hydrochloric acid is 1.0-1.6 mol/L; the molar ratio of the benzyl substituted gluconic acid to the hydrochloric acid is 1: 1.1 to 1.25; pumping the organic solvent solution of the hydrochloric acid into the second micro-structure mixer at the flow rate of 0.25-0.5 mL/min; the volume of the second microreactor is 10-50 mL; the residence time of the reaction is 8-20 min; the reaction temperature in the second microreactor is-10-50 ℃.

5. The method according to any one of claims 1 to 4, wherein the organic solvent is one or more of acetonitrile, toluene, N-dimethylformamide, tetrahydrofuran and dichloromethane.

6. The method according to claim 1, wherein in the step (3), the concentration of the aqueous solution of sodium hydroxide and hydrogen peroxide is 1.25-2 mol/L; the molar ratio of the sodium hydroxide to the hydrogen peroxide is 1: 1.2-1.5; the temperature of the aqueous solution of sodium hydroxide and hydrogen peroxide and the effluent liquid in the step (2) is-10 ℃ to 60 ℃ when being stirred and mixed; the concentration of the tetrahydrofuran solution of Tempo is 0.5-0.8mol/L, and the molar ratio of sodium hydroxide to Tempo is 1: 0.5-1.0; the post-treatment comprises the steps of cooling the reaction effluent to room temperature, injecting the reaction effluent into a mixed solution of water and ethyl acetate, combining organic extracts, drying, filtering, concentrating in vacuum, and separating by fast column chromatography to obtain a pure product.

7. The method of claim 1, wherein in step (3), the flow rate at which the aqueous solution of hydrogen peroxide and sodium hydroxide is pumped into the third micro-structured mixer is from 0.625 to 0.71mL/min, and the flow rate at which the tetrahydrofuran solution at Tempo is pumped into the third micro-structured mixer is from 0.04 to 0.125 mL/min; the volume of the third microreactor is 10-50 mL; the residence time of the reaction is 5-15 min; the reaction temperature in the third microreactor is 20-100 ℃.

8. The method of claim 1, wherein the first-stage microchannel reactor device comprises a pump a, a pump B, a first micro-structured mixer, and a first microreactor, the pump a and the pump B being connected in parallel via a connecting tube and the first micro-structured mixer, the first micro-structured mixer and the first microreactor being connected in series via a connecting tube; the second section of continuous microchannel reaction device comprises a pump C, a second micro-structure mixer and a second microreactor, wherein the pump C is connected with the second micro-structure mixer in series through a connecting pipe, and the second micro-structure mixer is connected with the second microreactor in series through the connecting pipe; the third-stage continuous microchannel reaction device comprises a pump D, a pump E, a third micro-structure mixer, a third microreactor and a first receiving device, wherein the pump D and the pump E are connected in parallel through a connecting pipe and the third micro-structure mixer, the third microreactor and the first receiving device are connected in series through the connecting pipe.

9. The method of claim 8 wherein the first, second and third micro-mixers are T-, Y-and inverted Y-shaped; the first micro reactor, the second micro reactor and the third micro reactor are of a channel type reactor or a heart type structure reactor.

10. The method of claim 8, wherein the connecting tube has a diameter of 0.5 to 2mm and a length of 50 to 100 cm; and the diameters of the pipelines of the first micro-reactor, the second micro-reactor and the third micro-reactor are 0.5-4 mm.