KR102583730B1 - Gliflozin synthesis method using methanesulfonylated intermediates in a continuous flow chemistry process - Google Patents

Abstract

The present invention relates to a method for synthesizing glyflozin, comprising: a first step of producing a first product by reacting an initial reactant, a stream containing lactone, and a stream containing n -Butyllithium; and a second step of producing a second product by reacting a stream containing the first product and a stream containing a mesylation reagent; and a third step of producing a third product by reacting a stream containing the second product and a stream containing an acid.

Description

Method for synthesizing glyflozin using methanesulfonylation intermediate in a continuous reaction process {GLIFLOZIN SYNTHESIS METHOD USING METHANESULFONYLATED INTERMEDIATES IN A CONTINUOUS FLOW CHEMISTRY PROCESS}

The present invention relates to a method for synthesizing glyflozin with improved economic efficiency and environmental friendliness through a continuous reaction process.

Diabetes occurs when there is a problem with insulin secretion, such as decreased insulin secretion or resistance due to genetic or environmental causes, or an abnormality in the function of insulin, so glucose in the blood cannot be delivered and stored in cells, and the blood sugar level increases excessively. It is a metabolic disease in which the blood sugar level is much higher than that of normal people.

Diabetes is largely classified into type 1 diabetes and type 2 diabetes.

Unlike type 1 diabetes, also known as juvenile diabetes, type 2 diabetes is an acquired factor caused by lack of exercise, obesity, or stress, and occurs when insulin secretion is smoothly controlled but insulin does not function properly, resulting in blood sugar control failure. (Non-patent document 0001).

Type 1 is reported to be caused by congenital factors and specific infections, and type 2 is generally reported to be caused by lifestyle habits and genetic influences.

The diabetes treatment market has grown rapidly from USD 32 billion worldwide and KRW 449.1 billion domestically in 2010 to USD 70.8 billion globally and KRW 630 billion domestically in 2015, and is expected to continue growing in the future.

Meanwhile, SGLT-2 (sodium/glucose cotransporter 2), along with SGLT-1 (sodium/glucose cotransporter 1), is a transporter responsible for excessive blood sugar reabsorption in the kidney, and SGLT-2 plays most of the role. .

When SGLT-2 inhibitors inhibit the SGLT-2 transporter, blood sugar excreted in urine increases, lowering blood sugar and releasing calories held in blood sugar, resulting in a weight loss effect.

DPP4 inhibitors account for the highest proportion in the diabetes treatment market, but SGLT-2 inhibitors are insulin-independent compared to DPP4 inhibitors, so there is no concern about hypoglycemia and have a weight loss effect, so their growth potential is high.

About 10 types of gliflozin, which are classified as drugs that inhibit SGLT-2, are in commercialization and clinical trials, including Invocana (canagliflozin), Farxiga (dapagliflozin), Jardiance (empagliflozin), and Suglet ( ipragliflozin) and others are sold in Korea.

The synthesis process of glyflozin includes common reaction steps, and this synthesis process involves the production of large amounts of waste acids (BF ₃ , Et ₃ SiH, MeSO ₃ H) and waste bases (DIPEA, pyridine), and has safety and There is a problem of low efficiency.

In order to solve the problems in the synthesis process of glyflozin, the present inventors developed a method for synthesizing glyflozin based on a continuous reaction process that not only has excellent process efficiency but is also environmentally friendly.

Non-patent document 0001: Stumvoll M, et al., Lancet 365:1333-46 (2005)

The present invention is intended to solve the problems of the prior art described above, and aims to provide a method for synthesizing glyflozin that is environmentally friendly and economical.

According to one aspect of the present invention, a stream containing any one compound selected from the group consisting of compounds of the following formulas 1a to 1e and a compound of formula 2, and a stream containing n -butyllithium are reacted. A first step of producing a first product, a compound of any one of the following formulas 3a to 3e; and a second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of any one of the following formulas 4a to 4e; And a third step of reacting the stream containing the second product and the stream containing the acid to produce a third product, a compound of any one of the following formulas 5a to 5e. do.

[Formula 1a]

[Formula 1b]

[Formula 1c]

[Formula 1d]

[Formula 1e]

[Formula 2]

[Formula 3a]

[Formula 3b]

[Formula 3c]

[Formula 3d]

[Formula 3e]

[Formula 4a]

[Formula 4b]

[Formula 4c]

[Formula 4d]

[Formula 4e]

[Formula 5a]

[Formula 5b]

[Formula 5c]

[Formula 5d]

[Formula 5e]

In the above equation,

R ₁ is halogen,

Y ₁ is an oxygen or sulfur atom,

X ₁ is a protecting group.

In one embodiment, the method for synthesizing glyflozin may be performed using a flow reactor.

In one embodiment, the gliflozin is canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and Luceo. One or more may be selected from the group consisting of luseogliflozin.

In one embodiment, the first step may be performed at a temperature of -70°C or lower.

In one embodiment, the flow rate of the stream containing any one compound selected from the group consisting of compounds 1a to 1e and the compound of Formula 2 in the first step is 0.4 to 10 mL/min, and the n- butyllithium The flow rate of the stream containing may be 0.3 to 12 mL/min.

In one embodiment, the mesylation reagent may be any one selected from the group consisting of methanesulfonic acid chloride (MeSO ₂ Cl), methanesulfonic acid bromide (MeSO ₂ Br), or methanesulfonic acid anhydride ((MeSO ₂ ) ₂ O). .

In one embodiment, the second step may be performed at a temperature of 15 to 35°C.

In one embodiment, the flow rate of the stream containing the first product in the second step may be 0.5 to 20 mL/min, and the flow rate of the stream containing the mesylation reagent may be 0.2 to 3.5 mL/min. .

In one embodiment, the acid in the third step may be hydrochloric acid, hydrobromic acid, nitric acid, acetic acid, carbonic acid, and sulfuric acid.

According to another aspect of the present invention, a stream containing a compound of Formula 1c and a compound of Formula 2 below, and a stream containing n -Butyllithium are reacted to produce a compound of Formula 3c below as the first product. The first step of manufacturing; and a second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of Formula 4c below; And a third step of reacting the stream containing the second product and the stream containing the acid to produce a third product, a compound of formula 5c below. A method for synthesizing empagliflozin is provided, including a.

[Formula 1c]

[Formula 2]

[Formula 3c]

[Formula 4c]

[Formula 5c]

In the above equation,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

In one embodiment, the method for synthesizing empagliflozin may be performed using a flow reactor.

According to the present invention, the synthesis method is not only economically efficient, but the yield can be significantly increased.

In addition, the synthesis method is environmentally friendly because the production of related substances due to the reaction is minimized and the amount of solvent used is reduced.

The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.

Figure 1 schematically illustrates a method for continuously synthesizing glyflozin according to an embodiment of the present invention.
Figure 2 is a schematic diagram of the n- butyllithium ( n -BuLi) reaction process and mesylation reaction according to an embodiment of the present invention.
Figure 3 is a schematic diagram of a deprotection reaction process according to an embodiment of the present invention.

Hereinafter, the present invention will be described with reference to the attached drawings. However, the present invention may be implemented in various different forms and, therefore, is not limited to the embodiments described herein.

When a part is said to "include" a certain component, this means that it does not exclude other components, but may further include other components, unless specifically stated to the contrary.

Unless otherwise defined herein, all technical and scientific terms used have the same meaning as commonly understood by a person of ordinary skill in the art.

Various scientific dictionaries containing terms included in this specification are well known and available in the art. Although any methods and materials similar or equivalent to those described herein can be found of use in the practice or testing of the invention, several methods and materials are described. The present invention is not limited to specific methodologies, protocols and reagents, as they can be used in various ways depending on the context in which they are used by those skilled in the art.

According to one aspect of the present invention, a stream containing any one compound selected from the group consisting of compounds of the following formulas 1a to 1e and a compound of formula 2, and a stream containing n - butyllithium are reacted. A first step of producing a first product, a compound of any one of the following formulas 3a to 3e; and a second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of any one of the following formulas 4a to 4e; And a third step of reacting the stream containing the second product and the stream containing the acid to produce a third product, a compound of any one of the following formulas 5a to 5e. A method for synthesizing glyflozin is provided, including: do.

[Formula 1a]

[Formula 1b]

[Formula 1c]

[Formula 1d]

[Formula 1e]

[Formula 2]

[Formula 3a]

[Formula 3b]

[Formula 3c]

[Formula 3d]

[Formula 3e]

[Formula 4a]

[Formula 4b]

[Formula 4c]

[Formula 4d]

[Formula 4e]

[Formula 5a]

[Formula 5b]

[Formula 5c]

[Formula 5d]

[Formula 5e]

In the above equation,

R ₁ is halogen,

Y ₁ is an oxygen or sulfur atom,

X ₁ is a protecting group.

The “halogen” may be fluorine, chlorine, bromine, iodine, etc.

The “protecting group” refers to a substituent or modification commonly used to block or protect a specific functional group while reacting other functional groups on a compound. Protecting groups are selected to create the desired unprotected group by liberating or re-modifying the substituents. Hydroxy-protecting groups to protect hydroxyl groups include isopropylidene ketal and cyclohexanone dimethyl ketal (which forms 1,3-dioxane with two adjacent hydroxyl groups), 4-methoxy-1-methylbenzene ( (forming 1,3-dioxane with two adjacent hydroxyl groups), acetyl, chloroacetyl, benzoyl, and silyl (e.g., trimethylsilyl; TMS).

The gliflozin is canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and luseogliflozin. ), but is not limited thereto.

The glyflozin synthesis method can be performed using a flow reactor. The method of synthesizing glyflozin using the flow reactor not only has significantly higher yield than the conventional batch process, but also has excellent safety, and the final product can be synthesized efficiently by precisely controlling the temperature and flow rate.

The “flow reactor” may include a flow path connecting the storage unit, mixing unit, and reaction unit, respectively.

The storage unit can store the reactant before it is introduced into the reaction and discharge the reactant according to the user's operation.

The mixing unit may uniformly mix the reactants introduced from the storage unit. In the reaction unit, reactants included in the mixture may react with each other.

The mixing section and the reaction section may be mixed and the reaction may be performed at the same time, and may exist individually or integrated.

The yield of the final product formed and the generation rate of impurities can be adjusted by adjusting the temperature and pressure of the flow reactor, the time for which the reactants are left, and the flow rate.

The flow path connects the storage section, mixing section, or reaction section of the system and can move reactants or products.

The first step may be performed at a temperature of -70°C or lower, preferably -75°C or lower, and more preferably -78°C.

In the first step, the flow rate of the stream containing any one compound selected from the group consisting of compounds 1a to 1e and the compound of Formula 2 is 0.4 to 10 mL/min, preferably 0.5 to 9 mL/min, more preferably Typically, it may be 0.6 to 8 mL/min, and the flow rate of the stream containing n- butyllithium is 0.3 to 12 mL/min, preferably 0.4 to 11 mL/min, more preferably 0.469 to 10.0 mL/min. It can be min.

The mesylation reagent may be any one selected from the group consisting of methanesulfonic acid chloride (MeSO ₂ Cl), methanesulfonic acid bromide (MeSO ₂ Br), or methanesulfonic acid anhydride ((MeSO ₂ ) ₂ O), but is not limited thereto.

The “mesylation reagent” may be any mesylation reagent that can be used to insert MeSO ₂ -(CH ₃ SO ₂ -, Ms-) into Formulas 3a to 3e. Suitable mesylating reagents include methanesulfonic acid anhydride ((MeSO ₂ ) ₂ O) and methanesulfonic acid halides, including methanesulfonic acid chloride (MeSO ₂ Cl) and methanesulfonic acid bromide (MeSO ₂ Br). Most preferably, it may be methanesulfonic acid chloride (MeSO ₂ Cl).

The second step may be performed at a temperature of 15 to 35°C, preferably 20 to 30°C, and more preferably 25°C.

The flow rate of the stream containing the first product in the second step may be 0.5 to 20 mL/min, preferably 1 to 19 mL/min, more preferably 1.069 to 18 mL/min, and the mesylation The flow rate of the stream containing the reagent may be 0.2 to 3.5 mL/min, preferably 0.35 to 3.25 mL/min, and more preferably 0.5 to 3.0 mL/min.

In the third step, the acid may be hydrochloric acid, hydrobromic acid, nitric acid, acetic acid, carbonic acid, and sulfuric acid, but is not limited thereto.

The "acid" may be any acid such as strong acid or weak acid, for example, hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ), nitric acid (HNO ₃ ), acetic acid (CH ₃ COOH), carbonic acid (H ₂ CO ₃ ), hydrobromic acid (HBr), etc.

According to one embodiment of the present invention, a stream containing a compound of formula 1c below and a compound of formula 2 below, and a stream containing n -butyllithium are reacted to produce a first product of formula 3c below: The first step of preparing a compound; and a second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of Formula 4c below; And a third step of reacting the stream containing the second product and the stream containing the acid to produce a third product, a compound of formula 5c below. A method for synthesizing empagliflozin is provided, including:

[Formula 1c]

[Formula 2]

A first product represented by the following Chemical Formula 3c can be formed through a coupling reaction between Chemical Formula 1c and Chemical Formula 2 using n- butyllithium.

[Formula 3c]

The first product represented by Formula 3c may form a second product represented by Formula 4c below through a mesylation reaction.

[Formula 4c]

The second product represented by Formula 4c can form empagliflozin, the final product represented by Formula 5c, through a demesylation reaction.

[Formula 5c]

In the above equation,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

The empagliflozin synthesis method can be performed using a flow reactor.

Formula 1c may preferably be Formula 1c'.

[Formula 1c']

Formula 2 may preferably be Formula 2'.

[Formula 2']

The formula 3c may be preferably formula 3c'.

[Formula 3c']

The formula 4c may be preferably formula 4c'.

[Formula 4c']

The formula 5c may be preferably formula 5c'.

[Formula 5c']

According to one embodiment of the present invention, a stream containing a compound of formula 1a below and a compound of formula 2 below, and a stream containing n -butyllithium are reacted to produce a first product of formula 3a below: The first step of preparing a compound; and a second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of Formula 4a below; and a third step of reacting the stream containing the second product and the stream containing an acid to produce a third product, a compound of Formula 5a below.

[Formula 1a]

[Formula 2]

A first product represented by the following Chemical Formula 3a can be formed through a coupling reaction between Chemical Formula 1a and Chemical Formula 2 using n- butyllithium.

[Formula 3a]

The first product represented by Formula 3a may form a second product represented by Formula 4a below through a mesylation reaction.

[Formula 4a]

The second product represented by Formula 4a can form canagliflozin, the final product represented by Formula 5a below, through a demesylation reaction.

[Formula 5a]

In the above equation,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

The canagliflozin synthesis method may be performed using a flow reactor.

The formula (1a) may be preferably formula (1a').

[Formula 1a']

Formula 2 may preferably be Formula 2'.

[Formula 2']

The formula (3a) may be preferably formula (3a').

[Formula 3a']

The formula (4a) may be preferably formula (4a').

[Formula 4a']

Formula 5a may preferably be Formula 5a'.

[Formula 5a']

According to one embodiment of the present invention, a stream containing a compound of formula 1b below and a compound of formula 2 below, and a stream containing n -butyllithium are reacted to produce a first product of formula 3b below: The first step of preparing a compound; and a second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of Formula 4b below; And a third step of reacting the stream containing the second product and the stream containing the acid to produce a third product, a compound of Formula 5b below. A method for synthesizing dapagliflozin is provided, including a.

[Formula 1b]

[Formula 2]

A first product represented by the following Chemical Formula 3b can be formed through a coupling reaction between Chemical Formula 1b and Chemical Formula 2 using n- butyllithium.

[Formula 3b]

The first product represented by Formula 3b may form a second product represented by Formula 4b below through a mesylation reaction.

[Formula 4b]

The second product represented by Formula 4b can form dapagliflozin, the final product represented by Formula 5b below, through a demesylation reaction.

[Formula 5b]

In the above equation,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

The dapagliflozin synthesis method can be performed using a flow reactor.

Formula 1b may be preferably Formula 1b'.

[Formula 1b']

Formula 2 may preferably be Formula 2'.

[Formula 2']

Formula 3b may be preferably Formula 3b'.

[Formula 3b']

Formula 4b may be preferably Formula 4b'.

[Formula 4b']

Formula 5b may be preferably Formula 5b'.

[Formula 5b']

According to one embodiment of the present invention, a stream containing a compound of formula 1d and a compound of formula 2 below, and a stream containing n -Butyllithium are reacted to produce a first product of formula 3d below: The first step of preparing a compound; and a second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of formula 4d below; And a third step of reacting the stream containing the second product and the stream containing the acid to produce a third product, a compound of the formula 5d below. A method for synthesizing ipragliflozin is provided, including:

[Formula 1d]

[Formula 2]

A first product represented by the following Chemical Formula 3d can be formed through a coupling reaction between Chemical Formula 1d and Chemical Formula 2 using n- butyllithium.

[Formula 3d]

The first product represented by Formula 3d may form a second product represented by Formula 4d below through a mesylation reaction.

[Formula 4d]

The second product represented by Formula 4d can form ipragliflozin, the final product represented by Formula 5d below, through a demesylation reaction.

[Formula 5d]

In the above equation,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

The method for synthesizing ipragliflozin can be performed using a flow reactor.

The formula 1d may preferably be the formula 1d'.

[Formula 1d']

Formula 2 may preferably be Formula 2'.

[Formula 2']

The formula 3d may be preferably formula 3d'.

[Formula 3d']

The formula 4d may be preferably formula 4d'.

[Formula 4d']

The formula 5d may be preferably formula 5d'.

[Formula 5d']

According to one embodiment of the present invention, a stream containing a compound of formula 1e and a compound of formula 2 below, and a stream containing n -Butyllithium are reacted to produce a first product of formula 3e below: The first step of preparing a compound; and a second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of Formula 4e below; And a third step of reacting the stream containing the second product and the stream containing the acid to produce a third product, a compound of formula 5e below. A method for synthesizing luceogliflozin is provided, including a.

[Formula 1e]

[Formula 2]

A first product represented by the following Chemical Formula 3e can be formed through a coupling reaction between Chemical Formula 1e and Chemical Formula 2 using n- butyllithium.

[Formula 3e]

The first product represented by Formula 3e may form a second product represented by Formula 4e below through a mesylation reaction.

[Formula 4e]

The second product represented by Formula 4e can form luseogliflozin, the final product represented by Formula 5e below, through a demesylation reaction.

[Formula 5e]

In the above equation,

R ₁ is halogen,

Y ₁ is a sulfur atom,

X ₁ is a protecting group.

The luceogliflozin synthesis method can be performed using a flow reactor.

The formula 1e may be preferably formula 1e'.

[Formula 1e']

Formula 2 may preferably be Formula 2'.

[Formula 2']

The formula 3e may be preferably formula 3e'.

[Formula 3e']

Formula 4e may preferably be Formula 4e'.

[Formula 4e']

The formula 5e may be preferably formula 5e'.

[Formula 5e']

Experimental example: continuous process (flow reactor system)

n -Butyllithium ( n -BuLi) reaction and mesylation reaction

Referring to Figure 2, As the first step in the empagliflozin synthesis process, a coupling reaction using n -butyllithium ( n -BuLi) and a mesylation reaction using a mesylation reagent were performed.

In a continuous process system (flow reactor system), the coupling reaction using n -butyllithium was performed at -78°C, and the mesylation reaction using a mesylation reagent was performed at 25°C.

Experiment example Concet. (M) Temp.(℃) Flow (mL/min) HPLC(area%) RetentionTime(min) EM1(A) TMS-lactone ( B ) n -BuLi(C) MeSO ₂ Cl(D) P1(A+B) P2(C) P3(D) EM3-Ms One 0.5 0.6 1.6 concentration. -78℃, 25℃ 0.6 0.469 0.5 86% 18 2 0.1 0.1 0.2 concentration. -78℃, 25℃ 8.0 10.0 3.0 86% One

Deprotection reaction

In order to remove mesyl introduced to protect TMS (tetramethylsilane) and hydroxy residues, which are the protecting groups of TMS-lactone used as a raw material in the empagliflozin synthesis process, A deprotection reaction using acid is required.

Referring to Figure 3, the third product (EM3-Ms) obtained by a coupling reaction using n- butyllithium and a hydroxy group protection reaction using methanesulfonic acid chloride (MeSO ₂ Cl). A deprotection reaction using acid was performed.

Experimental Example 1

18.385 g of initial reactant (EM1) and 23.3435 g of TMS-lactone were taken, dissolved in 100 mL of THF (Tetrahydrofuran), and connected to pump 1. 1.6M n- butyllithium (in hexane) was connected to pump 2. Methanesulfonic acid chloride was connected to pump 3.

The reactor was made of 1/8 Sus material, had an internal capacity of 18ml and 3ml, and was immersed in a low temperature reactor at -78°C to maintain the temperature.

The flow rate of pump 1 was simultaneously started at 0.6 mL/min, the flow rate of pump 2 was 0.469 mL/min, and the flow rate of pump 3 was 0.5 mL/min.

After about 18 minutes, the product was formed, and after about 20 minutes, the product was collected, worked up with ethyl acetate and distilled water, and analyzed with high performance liquid chromatography. did.

As a result of analysis using High Performance Liquid Chromatography, the purity of Chemical Formula 4 (EM3-Ms) was confirmed to be approximately 86%, and the purity of Chemical Formula 2 was confirmed to be approximately 8%.

Experimental Example 2

3.677 g of the initial reactant (EM1) and 4.6687 g of TMS-lactone were taken, dissolved in 100 mL of THF (Tetrahydrofuran), and connected to pump 1. 1.6M n- butyllithium (in hexane) was connected to pump 2. Methanesulfonic acid chloride was connected to pump 3.

The reactor was made of 1/8 Sus material, had an internal capacity of 3ml and 1.8ml, and was immersed in a low temperature reactor at -78°C to maintain the temperature.

The flow rate of pump 1 was 8.0 mL/min, the flow rate of pump 2 was 10.0 mL/min, and the flow rate of pump 3 was started at 3.0 mL/min.

After about 1 minute, the product was formed, and after about 3 minutes, the product was collected, worked up with ethyl acetate and distilled water, and analyzed with high performance liquid chromatography. did.

As a result of analysis using High Performance Liquid Chromatography, the purity of Chemical Formula 4 (EM3-Ms) was confirmed to be approximately 86%, and the purity of Chemical Formula 2 was confirmed to be approximately 4%.

The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive. For example, each component described as unitary may be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.

The scope of the present invention is indicated by the claims described below, and all changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.

Claims (11)

A stream containing a compound selected from the group consisting of compounds of Formula 1a to 1e below, a stream containing a compound of Formula 2, and a stream containing n -Butyllithium are reacted to produce the first product, Formula 3a A first step of preparing the compound of any one of to 3e at a temperature of -70°C or lower; and
A second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of formulas 4a to 4e below; and
A method for synthesizing glyflozin comprising a third step of reacting a stream containing the second product and a stream containing an acid to produce a third product, a compound of any one of the following formulas 5a to 5e.
[Formula 1a]

[Formula 1b]

[Formula 1c]

[Formula 1d]

[Formula 1e]

[Formula 2]

[Formula 3a]

[Formula 3b]

[Formula 3c]

[Formula 3d]

[Formula 3e]

[Formula 4a]

[Formula 4b]

[Formula 4c]

[Formula 4d]

[Formula 4e]

[Formula 5a]

[Formula 5b]

[Formula 5c]

[Formula 5d]

[Formula 5e]

In the above equation,
R ₁ is halogen,
Y ₁ is an oxygen or sulfur atom,
X ₁ is a protecting group. According to paragraph 1,
A method of synthesizing glyflozin performed using a flow reactor. According to paragraph 1,
One of the group consisting of canagliflozin, dapagliflozin, empagliflozin, ipragliflozin and luseogliflozin The method of synthesizing glyflozin selected above. delete According to paragraph 1,
In the first step, the flow rate of the stream containing any one compound selected from the group consisting of compounds 1a to 1e and the compound of Formula 2 is 0.4 to 10 mL/min,
A method for synthesizing glyflozin wherein the flow rate of the stream containing n- butyllithium is 0.3 to 12 mL/min. According to paragraph 1,
The mesylation reagent is any one selected from the group consisting of methanesulfonic acid chloride (MeSO ₂ Cl), methanesulfonic acid bromide (MeSO ₂ Br), or methanesulfonic anhydride ((MeSO ₂ ) ₂ O). According to paragraph 1,
The second step is a method of synthesizing glyflozin performed at a temperature of 15 to 35°C. According to paragraph 1,
The flow rate of the stream containing the first product in the second step is 0.5 to 20 mL/min,
A method for synthesizing glyflozin, wherein the flow rate of the stream containing the mesylation reagent is 0.2 to 3.5 mL/min. According to clause 1,
In the third step, the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, acetic acid, carbonic acid, and sulfuric acid. The first product, a compound of Formula 3c, is prepared at a temperature of -70°C or lower by reacting a stream containing the compound of Formula 1c and the compound of Formula 2, and a stream containing n -Butyllithium. The first step is to do; and
A second step of reacting the stream containing the first product and the stream containing a mesylation reagent to produce a second product, a compound of formula 4c; and
A method for synthesizing empagliflozin comprising a third step of reacting a stream containing the second product and a stream containing an acid to produce a third product, a compound of formula 5c:
[Formula 1c]

[Formula 2]

[Formula 3c]

[Formula 4c]

[Formula 5c]

In the above equation,
R ₁ is halogen,
Y ₁ is an oxygen atom,
X ₁ is a protecting group. According to clause 10,
Empagliflozin synthesis method performed using a flow reactor.