WO2021101003A1 - Method for synthesis of gliflozin by using methanesulfonylation intermediate in continuous reaction process - Google Patents

Abstract

The present invention relates to a method for synthesis of gliflozin and provides a synthesis method comprising: a first step of reacting a stream containing an initial reactant and a lactone with a stream containing n-butyllithium to prepare a first product; a second step of reacting a stream containing the first product with a stream containing a mesylation reagent to prepare a second product; and a third step of reacting a stream containing the second product with a stream containing an acid to prepare a third product.

Description

Method for synthesizing gliflozin using methanesulfonylated intermediates in a continuous reaction process

The present invention relates to a method for synthesizing gliflozin with improved economy and environment-friendliness through a continuous reaction process.

The present invention was made in accordance with the project number 10082393 under the support of the Ministry of Trade, Industry and Energy of the Republic of Korea. The research management institution for the project is "Korea Institute of Industrial Technology Evaluation", the name of the research project is "Industrial Technology Innovation Project", and the name of the research project is "[RCMS ]Development of eco-friendly process of SGLT-2 inhibitor through flow reaction (3/4)", the research period is "2017.10.01.-2020.06.30".

This patent application claims priority to Korean Patent Application No. 10-2019-0150985 filed with the Korean Intellectual Property Office on November 22, 2019, and the disclosure of the patent application is incorporated herein by reference.

In diabetes, due to genetic and environmental causes, there is a problem in the secretion of insulin such as decreased insulin secretion and resistance, or an abnormal function of insulin occurs, so that glucose in the blood cannot be delivered and stored to the cells, and the blood sugar level becomes too high. It is a metabolic disease that is much higher than that of a normal person.

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

Unlike type 1 diabetes, which is called childhood diabetes, type 2 diabetes is an acquired factor due to lack of exercise, obesity, or stress, and it occurs when insulin secretion is smoothly controlled, but blood sugar control fails because insulin does not function properly. (Stumvoll M, et al., Lancet 365:1333-46(2005)).

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

The diabetes treatment market rapidly increased from $32 billion worldwide in 2010 and KRW 449.1 billion in Korea to $70.7 billion worldwide in 2015 and KRW 630 billion in Korea, and is expected to continue to grow in the future.

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

When the SGLT-2 inhibitor inhibits the SGLT-2 transporter, the blood sugar excreted in the urine increases, so the blood sugar decreases and the calories held by the blood sugar are excreted, resulting in a weight loss effect.

Although DPP4 inhibitors occupy the highest proportion in the diabetes treatment market, SGLT-2 inhibitors are insulin-independent compared to DPP4 inhibitors, so there is no fear of hypoglycemia and has a weight reduction effect, so its growth potential is high.

Glyflozin, which is classified as a drug that inhibits SGLT-2, is commercially available and clinically in progress, and invocana (canagliflozin), posiga (dapagliflozin), jadian (empagliflozin), and Suglet ( ipragliflozin), etc. are released in Korea.

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

In order to solve the problem of the synthesis process of gliflozin, the present inventors have derived a method for synthesizing gliflozin based on a continuous reaction process that is not only excellent in process efficiency, but also advantageous in terms of environment.

The present invention is to solve the problems of the prior art described above, and an object of the present invention is to provide a method for synthesizing gliflozin which is eco-friendly and economical.

According to an aspect of the invention, to react the any one of the compound and a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound of formula (II) selected from the group consisting of compounds of formula 1a to 1e A first step of preparing a compound of any one of the following formulas 3a to 3e, which is a first product; And a second step of reacting the stream containing the first product and the stream containing the mesylation reagent to produce a second product, a compound of any one of the following Chemical Formulas 4a to 4e; And a third step of reacting a stream containing the second product and a stream containing an acid to prepare 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]

[Chemical 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 formula,

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 gliflozin may be performed using a flow reactor.

In one embodiment, the gliflozin is canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and luseo 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 less.

In one embodiment, the flow rate of the stream containing any one compound selected from the group consisting of compounds of 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 _{chloromethanesulfonic acid (MeSO 2} Cl), bromide methanesulfonic acid (MeSO ₂ Br), or methanesulfonic anhydride ((MeSO ₂ ) _{2 O).} .

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

In one embodiment, in the second step, the flow rate of the stream containing the first product 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 invention, to to a first product by reacting a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound of formula 2 and a compound of formula 1c of the compound of formula 3c A first step of manufacturing; And a second step of reacting the stream containing the first product and the stream containing the mesylation reagent to prepare a second product of the compound of Formula 4c; And a third step of reacting the stream containing the second product and the stream containing the acid to prepare a third product of the compound represented by the following formula (5c).

[Formula 1c]

[Formula 2]

[Formula 3c]

[Formula 4c]

[Formula 5c]

In the above formula,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

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

According to the present invention, the synthesis method is not only excellent in economic efficiency, but also the yield can be remarkably increased.

In addition, the synthesis method is eco-friendly because the generation of related substances according to the reaction is minimized and the amount of solvent used is reduced.

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

1 is a schematic diagram of a method for synthesizing gliflozin in a continuous manner according to an embodiment of the present invention.

2 is a schematic diagram of an n- butyllithium ( n- BuLi) reaction process and a mesylation reaction according to an embodiment of the present invention.

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 accompanying 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 "includes" a certain component, this means that other components may be further provided, rather than excluding 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 one of ordinary skill in the art.

Various scientific dictionaries including terms included herein are well known and available in the art. Although any methods and materials similar or equivalent to those described herein are found to be used in the practice or testing herein, several methods and materials have been described. The present invention is not limited to specific methodologies, protocols and reagents, since it can be used in a variety of ways, depending on the context of use by those skilled in the art.

According to an aspect of the invention, to the reaction stream containing the stream, and n- butyl lithium (n- Butyllithium), including any of the compounds and the compounds of formula (II) selected from the group consisting of compounds of formula 1a to 1e A first step of preparing a compound of any one of the following formulas 3a to 3e, which is a first product; And a second step of reacting the stream containing the first product and the stream containing the mesylation reagent to produce a second product, a compound of any one of the following Chemical Formulas 4a to 4e; And a third step of reacting a stream containing the second product and a stream containing an acid to prepare 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]

[Chemical 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 formula,

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, or the like.

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 the compound. The protecting group is selected to release or re-modify the substituent, thereby producing the desired unprotected group. Hydroxy-protecting groups for protecting the hydroxyl group are 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 (eg, trimethylsilyl; TMS), and the like.

The gliflozin is canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and luseogliflozin. ) May be selected from the group consisting of, but is not limited thereto.

The method for synthesizing gliflozin may be performed using a flow reactor. The method for synthesizing gliflozin using the flow reactor has not only remarkably excellent yield but also excellent safety compared to the conventional batch process, and the final product can be efficiently synthesized by precisely controlling the temperature and flow rate.

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

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

The temperature and pressure of the flow reactor, the time at which the reactants are allowed to stand, and the flow rate may be adjusted to control the yield of the final product and the generation rate of impurities.

The flow path may connect a storage unit, a mixing unit, or a reaction unit of the system, and may move a reactant or a product.

The first step may be performed at a temperature of -70°C or less, preferably -75°C or less, 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 the compounds of 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 Preferably 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/ can be min.

The mesylation reagent may be _{any one selected from the group consisting of chloromethanesulfonic acid (MeSO 2} Cl), brominated methanesulfonic acid (MeSO ₂ Br), or methanesulfonic 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 mesylation reagents include methanesulfonic anhydride ((MeSO ₂ ) ₂ O), and methanesulfonic acid halides including chloromethanesulfonic acid (MeSO ₂ Cl), brominated methanesulfonic acid (MeSO ₂ Br), and the like. Most preferably, it may be chlorinated methanesulfonic acid (MeSO ₂ Cl).

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

In the second step, the flow rate of the stream containing the first product 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, 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 use 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 ) and hydrobromic acid (HBr).

According to one embodiment of the invention, reacting a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound and a compound of formula (II) of formula 1c of claim 1 to the product formula 3c A first step of preparing a compound; And a second step of reacting the stream containing the first product and the stream containing the mesylation reagent to prepare a second product of the compound of Formula 4c; And a third step of reacting a stream containing the second product and a stream containing an acid to prepare a third product of the compound represented by the following formula (5c).

[Formula 1c]

[Formula 2]

The first product represented by the following Formula 3c may be formed by a coupling reaction of Formula 1c and Formula 2 using n-butyllithium.

[Formula 3c]

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

[Formula 4c]

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

[Formula 5c]

In the above formula,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

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

Formula 1c may be, preferably, Formula 1c'.

[Formula 1c']

Formula 2 may be, preferably, Formula 2'.

[Formula 2']

The Chemical Formula 3c may be preferably Chemical Formula 3c'.

[Formula 3c']

Formula 4c may be, preferably, Formula 4c'.

[Formula 4c']

The Chemical Formula 5c may be preferably Chemical Formula 5c'.

[Formula 5c']

According to one embodiment of the invention, reacting a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound and a compound of formula (II) of the formula (1a) of the formula (3a) to first product A first step of preparing a compound; And a second step of reacting a stream containing the first product and a stream containing a mesylation reagent to prepare a second product of the compound of Formula 4a; And a third step of reacting the stream containing the second product and the stream containing the acid to prepare a third product of the compound of Formula 5a.

[Formula 1a]

[Formula 2]

The first product represented by the following Formula 3a may be formed by a coupling reaction of Formula 1a and Formula 2 using n-butyllithium.

[Formula 3a]

The first product represented by Formula 3a may form a second product represented by the following Formula 4a by a mesylation reaction.

[Formula 4a]

The second product represented by Formula 4a may form canagliflozin, a final product represented by Formula 5a, by a demesylation reaction.

[Formula 5a]

In the above formula,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

The method for synthesizing cannagliflozin may be performed using a flow reactor.

Formula 1a may be, preferably, Formula 1a'.

[Formula 1a']

Formula 2 may be, preferably, Formula 2'.

[Formula 2']

Formula 3a may be, preferably, Formula 3a'.

[Formula 3a']

Formula 4a may be, preferably, Formula 4a'.

[Formula 4a']

Formula 5a may be, preferably, Formula 5a'.

[Formula 5a']

According to one embodiment of the invention, reacting a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound and a compound of formula (II) of formula 1b of the formula 3b to a first product A first step of preparing a compound; And a second step of reacting the stream including the first product and the stream including the mesylation reagent to prepare a second product of the compound of Formula 4b; And a third step of reacting a stream containing the second product and a stream containing an acid to prepare a third product of the compound of Formula 5b below.

[Formula 1b]

[Formula 2]

The first product represented by the following Formula 3b may be formed by a coupling reaction of Formula 1b and Formula 2 using n-butyllithium.

[Formula 3b]

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

[Formula 4b]

The second product represented by Formula 4b may form dapagliflozin, which is the final product represented by Formula 5b, by a demesylation reaction.

[Formula 5b]

In the above formula,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

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

Formula 1b may be, preferably, Formula 1b'.

[Formula 1b']

Formula 2 may be, preferably, 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 invention, to compounds of formula 1d and to the stream containing the compound of formula (2), and n- butyl lithium to the first product stream by reacting a formula 3d including the (n-Butyllithium) A first step of preparing a compound; And a second step of reacting the stream containing the first product and the stream containing the mesylation reagent to prepare a second product of the compound of Formula 4d below. And a third step of reacting the stream containing the second product and the stream containing the acid to prepare a third product of the compound of Formula 5d below.

[Formula 1d]

[Formula 2]

The first product represented by the following Chemical Formula 3d may be formed by a coupling reaction of Chemical Formula 1d and Chemical Formula 2 using n-butyllithium.

[Chemical Formula 3d]

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

[Formula 4d]

The second product represented by Formula 4d may form ipragliflozin, which is the final product represented by Formula 5d, by a demesylation reaction.

[Formula 5d]

In the above formula,

R ₁ is halogen,

Y ₁ is an oxygen atom,

X ₁ is a protecting group.

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

Formula 1d may be, preferably, Formula 1d'.

[Formula 1d']

Formula 2 may be, preferably, Formula 2'.

[Formula 2']

Formula 3d may be, preferably, Formula 3d'.

[Chemical Formula 3d']

Formula 4d may be, preferably, Formula 4d'.

[Formula 4d']

Formula 5d may be, preferably, Formula 5d'.

[Formula 5d']

According to one embodiment of the invention, reacting a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound and a compound of formula 2 of the formula 1e of claim 1 to the product formula 3e A first step of preparing a compound; And a second step of reacting the stream including the first product and the stream including the mesylation reagent to prepare a second product of the compound of Formula 4e; And a third step of reacting the stream containing the second product and the stream containing the acid to prepare a third product of the compound represented by the following formula (5e).

[Formula 1e]

[Formula 2]

The first product represented by the following Formula 3e may be formed by a coupling reaction of Formula 1e and Formula 2 using n-butyl lithium.

[Formula 3e]

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

[Formula 4e]

The second product represented by Formula 4e may form luseogliflozin, which is the final product represented by Formula 5e, by a demesylation reaction.

[Formula 5e]

In the above formula,

R ₁ is halogen,

Y ₁ is a sulfur atom,

X ₁ is a protecting group.

The method for synthesizing luceogliflozin may be performed using a flow reactor.

Formula 1e may be preferably Formula 1e'.

[Formula 1e']

Formula 2 may be, preferably, Formula 2'.

[Formula 2']

The Chemical Formula 3e may be preferably Chemical Formula 3e'.

[Chemical Formula 3e']

Formula 4e may be preferably Formula 4e'.

[Formula 4e']

Formula 5e may be preferably Formula 5e'.

[Formula 5e']

Experimental example: flow reactor system

n -Butyl lithium ( n -BuLi) reaction and mesylation reaction

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

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

Experimental 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	concent.	-78℃, 25℃	0.6	0.469	0.5	86%	18
2	0.1	0.1	0.2	concent.	-78℃, 25℃	8.0	10.0	3.0	86%	One

Deprotection reaction

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

3, a third product (EM3-Ms) obtained by a coupling reaction using n- _{butyllithium and a hydroxy group protection reaction using chloromethanesulfonic acid (MeSO 2 Cl)} A deprotection reaction using an acid was performed.

Experimental Example 1

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

The reactor was made of 1/8 Sus, the internal capacity was 18ml, 3ml, and the temperature was maintained by immersing in a low temperature reactor at -78℃.

The flow rate of pump 1 was 0.6 mL/min, the flow rate of pump 2 was 0.469 mL/min, and the flow rate of pump 3 was started simultaneously at 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 by High Performance Liquid Chromatography. I did.

As a result of analysis by High Performance Liquid Chromatography, it was confirmed that the purity of Formula 4 (EM3-Ms) was about 86% and that of Formula 2 was about 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 the pump 2. Chloride methanesulfonic acid was connected to pump 3.

The reactor was made of 1/8 Sus, and the internal capacity was 3ml and 1.8ml, and the temperature was maintained by immersing in a low temperature reactor at -78℃.

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

The product was formed after about 1 minute, and after about 3 minutes, the product was collected, worked-up with ethyl acetate and distilled water, and analyzed by High Performance Liquid Chromatography. I did.

As a result of analysis by High Performance Liquid Chromatography, it was confirmed that the purity of Formula 4 (EM3-Ms) was about 86% and that of Formula 2 was about 4%.

The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that other specific forms can be easily modified without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative and non-limiting in all respects. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as being distributed may also be implemented in a combined form.

The scope of the present invention is indicated by the claims to be described later, and all changes or modified forms derived from the meaning and scope of the claims and the concept of equivalents thereof should be construed as being included in the scope of the present invention.

Claims (11)

1. Order of reacting any one of the compound and a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound of formula (II) selected from the group consisting of compounds of formula 1a to 1e first product formula (3a) A first step of preparing a compound of any one of to 3e; And

   A second step of reacting the stream containing the first product and the stream containing the 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 prepare a third product, a compound of any one of the following Formulas 5a to 5e; and a method for synthesizing gliflozin comprising.

   [Formula 1a]

   

   [Formula 1b]

   

   [Formula 1c]

   

   [Formula 1d]

   

   [Formula 1e]

   

   [Formula 2]

   

   [Formula 3a]

   

   [Formula 3b]

   

   [Formula 3c]

   

   [Chemical 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 formula,

   R ₁ is halogen,

   Y ₁ is an oxygen or sulfur atom,

   X ₁ is a protecting group.
2. The method of claim 1,

   A method for synthesizing gliflozin performed using a flow reactor.
3. The method of claim 1,

   One from the group consisting of canagliflozin, dapagliflozin, empagliflozin, ipragliflozin and luseogliflozin The gliflozin synthesis method selected above.
4. The method of claim 1,

   The first step is a method for synthesizing gliflozin performed at a temperature of -70°C or less.
5. The method of claim 1,

   In the first step, the flow rate of the stream containing any one compound selected from the group consisting of compounds of 1a to 1e and the compound of formula 2 is 0.4 to 10 mL/min,

   The flow rate of the stream containing n- butyllithium is 0.3 to 12 mL/min gliflozin synthesis method.
6. The method of claim 1,

   The mesylation reagent is any one selected from the group consisting of chlorinated methanesulfonic acid (MeSO ₂ Cl), brominated methanesulfonic acid (MeSO ₂ Br), or methanesulfonic anhydride ((MeSO ₂ ) _{2 O).}
7. The method of claim 1,

   The second step is a method for synthesizing gliflozin performed at a temperature of 15 to 35°C.
8. The method of claim 1,

   The flow rate of the stream containing the first product in the second step is 0.5 to 20 mL/min,

   The flow rate of the stream containing the mesylation reagent is 0.2 to 3.5 mL / min gliflozin synthesis method.
9. The method of claim 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.
10. To the first step for preparing a compound of Formula 3c to a first product by reacting a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound of formula 2 and a compound of formula 1c; And

    A second step of reacting the stream including the first product and the stream including the mesylation reagent to prepare a second product of the compound of Formula 4c; And

    A third step of reacting a stream containing the second product and a stream containing an acid to prepare a third product of the compound represented by the following formula (5c); empagliflozin synthesis method comprising:

    [Formula 1c]

    

    [Formula 2]

    

    [Formula 3c]

    

    [Formula 4c]

    

    [Formula 5c]

    

    In the above formula,

    R ₁ is halogen,

    Y ₁ is an oxygen atom,

    X ₁ is a protecting group.
11. The method of claim 10,

    Empagliflozin synthesis method carried out using a flow reactor (flow reactor).

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