KR20190129416A - A synthesis method of gliflozin using continuous process - Google Patents

Abstract

The present invention relates to a method for gliflozin synthesis, comprising the steps of: (a) preparing a first product by making a stream comprising an initial reactant and a lactone react with a stream comprising n-Butyllithium; and (b) making the stream comprising the first product react with a stream comprising p-toluenesulfonic acid (PTSA) to produce a second product.

Description

Glyflozin Synthesis Method Using Continuous Reaction Process {A SYNTHESIS METHOD OF GLIFLOZIN USING CONTINUOUS PROCESS}

The present invention relates to a method for synthesizing glyflozin, which is economically and environmentally friendly through a continuous reaction process.

Diabetes has problems with insulin secretion, such as decreased insulin secretion and resistance due to genetic and environmental causes, or abnormal function of insulin, causing glucose in the blood to not be transferred to and stored in the cells, resulting in too much blood in the blood. It is a metabolic disease that is much higher than normal.

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

Unlike type 1 diabetes, which is called pediatric diabetes, type 2 diabetes is caused by lack of exercise, obesity, or stress, which causes insulin secretion to be controlled smoothly, but when insulin fails to function properly, blood glucose control fails. (Stumvoll M, et al., Lancet 365: 1333-46 (2005)).

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

The diabetes treatment market grew rapidly from $ 32 billion worldwide in 2010, to W471.1 billion in Korea, to $ 70.7 billion worldwide in 2015, and 630 billion won in Korea, and is expected to continue to grow in the future.

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

When the SGLT-2 inhibitor inhibits the SGLT-2 transporter, the blood sugar released into the urine increases, thus lowering blood sugar and releasing calories retained by the blood sugar, resulting in weight loss.

Although DPP4 inhibitors account for the largest share in the diabetes treatment market, SGLT-2 inhibitors are insulin-independent compared to DPP4 inhibitors, so there is no fear of hypoglycemia and growth potential is high because they have weight loss effects.

Gliflozin, classified as a drug that inhibits SGLT-2, is currently in production and clinical trials, and can be obtained by invocana (canagliflozin), dapagliflozin, evidia (empagliflozin), and shingles ( ipragliflozin) is released in Korea.

The synthesis process of glyflozin involves a common reaction step, which involves the production of large amounts of waste acid (BF ₃ , Et ₃ SiH, MeSO ₃ H) and waste bases (DIPEA, pyridine), There is a problem of low efficiency.

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

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

According to one aspect of the invention, (a) reacting a stream comprising an initial reactant and a lactone, and a stream comprising n- butyllithium (n-Butyllithium) to prepare a first product; And (b) reacting the stream comprising the first product and the stream comprising p-toluenesulfonic acid (PTSA) to prepare a second product.

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

In one embodiment, the glyflozin is canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, ruseo One or more selected from the group consisting of luseogliflozin, ertugliflozin, and tofogliflozin, remogliflozin.

In one embodiment, the step (a) may be carried out at a temperature of -40 ℃ or more.

In one embodiment, the flow rate of the stream comprising the initial reactant and lactone in step (a) is 0.25 to 1.0 mL / min, the flow rate of the stream comprising n- butyllithium is 0.3 to 1.2 mL / min Can be.

In one embodiment, step (b) may be carried out at a temperature of 25 to 60 ℃.

In one embodiment, the flow rate of the stream comprising the first product in step (b) is 0.3 to 1.2 mL / min, the flow rate of the stream comprising p-toluenesulfonic acid is 0.25 to 1.0 mL / min Can be.

According to another aspect of the invention, (a) reacting a stream comprising a compound of formula (1) and a compound of formula (2), and a stream comprising n- butyllithium (n-Butyllithium) to prepare a first product step; And (b) reacting the stream comprising the first product and the stream comprising p-toluenesulfonic acid (PTSA) to prepare a second product. The empagliflozin synthesis method includes Is provided.

[Formula 1]

[Formula 2]

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

According to the present invention, the synthesis method can be carried out at a relatively high temperature compared to the conventional batch process, it is not only excellent economical efficiency can be significantly increased yield.

In addition, the synthesis method is environmentally friendly because the production of the flexible material according to the reaction is minimized, and the amount of the solvent used is reduced.

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

Figure 1 illustrates a continuous synthesis method of glyflozin according to an embodiment of the present invention.
2 is a schematic of n -BuLi reaction process in accordance with one embodiment of the present invention.
Figure 3 illustrates a deprotection reaction process according to an embodiment of the present invention.

As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.

Throughout the specification, when a part is "connected" to another part, it includes not only "directly connected" but also "indirectly connected" with another member in between. .

When a part is said to "include" a certain component, this means that it may further include other components, without excluding other components, unless specifically stated otherwise.

Unless defined otherwise 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 that include the terms included herein are well known and available in the art. While any methods and materials similar or equivalent to those described herein are found to be used in the practice or testing herein, some methods and materials have been described. Depending on the context used by those skilled in the art, the present invention is not limited to specific methodologies, protocols, and reagents, because it can be used in a variety of ways.

As used herein, the singular encompasses the plural objects unless the context clearly dictates otherwise. Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings.

According to one aspect of the invention, (a) reacting a stream comprising an initial reactant and a lactone, and a stream comprising n- butyllithium (n-Butyllithium) to prepare a first product; And (b) reacting the stream comprising the first product and the stream comprising p-toluenesulfonic acid (PTSA) to prepare a second product.

The glyflozin is canagliflozin, dapagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin ), Ertugliflozin, and tofogliflozin, tomogliflozin, and at least one selected from the group consisting of (remogliflozin), but is not limited thereto.

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

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

The reservoir may store the reactants before they are introduced into the reaction and discharge the reactants according to the user's manipulation.

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, may be present separately or integrated.

By adjusting the temperature, pressure and the time, flow rate and the like of the flow reactor can be adjusted the yield and impurity generation rate of the final product is formed.

The flow path may connect the reservoir, mixing or reaction portion of the system and move the reactants or products.

The step (a) may be carried out at a temperature of -40 ℃ or more.

The step (a) is an n- BuLi reaction, and in the case of a conventional batch process, the reactivity is low and low temperature (for example, −70 ° C.) is insufficient, and according to the glyflozin synthesis method of the present invention, Step a) is carried out at a temperature above -40 ° C., so that the process efficiency can be significantly improved.

In step (a), the flow rate of the stream including the initial reactant and the lactone may be 0.25 to 1.0 mL / min, and the flow rate of the stream including n- butyllithium may be 0.3 to 1.2 mL / min.

Step (b) may be carried out at a temperature of 25 to 60 ℃.

In step (b), the flow rate of the stream comprising the first product may be 0.3 to 1.2 mL / min, and the flow rate of the stream comprising p-toluenesulfonic acid may be 0.25 to 1.0 mL / min.

According to another aspect of the invention, (a) reacting a stream comprising a compound of formula (1) and a compound of formula (2), and a stream comprising n- butyllithium (n-Butyllithium) to prepare a first product step; And (b) reacting the stream comprising the first product and the stream comprising p -toluenesulfonic acid (PTSA) to produce a second product. The empagliflozin synthesis method includes Is provided.

[Formula 1]

[Formula 2]

The first product may be a compound of Formula 3 below.

[Formula 3]

The second product may be a compound of Formula 4 below.

[Formula 4]

The second product may form a third product by an acetylation reaction.

The third product may be a compound of Formula 5 below.

[Formula 5]

The third product may form an end product empagliflozin by deacetylation.

The empagliflozin may be a compound of Formula 6 below.

[Formula 6]

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

Hereinafter, the present invention will be described in more detail with reference to Examples.

Experimental Example  One : Batch  fair

In the batch type experiment, the reaction conditions were set with reference to Org. Lett. 2014, 16, 4090409.

In the lithiation and coupling reaction using n- butyllithium, the reaction initial temperatures were set differently and compared (Table 1).

The IPC purity of the reaction proceeded under the reaction conditions of -20 ° C and -50 ° C was 58.58% and 73.88%, respectively, showing lower reactivity than the reaction condition of -70 ° C (IPC purity: 83.77%).

In the reaction at -50 ° C, the unreacted aryl compound (RT 29min) remained after being quenched without lithiation, but was reacted at -20 ° C. (impurity) was formed.

division EM1 TMS- lactone n- Buli Temp Time IPC KNY-18045 5 g 1.2 Equiv 2 equiv -70 ℃ 2h 83.77% KNY-18050 1 g 1.2 Equiv 2 equiv -50 ℃ 2h 73.88% KNY-18050 1 g 1.2 Equiv 2 equiv -20 ℃ 2h 58.58%

The glyflozin synthesis method of the present invention achieved a higher yield at a higher temperature (-40 ° C) than the reaction conditions of the conventional batch process, and significantly improved the reaction process using a safe and economical flow chemistry.

Experimental Example  2: flow reactor system

n - Buli  reaction

2, As a first step of the empagliflozin synthesis process, a coupling reaction using n -butyllithium ( n- BuLi) was performed.

Coupling reactions with n -butyllithium were carried out at −40 ° C. in a flow reactor system.

division
( Expt . #) Concecet . (M) Temp.
(℃) Flow (mL / min) RT29
(EM1-H) RT32
(EM1) Remark EM1
(A) TMS- lactone
(B) n - Buli
(C) P1
(A + B) P2
(C) One 0.8 0.88 1.6 -40 ℃ 0.25 0.3 7.1% 81.3% NH₄Cl quench 2 0.8 0.88 1.6 -40 ℃ 0.5 0.6 6.6% 87.5% NH₄Cl quench 3 0.8 0.88 1.6 -40 ℃ 1.0 1.2 9.3% 80.5% NH₄Cl quench

Deprotection  reaction

An acid deprotection reaction is required to remove tetramethylsilane (TMS), a protecting group of TMS-lactone used as a raw material during empagliflozin synthesis.

Referring to FIG. 3, PTSA (p-Toluenesulfonic acid) was mixed with a first product (EM2 Mix.) Obtained by a coupling reaction using n- butyllithium to perform a deprotection reaction.

division
( Expt . #) Concecet . (M) Temp.
(℃) Flow (mL / min) Run-time
(min) RT16
(EM3) RT29
(EM1-H) RT32
(EM1) Remark EM2 Mix.
(A) PTSA
(B) P1
(A) P2
(B) One 0.242 0.726 25 ℃ 0.6 0.5 4 48.1% 20.5% 13.2% - 2 0.242 0.726 25-40 ℃ 0.6 0.5 4 42.7% 22.0% 13.7% 20 min 3 0.242 0.726 40 ℃ 0.6 0.5 4 42.1% 22.3% 14.0% - 4 0.242 0.726 40-60 ℃ 0.6 0.5 4 42.4% 22.0% 13.0% 20 min 5 0.242 0.726 60 ℃ 0.6 0.5 4 43.6% 21.6% 13.6% - 6 0.242 0.726 25 ℃ 0.3 0.25 8 43.6% 21.6% 13.6% - 7 0.242 0.726 25-40 ℃ 0.3 0.25 8 41.5% 22.2% 12.2% 20 min 8 0.242 0.726 40 ℃ 0.3 0.25 8 48.4% 20.0% 12.7% - 9 0.242 0.726 40-60 ℃ 0.3 0.25 8 42.5% 21.7% 13.4% 20 min 10 0.242 0.726 60 ℃ 0.3 0.25 8 46.5% 20.6% 13.8% - 11 0.242 0.726 25 ℃ 1.2 1.0 2 45.3% 21.0% 13.4% - 12 0.242 0.726 25-40 ℃ 1.2 1.0 2 42.1% 22.0% 13.8% 20 min 13 0.242 0.726 40 ℃ 1.2 1.0 2 44.1% 21.4% 13.6% - 14 0.242 0.726 40-60 ℃ 1.2 1.0 2 41.5% 22.1% 12.8% 20 min 15 0.242 0.726 60 ℃ 1.2 1.0 2 45.3% 21.0% 13.1% -

Example  One

13.3 g of the initial reaction (EM1) and 16.43 g of TMS-lactone were taken and dissolved in 40 mL of THF (Tetrahydrofuran) and connected to pump 1. 1.6M n- butyllithium (in hexane) was connected to the pump 2.

The reactor was Sus material having a diameter of 3.175 mm x length 4 m, a diameter of 1.5875 mm x length 1 m, and immersed in a low temperature reactor at −40 ° C. to maintain temperature.

Pump 1 started at 0.25 / 0.5 / 1.0 mL / min and pump 2 at 0.3 / 0.6 / 1.2 mL / min.

The product was formed after about 39/20/10 minutes, and the product was collected, work-up and analyzed from about 42/23/13 minutes.

Example  2

7.3 g of the first product (EM2 Mix.) Was taken, dissolved in 40 mL of methanol and connected to pump 1. 5.5 g of PTSA was taken up and dissolved in 40 mL of methanol and connected to Pump 2.

The reactor was Sus material of diameter 3.175mm x length 4m, diameter 1.5875mm x length 1m and soaked in a water bath at 25/40/60 ° C. to maintain temperature.

Pump 1 started at 0.3 mL / min and pump 2 at 0.25 mL / min.

After about 36 minutes, the product was formed. From about 39 minutes, the product was collected, work-up and analyzed.

Example  3

7.3 g of the first product (EM2 Mix.) Was taken, dissolved in 40 mL of methanol and connected to pump 1. PTSA was taken in 5.5 g and dissolved in 40 mL of methanol and connected to Pump 2.

The reactor was Sus material of 3.175mm diameter x 4m length, 1.5875mm diameter x 1m length and soaked in a 25/40/60 degree waterbath to maintain temperature.

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

After about 18 minutes, the product was formed. From about 21 minutes, the product was collected, work-up and analyzed.

Example  4

7.3 g of the first product (EM2 Mix.) Was taken, dissolved in 40 mL of methanol and connected to pump 1. PTSA was taken in 5.5 g and dissolved in 40 mL of methanol and connected to Pump 2.

The reactor was Sus material of 3.175 mm diameter x 4 m length, 1.5875 mm diameter x 1 m length, and the reactor was immersed in a water bath at 25/40/60 degrees to maintain temperature.

Pump 1 started at 1.2 ml / min and Pump 2 at 1.0 ml / min.

After about 9 minutes, the product was formed. From about 12 minutes, the product was collected, work-up and analyzed.

The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms 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 exemplary in all respects and not restrictive. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.

The scope of the invention is indicated by the following claims, and it should be construed that all changes or modifications derived from the meaning and scope of the claims and their equivalents are included in the scope of the invention.

Claims (9)

(a) the step of reacting a stream containing the stream, and n- butyl lithium (n-Butyllithium), including the initial reactants and the lactone to prepare a first product; And
(b) reacting the stream comprising the first product and the stream comprising p -toluenesulfonic acid (PTSA) to prepare a second product. The method of claim 1,
Glyflozin synthesis method carried out using a flow reactor. The method of claim 1,
Canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, ultogliflozin A method of synthesizing glyflozin, at least one selected from the group consisting of ertugliflozin, and tofogliflozin, remogliflozin. The method of claim 1,
The step (a) is glyflozin synthesis method carried out at a temperature of -40 ℃ or more. The method of claim 1,
In step (a), the flow rate of the stream comprising the initial reactant and the lactone is 0.25 to 1.0 mL / min,
And a flow rate of the stream comprising n- butyllithium is 0.3 to 1.2 mL / min. The method of claim 1,
The step (b) is a glyflozin synthesis method carried out at a temperature of 25 to 60 ℃. The method of claim 1,
In step (b), the flow rate of the stream comprising the first product is 0.3 to 1.2 mL / min,
And a flow rate of the stream comprising p -toluenesulfonic acid is 0.25 to 1.0 mL / min. (a) a step of reacting a stream containing the stream, and n- butyl lithium (n-Butyllithium) comprising a compound and a compound of formula 2 of the formula (1) producing a first product; And
(b) reacting the stream comprising the first product and the stream comprising p -toluenesulfonic acid (PTSA) to produce a second product; empagliflozin synthesis method comprising a.
[Formula 1]

[Formula 2]

The method of claim 8,
Empagliflozin synthesis method carried out using a flow reactor (flow reactor).

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