CN114380775A - A kind of empagliflozin intermediate and preparation method thereof - Google Patents

Abstract

The present invention relates to an intermediate of empagliflozin. The present invention also relates to a method for preparing empagliflozin and its intermediates. It belongs to the technical field of medicinal chemistry. The preparation method of the empagliflozin intermediate of the present invention is to react the compound of formula VI with an organometallic reagent to obtain the compound of formula V; the compound of formula V is coupled with the compound of formula IV, and then treated with an acidic aqueous solution to obtain the compound of formula III. The preparation method of empagliflozin provided by the invention is a new preparation method of empagliflozin with short synthesis steps, simple and convenient operation, good intermediate purity, easy quality control and suitable for industrial production.

Description

A kind of empagliflozin intermediate and preparation method thereof

technical field

The invention belongs to the technical field of medicinal chemistry, and in particular relates to an intermediate of empagliflozin and a method for preparing empagliflozin and the intermediate thereof.

Background technique

Empagliflozin is a new sodium-glucose cotransporter 2 (SGLT2) inhibitor drug that specifically inhibits the reabsorption of glucose by the kidneys, allowing more sugar to be excreted through the patient's urine, thereby lowering the patient's blood sugar. Chemical name of empagliflozin: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl ) phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, the molecular formula is C ₂₃ H ₂₇ ClO ₇ , the molecular weight is 450.91, and the structural formula is as follows:

In addition to lowering blood sugar in patients, the FDA approved a new indication for Jardiance (empagliflozin) to reduce the risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease.

Regarding the preparation method of empagliflozin in the prior art, there are multiple synthetic routes:

Chinese published patent document CN102549005A has reported the following synthetic route:

The compound of formula II of this route is prepared by a one-pot reaction, and the compound of formula II is difficult to be crystallized and purified, its purity is low, and it is difficult to carry out quality control, and it is not suitable for industrial production.

Chinese published patent document CN103524468A has reported the following synthetic route:

In this route, an acetylation protection step is added, and the compound of formula VIII is crystallized and purified to improve the purity of the intermediate, but the operation is complicated and the yield is low due to the prolongation of the reaction step.

In order to meet the ever-expanding production demands of empagliflozin APIs and preparations, it is still necessary to develop empagliflozin preparation methods that are more suitable for industrialization and easier for quality control.

SUMMARY OF THE INVENTION

The purpose of the present invention is to aim at the deficiencies of the prior art, to provide a new intermediate for the production of empagliflozin, the intermediate has good purity and can shorten the steps of production of empagliflozin.

Another object of the present invention is to provide a preparation method for producing empagliflozin and its intermediates with short steps, simple operation, easy quality control, and suitable for industrialization.

The object of the present invention is achieved through the following technical solutions. The present invention discloses a new intermediate of empagliflozin, namely the compound of formula III:

The present invention also discloses the preparation method of the above-mentioned empagliflozin intermediate, the steps of which are:

(1) after the compound of formula VI reacts with the organometallic reagent, the compound of formula V is obtained;

(2) The compound of formula V is coupled with the compound of formula IV, and then treated with an acidic aqueous solution to obtain the compound of formula III.

The preparation method route of the empagliflozin intermediate of the present invention is as follows:

In the above formula:

X is halogen; preferably X is I or Br;

M is metal Li or MgCl;

R is a hydroxyl protecting group.

In the preparation method of above-mentioned empagliflozin intermediate:

The compound of formula V is prepared by the compound of formula IV through halogen-metal exchange reaction; the organometallic reagent is preferably an organometallic lithium reagent or a Grignard reagent; the molar ratio of the compound of formula VI to the organometallic reagent is preferably 1:0.9 ~1.5; the organometallic reagent is selected from n-butyllithium, n-hexyllithium, methyllithium, tert-butyllithium, isopropylmagnesium chloride, isopropylmagnesium chloride-lithium chloride complex, sec-butylmagnesium chloride- One or more combinations of lithium chloride complexes, particularly preferred are n-butyllithium, isopropylmagnesium chloride-lithium chloride complexes.

Preferably, between -80°C and 30°C, more preferably between -80°C and -10°C, the compound of formula IV is dissolved in an inert solvent or a mixture thereof and added to the compound of formula V or its derivative. In an inert solution, the coupling product is then subjected to acidic aqueous solution to remove the hydroxy protecting group and form a compound of formula III. The inert solvent is selected from tetrahydrofuran or the composition of tetrahydrofuran and toluene, preferably the composition of tetrahydrofuran and toluene; the acid is selected from one or more combinations of hydrochloric acid, sulfuric acid, methanesulfonic acid, and trifluoroacetic acid, especially Trifluoroacetic acid is preferred.

All of the above reactions are carried out under an inert atmosphere, preferably argon or nitrogen.

The present invention also provides a new method for preparing empagliflozin, which specifically comprises the following steps:

(1) after the compound of formula VI reacts with the organometallic reagent, the compound of formula V is obtained, the compound of formula V is coupled with the compound of formula IV, and then treated with an acidic aqueous solution to obtain the compound of formula III;

(2) the compound of formula III reacts with methanol in the presence of an acid to obtain the compound of formula II;

(3) The compound of formula II is reduced to obtain empagliflozin:

Preferably, in step (2), the acid is selected from one or a combination of hydrochloric acid, sulfuric acid, methanesulfonic acid, and trifluoroacetic acid, preferably hydrochloric acid.

Preferably, in step (3), the reducing agent is triethylsilane; the Lewis acid is aluminum trichloride or boron trifluoride ether, preferably aluminum trichloride; the solvent used is selected from acetonitrile or acetonitrile and The dichloromethane composition, preferably the acetonitrile to dichloromethane composition, more preferably the acetonitrile to dichloromethane volume ratio is 1:2.

Step (3) after the reduction reaction finishes, the following post-processing can also be carried out: dropwise addition of water to quench the reaction liquid separation, after the organic phase is concentrated, the crude product of the compound of formula I can be obtained by beating with dichloromethane, and the crude product of empagliflozin can be further reconstituted. Crystallization and purification.

Compared with the prior art, the present invention has the following beneficial effects: short synthesis route, convenient post-processing operation, good intermediate purity, easy quality control, and suitability for industrial production.

Detailed ways

The following examples further illustrate the technical solutions of the present invention. It should be understood that they should not be construed as limiting the scope of the present invention, but are merely exemplary illustrations and typical representations of the present invention. Several variants and improvements. These all belong to the protection scope of the present invention. The present invention will be specifically described below with reference to the embodiments, but the content of the present invention is not limited to the specific embodiments.

Example 1: Empagliflozin Intermediate Compound of Formula III (2R,3S,4R,5R)-1-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy) Benzyl)phenyl)-2,3,4,5,6-pentahydroxyhexyl-1-one preparation experiment one:

Add 23L of tetrahydrofuran, 230mL of toluene and 2.3kg of (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran to the 100L reaction kettle, stir to dissolve clear, nitrogen protection, cool down to - 80～-70 ℃, 3L of n-butyllithium solution (2.5M n-hexane solution) was added dropwise, and the temperature control reaction was completed for 1h. Under the temperature of -80～-70℃, add dropwise a mixed solution of 3.2kg 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone and 11.5L toluene. After reaction 1h. A mixture of 1.1kg trifluoroacetic acid and 2.3L water was added, and after the addition was raised to room temperature and stirred for 2 hours, the stirring was stopped. After standing, the solution was layered, the lower layer was separated, and concentrated to obtain 2.19kg of the compound of formula III with HPLC purity of 95.31%. . MS (m/z): 489.9023 [M+Na]. ¹ H NMR (500 MHz, (CD ₃ ) ₂ CO): δ = 7.70 (s, 1H), 7.49 (dt, 1H), 7.29 (dd, 1H), 7.10 (dd, 2H), 6.77 (dd, 2H) ,5.86(s,1H),4.94-4.96(m,1H),4.71-4.74(m,lH),4.30-4.31(m,lH),3.92-4.02(m,2H),3.86-3.89(m, 2H),3.71-83(d,2H),3.51-3.59(m,lH),3.42(s,2H),3.26-3.27(d,lH),3.19-3.23(m,lH),2.13-2.22( m,lH),1.92-1.98(m,lH). ¹³ C NMR (125MHz, (CD ₃ ) ₂ CO): δ=197.35, 155.90, 143.10, 137.60, 132.95, 131.85, 130.17, 129.86, 128.44, 126.73, 114.96, 97.91, 77.08, 75.0, 4, 73.8, 31 66.69, 61.73, 38.25, 32.81.

HPLC detection conditions are as follows:

Chromatographic column: Omni Bond Orca C8 (150*4.6mm, 5μm)

Mobile phase A: 005% trifluoroacetic acid aqueous solution;

Mobile phase B: 0.045% trifluoroacetic acid in acetonitrile

Column temperature: 40℃; Detection wavelength: 224nm: Injection volume 20μL

Elution gradient and flow rate:

time (minutes) Flow rate (mL/min) Mobile phase A (%) Mobile phase B (%) 0 1.5 70 30 10 1.5 70 30 12 1.5 44 56 twenty two 1.5 35 65 25 2.0 5 95 28 1.5 70 30 30 1.5 70 30

Example 2: Empagliflozin Intermediate Compound of Formula III (2R,3S,4R,5R)-1-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy) Benzyl)phenyl)-2,3,4,5,6-pentahydroxyhexyl-1-one preparation experiment 2:

Add 23L of tetrahydrofuran, 230mL of toluene and 2.3kg of (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran to the 100L reactor, stir to dissolve clear, nitrogen protection, cool down to - 30～-20 ℃, add 4.4L isopropylmagnesium chloride-lithium chloride (1.3M tetrahydrofuran solution) dropwise, and complete the temperature control reaction for 1h. Maintain the temperature at -30～-20℃, add dropwise the mixed solution of 3.2kg 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone and 11.5L toluene, after dropping Reaction for 1h. A mixture of 1.1kg trifluoroacetic acid and 2.3L water was added, and after the addition was raised to room temperature and stirred for 2 hours, the stirring was stopped. After standing, the solution was layered, the lower layer was separated, and concentrated to obtain 2.03kg of the compound of formula III, with a HPLC purity of 92.72%. .

HPLC detection conditions are as follows:

Chromatographic column: Omni Bond Orca C8 (150*4.6mm, 5μm)

Mobile phase A: 005% trifluoroacetic acid aqueous solution;

Mobile phase B: 0.045% trifluoroacetic acid in acetonitrile

Column temperature: 40℃; Detection wavelength: 224nm: Injection volume 20μL

Elution gradient and flow rate:

time (minutes) Flow rate (mL/min) Mobile phase A (%) Mobile phase B (%) 0 1.5 70 30 10 1.5 70 30 12 1.5 44 56 twenty two 1.5 35 65 25 2.0 5 95 28 1.5 70 30 30 1.5 70 30

Example 3: Compound of Formula II (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl )-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol preparation experiment

10L of methanol was added to the 100L reaction kettle, 2kg of the compound of formula III obtained in Example 1 was added, and 3.13kg of methanesulfonic acid was added dropwise under stirring. 20 L of dichloromethane was added, and after stirring, the mixture was allowed to stand for liquid separation, the organic phase was separated, and the aqueous phase was extracted with 10 L of dichloromethane. The organic phases were combined and washed with 10 L of water. The organic phase was transferred to a 50L reaction kettle, concentrated to dryness under reduced pressure, added 7L of acetonitrile, stirred and dissolved to obtain an acetonitrile solution of the compound of formula I and formula V. According to HPLC, the relative area of the compound of formula II was 92.45%.

Example 4: Compound of formula I Empagliflozin (1S)-1,5-anhydro-1-(4-chloro-3-[4-[(3S)-tetrahydrofuran-3yloxy]benzyl]phenyl )-D-glucitol preparation experiment one:

7L of acetonitrile, 7L of dichloromethane and 1.9kg of triethylsilane were added to the 100L reactor, the temperature was controlled not to exceed 30°C, and 2.2kg of aluminum trichloride was added to the reactor in batches. After the addition, the acetonitrile solution of the compound of formula II obtained in Example 3 was added to the reaction system under the condition of not exceeding 30° C., the addition was completed, and the reaction was stirred at room temperature.

After the reaction was completed, water was added to quench, and after standing, the solution was separated, the organic phase was separated, and the solvent was evaporated by concentration under reduced pressure. Add dichloromethane to make pulp, filter and vacuum dry to obtain 1.04kg of crude empagliflozin, the yield is 53.9%, and the HPLC purity is 98.05%.

The crude empagliflozin was recrystallized from toluene-ethyl acetate to obtain pure empagliflozin with HPLC purity of 99.79%.

Example 5: Compound of formula I Empagliflozin (1S)-1,5-anhydro-1-(4-chloro-3-[4-[(3S)-tetrahydrofuran-3yloxy]benzyl]phenyl )-D-glucitol preparation experiment two:

7L of acetonitrile, 7L of dichloromethane and 1.9kg of triethylsilane were added to the 100L reactor, the temperature was controlled not to exceed 30°C, and 3.88kg of boron trifluoride ether was added to the reactor in batches. After the addition, the acetonitrile solution of the compound of formula II obtained in Example 3 was added to the reaction system under the condition of not exceeding 30° C., the addition was completed, and the reaction was stirred at room temperature.

After the reaction was completed, water was added to quench, and after standing, the solution was separated, the organic phase was separated, and the solvent was evaporated by concentration under reduced pressure. Add dichloromethane to make slurry, filter and vacuum dry to obtain 1.21 kg of crude empagliflozin, the yield is 62.7%, and the HPLC purity is 98.34%.

The crude empagliflozin was recrystallized from toluene-ethyl acetate to obtain pure empagliflozin with HPLC purity of 99.82%.

The above are only examples of the embodiments of the present invention. It should be pointed out that for those skilled in the art, the empagliflozin intermediate described in the present invention will not be deviated from the content, spirit and scope of the present invention. Changes or appropriate changes and combinations of the preparation method of the body and empagliflozin to achieve the technology of the present invention, all similar improvements and modifications are obvious to those skilled in the art, and these improvements and modifications are deemed to be included in the within the content, spirit and scope of the present invention.

Claims (10)

1. an intermediate of empagliflozin, is characterized in that, this intermediate is the compound shown in following formula III structure:

2. a preparation method of empagliflozin intermediate as claimed in claim 1, is characterized in that, its step is: (1) after the compound of formula VI reacts with the organometallic reagent, the compound of formula V is obtained; (2) the compound of formula V is coupled with the compound of formula IV, and then treated with an acidic aqueous solution to obtain the compound of formula III;

where: X is halogen; M is metal Li or MgCl; R is a hydroxyl protecting group. 3. preparation method according to claim 2 is characterized in that: in formula, X is I or Br. 4 . The preparation method according to claim 2 , wherein the organometallic reagent is an organometallic lithium reagent or a Grignard reagent; and the molar ratio of the compound of formula VI to the organometallic reagent is 1:1.0-1.5. 5 . 5. preparation method according to claim 2 or 4 is characterized in that: described organometallic reagent is selected from n-butyl lithium, n-hexyl lithium, methyl lithium, tert-butyl lithium, isopropyl magnesium chloride, isopropyl One or a combination of s-butylmagnesium chloride-lithium chloride complex and sec-butylmagnesium chloride-lithium chloride complex. 6. preparation method according to claim 2 is characterized in that: reaction solvent is the composition of tetrahydrofuran and toluene. 7. The preparation method according to claim 2, wherein the acid in the acidic aqueous solution is selected from one or a combination of hydrochloric acid, sulfuric acid, methanesulfonic acid, and trifluoroacetic acid. 8. a preparation method of empagliflozin is characterized in that, the method takes the compound of formula III described in claim 1 as a raw material, the compound of formula III reacts with methanol in the presence of an acid to obtain the compound of formula II, and the compound of formula II is reduced to obtain The compound of formula I, empagliflozin;

9. The preparation method of empagliflozin according to claim 8, wherein the acid is selected from one or more combinations of hydrochloric acid, sulfuric acid, methanesulfonic acid, and trifluoroacetic acid. 10 . The preparation method of empagliflozin according to claim 8 , wherein the reducing agent used for reduction is triethylsilane; and the Lewis acid is selected from aluminum trichloride or boron trifluoride ether. 11 .