DESC:“AN IMPROVED PROCESS FOR PREPARATION OF DAPAGLIFLOZIN
PROPANEDIOL MONOHYDRATE”

FIELD OF THE INVENTION

The present invention relates to an improved process for preparing Dapagliflozin propanediol monohydrate, represented by formula (I). The invention also relates to the preparation of a substantially pure tetra acetyl intermediate of formula (VI) by recrystallization using n-heptane and ethanol.

BACKGROUND OF THE INVENTION

Dapagliflozin (S)-propylene glycol monohydrate is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, chemically known as (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, a compound combined with (2S)-1,2-propanediol in a 1:1:1 ratio, forming a hydrate. It is indicated for the treatment of type 2 diabetes and marketed under the brand name FARXIGA®.

The US patent 6515117 discloses Dapagliflozin first, along with pharmaceutically acceptable salts, stereoisomers, and prodrug esters thereof. It also details the preparation of Dapagliflozin through several steps: first, an unprotected O-methyl compound is prepared. Next, the methyl group is removed using triethylsilane and boron trifluoride diethyl etherate (BF3.Et2O). The reaction mixture is then worked up with ethyl acetate and water. This is followed by the preparation of tetra-acetyl Dapagliflozin using acetic anhydride in the presence of pyridine and dimethylaminopyridine (DMAP). Finally, deprotection of tetra-acetyl Dapagliflozin with lithium hydroxide monohydrate yields Dapagliflozin as an off-white solid with a purity of 94%.

PCT publication WO 2016/147197 discloses a process for the preparation of Dapagliflozin propanediol monohydrate, wherein the compound of formula (II) is reacted with the compound of formula (III) in the presence of n-butyllithium in hexanes to obtain the compound of formula (III). This compound subsequently converts into Dapagliflozin in the presence of triethylsilane, BF3.OEt2. Finally, Dapagliflozin is reacted with L-proline in the presence of ethyl acetate to form an L-proline complex, which is then converted back into Dapagliflozin using a mixture of ethyl acetate, n-heptane, and sodium bicarbonate.

WO 2021/260617 discloses a process for preparing tetra-acetyl Dapagliflozin (formula VI). This process involves reacting the compound of formula (V) with an acylating agent in the presence of a base and catalyst, followed by purification using cyclohexane and methanol to obtain the substantially pure compound of formula (VI).

This crystallization method using cyclohexane and methanol suffers from a very low yield, making it industrially impractical.

The processes described in the prior art suffer from several drawbacks: they are unsuitable for scaling up at the plant level, can be difficult to execute, deliver lower yields. In light of these limitations, there is a pressing need for improved methods that overcome the shortcomings of existing approaches. These new methods should ideally utilize less expensive and/or easier-to-handle reagents and solvents, require smaller quantities of these materials, and provide a higher yield of the desired product.

The present invention provides a simple, cost-effective process with high purity and good yield, suitable for industrial applications

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparing Dapagliflozin propanediol monohydrate, represented by formula (I). The invention also relates to the preparation of a substantially pure tetra acetyl intermediate of formula (VI) by recrystallization using n-heptane and ethanol.

One aspect of the present invention provides an improved process for the preparation of Dapagliflozin (S)-propylene glycol monohydrate (I), comprising the steps of:

a) coupling the compound of formula (II) with the glycoside compound of formula (III) in the presence of an organolithium compound and an organic solvent, followed by methylation using methanol in the presence of an acid and an organic solvent to obtain the in-situ compound of formula (IV);

b) removing methoxy group of the in-situ compound of formula (IV), in the presence of a reducing agent, Lewis acid, and an organic solvent, to obtain the in-situ compound of formula (V);

c) acetylating the in-situ compound of formula (V) by treating with an acetylating reagent in the presence of a base, catalyst and an organic solvent, followed by recrystallize the resulting product with n-heptane and ethanol to obtain a substantially pure compound of formula (VI); and

d) converting the compound (VI) obtained in step (c) to Dapagliflozin propanediol monohydrate of formula (I).

Another aspect of the present invention provides preparation of substantially pure tetra acetyl intermediate of formula (VI) by recrystallization with n-heptane and ethanol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for preparing Dapagliflozin propanediol monohydrate, represented by formula (I). The invention also relates to the preparation of a substantially pure tetra acetyl intermediate of formula (VI) by recrystallization using n-heptane and ethanol.

One embodiment of the present invention provides an improved process for the preparation of Dapagliflozin (S)-propylene glycol monohydrate (I), comprising the steps of:

a) coupling the compound of formula (II) with the glycoside compound of formula (III) in the presence of an organolithium compound and an organic solvent, followed by methylation using methanol in the presence of an acid and an organic solvent to obtain the in-situ compound of formula (IV);

b) removing methoxy group of the in-situ compound of formula (IV), in the presence of a reducing agent, Lewis acid, and an organic solvent, to obtain the in-situ compound of formula (V);

c) acetylating the in-situ compound of formula (V) by treating with an acetylating reagent in the presence of a base, catalyst and an organic solvent, followed by recrystallize the resulting product with n-heptane and ethanol to obtain a substantially pure compound of formula (VI); and

d) converting the compound (VI) obtained in step (c) to Dapagliflozin propanediol monohydrate of formula (I).

According to one embodiment of the present invention provides a process for preparing Dapagliflozin propanediol monohydrate (Formula I). The process involves coupling of (formula II) and (formula III) in the presence of organolithium and solvent, followed by methylation using methanol in the presence of an acid and an organic solvent to obtain intermediate (formula IV). The methoxy group of (formula IV) is then removed with a reducing agent and Lewis acid to give intermediate (formula V). This intermediate is acetylated using an acetylating reagent in the presence of a base, catalyst, and solvent, and then recrystallized with n-heptane and ethanol to obtain pure (formula VI). Finally, (formula VI) is treated with S (+)-propanediol in the presence of a base and a solvent to afford the final product, Dapagliflozin propanediol monohydrate.

According to an embodiment of the present invention, wherein the organolithium compound is selected from n-, sec- or tert-butyllithium (BuLi) and n-hexyllithium.

According to an embodiment of the present invention, wherein the acid is selected from methanesulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, or hydrochloric acid.

According to an embodiment of the present invention, wherein the reducing agents is selected from triethylsilane, triethylsilyl hydride, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes or diisobutyl aluminium hydride.

According to an embodiment of the present invention, wherein the Lewis acid is selected from aluminium chloride, boron trifluoride diethyl etherate, boron trifluoride acetic acid complex (BF3.2CH3COOH), trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, toluene sulfonic acid, trifluoroacetic acid or acetic acid.

According to an embodiment of the present invention, wherein the acetylating reagent is selected from acetic anhydride (Ac2O) or acetyl chloride (AcCl).

According to an embodiment of the present invention, wherein the base used in hydrolyzing compound of formula (VI) is selected from alkali metal hydroxide such as lithium hydroxide (LiOH), sodium hydroxide (NaOH), and potassium hydroxide (KOH).

According to an embodiment of the present invention, wherein the solvent is selected from acetonitrile, chloroform, tetrahydrofuran (THF), hexane, n-heptane, dioxane, dimethyl sulfoxide (DMSO), toluene, diethylether, dichloromethane (DCM), ethanol, water, methyl tert butyl ether (MTBE), methanol, isopropyl alcohol (IPA), cyclohexane, isopropyl acetate, dimethylformamide (DMF), 1,2-dimethoxyethane or mixtures thereof.

According to an embodiment of the present invention, the acid portion is added to the methylation reaction at 25°C to 30°C until the pH of the reaction mixture reaches between 7.0 and 8.0.

According to the embodiment of the present invention, wherein the removing methoxy group of compound of formula (V) is carried out at a temperature below -20°C.

According to an embodiment of the present invention, the preparation of Dapagliflozin propanediol monohydrate of formula (I) is achieved without isolating the intermediates of formula (IV) and (V). This eliminates the need for isolation steps, resulting in a more economical process.

Another embodiment of the present invention relates to the preparation of a substantially pure tetra-acetyl intermediate of formula (VI) by recrystallization with n-heptane and ethanol.

According to the embodiment of the present invention relates to the preparation of a substantially pure tetra-acetyl intermediate of formula (VI), comprising the following steps:

a) dissolving the crude compound of formula (VI) in ethanol and n-heptane;
b) optionally, heating the obtained solution from step (a) at a temperature of 75-80°C;
c) optionally, cooling the solution from step (b) to room temperature; and
d) isolating the resulting high-purity tetra-acetyl Dapagliflozin (formula VI).

According to the embodiment of the present invention, substantially pure," as used herein, refers to a compound with a purity greater than 98%, preferably greater than 99%, as determined by HPLC.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXAMPLES:

Example -1: Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol [in-situ].
4-Bromo-1-chloro-2-(4-ethoxybenzyl) benzene (100 g) and THF (300 mL) were charged into the round-bottom flask. The reaction mixture was then cooled to -78 to -90°C. A mixture of THF (100 mL), trimethylsilyl glucono lactone (190 g), and n-butyl lithium in hexanes (200 mL) was added. The reaction mixture was stirred at the same temperature for 3-4 hours. Concentrated HCl (100 mL) and methanol (500 mL) were added. The reaction mixture temperature was raised to 25-30°C and stirred for 3-4 hours. After the reaction completion, purified water was added to the mixture, and the layers were separated. The pH was adjusted to 7.0-8.0 using a sodium bicarbonate (100 g) solution. The layers were separated again, and the dichloromethane layer was washed with sodium chloride solution. Finally, the obtained product was distilled. Co-distillation with toluene (100 mL) yielded (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyl methyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (130 g).

Yield: 96%.

Purity by HPLC- 85.0%.

Example-2: Preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl]-6-hydroxy methyl)oxane-3,4,5-triol [in-situ].
The in-situ (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (130 g) was charged into an RB flask along with dichloromethane (650 mL), acetonitrile (260 mL), and triethylsilane (51.6 g). The reaction mass was then cooled to -20 to -30°C. Boron trifluoride diethyl etherate (84.5g) was added, and the mixture was stirred for 1-2 hours. After the reaction was complete, the reaction mass was quenched with diluted sodium chloride solution. The layers were separated, and the organic layer was concentrated to obtain the desired product (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol.

Yield: (115 g; 95%); HPLC purity- 85.5%

Example-3: Preparation of (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (Tetra acetyl Dapagliflozin)
The in-situ (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxylmethyl)oxane-3,4,5-triol (110g), dichloromethane (550 mL) and of TEA (108.6g) were charged in to RB flask. The reaction mixture was then cooled to 10-15°C. Acetic anhydride (123.5g) and a mixture of DMAP and DCM solution were added to the reaction mixture and stirred for 2-3 hours. After the reaction was complete, the reaction mass was quenched with water, and the two layers were separated. The organic layer was concentrated to form a solid, which was further recrystallized.
To recrystallize, ethanol (400 mL) and n-heptane (600 mL) were added to the crude compound. The reaction mixture was heated to 75-80°C and stirred for 30 minutes to obtain a clear solution. The reaction mass was then allowed to cool to 25-30°C and stirred for 2-3 hours. The solid was then filtered, washed with n-heptane, and dried at 50-55°C for 10 minutes, to obtain the high-purity Tetra-acetyl Dapagliflozin (105g)

Yield: 68%; Purity by HPLC: 99.90%; Single maximum impurity below 0.1 % level.

Example-4: Preparation of Dapagliflozin propanediol monohydrate.
(2R, 3R, 4R, 5S, 6S)-2-(Acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (100 g), methanol (100 mL) and aqueous sodium hydroxide solution (30 g) were charged in to the RB flask. Purified water (760 mL) was then added, and the mixture was stirred for 1-2 hours at 60-65°C. After the reaction was complete, the reaction mass was cooled to 25-30°C. MTBE and dilute hydrochloric acid were then added to the reaction mass, followed by separation of the layers. The MTBE-aqueous layer was collected and stirred for 10 minutes. Subsequently, (S)-(+)-1,2-propanediol (13.3 g) and 0.5 g of seed material were added and stirred for 1-2 hours. Finally, cyclohexane (550 mL) was added, and the reaction mass was stirred for 8-10 hours at 25-30°C to obtain Dapagliflozin propane diol monohydrate (83 g).

Yield: 95%; Purity by HPLC-99.90%.
,CLAIMS:We Claim,

1. An improved process for the preparation of Dapagliflozin propanediol monohydrate (I), comprising the steps of:

a) coupling the compound of formula (II) with the glycoside compound of formula (III) in the presence of an organolithium and an organic solvent, followed by methylation using methanol in the presence of an acid and an organic solvent to obtain the in-situ compound of formula (IV);

b) removing methoxy group of the in-situ compound of formula (IV), in the presence of a reducing agent, Lewis acid, and an organic solvent, to obtain the in-situ compound of formula (V);

c) acetylating the in-situ compound of formula (V) by treating with an acetylating reagent in the presence of a base, catalyst and an organic solvent, followed by recrystallize the resulting product with n-heptane and ethanol to obtain a substantially pure compound of formula (VI); and

d) converting the compound (VI) obtained in step (c) to Dapagliflozin propanediol monohydrate of formula (I).

2. The process as claimed in claim 1, wherein the organolithium compound is selected from n-, sec- or tert-butyllithium (BuLi) and n-hexyllithium.

3. The process as claimed in claim 1, wherein the acid is selected from methanesulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, or hydrochloric acid.

4. The process as claimed in claim 1, wherein the reducing agents used is selected from triethylsilane, triethylsilyl hydride, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, diisobutyl or aluminium hydride.

5. The process as claimed in claim 1, wherein the Lewis acid used is selected from aluminium chloride, boron trifluoride diethyl etherate, boron trifluoride acetic acid complex (BF3.2CH3COOH), trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, toluene sulfonic acid, trifluoroacetic acid and acetic acid.

6. The process as claimed in claim 1, wherein the acetylating reagent is selected from acetic anhydride (Ac2O) or acetyl chloride (AcCl).

7. The process as claimed in claim 1, wherein the base used for hydrolyzing the compound of formula (VI) is selected from alkali metal hydroxides, such as lithium hydroxide (LiOH), sodium hydroxide (NaOH), or potassium hydroxide (KOH).

8. The process as claimed in claim 1, wherein the solvent is selected from acetonitrile, chloroform, tetrahydrofuran (THF), hexane, n-heptane, dioxane, dimethyl sulfoxide (DMSO), toluene, diethylether, dichloromethane (DCM), ethanol, water, methyl tert butyl ether [MTBE], methanol, isopropyl alcohol (IPA), cyclohexane, isopropyl acetate, dimethylformamide (DMF), 1,2-dimethoxyethane or mixtures thereof.

9. A process for preparation of substantially pure tetra acetyl intermediate of formula (VI) by recrystallization with n-heptane and ethanol.

10. The process for preparing the substantially pure tetra-acetyl intermediate of formula (VI), as claimed in claim 9, comprises the steps of:

a) dissolving the crude compound of formula (VI) in ethanol and n-heptane;
b) optionally, heating the obtained solution from step (a) at a temperature of 75-80°C;
c) optionally, cooling the solution from step (b) to room temperature; and
d) isolating the resulting high-purity tetra-acetyl Dapagliflozin (formula VI).