DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION
Process for the preparation of Bexagliflozin and its intermediates.

APPLICANT
HONOUR LAB LIMITED
H.No: 8-3-166/7/1, Erragadda, Hyderabad-500 018,
Telangana, India.
Nationality: Indian company.

The following specification describes the invention and ascertains the nature of this invention & the manner in which to be performed.

FIELD OF THE INVENTION
The present application relates to a process for preparation of Bexagliflozin of formula (I). by using intermediate of Formula IV.

---
Formula-I

BACK GROUND OF THE INVENTION
Bexagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Bexagliflozin is chemically known as (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and is represented by the following structural formula I.

---
Formula-I

Bexagliflozin was approved in US under the brandname of BRENZAVVY. Bexagliflozin and process for its preparation was first disclosed in the US7,838,499 (US’499 patent) .

The following scheme-1 describes the process of Bexagliflozin, in examples as given in US7,838,499

US’499 discloses the process for preparing compound of bexagliflozin intermediate generically as shown below:

The said process involves column chromatography purification for the preparation of bexagliflozin intermediate , and not be suitable for large scale production.

US 9,061,060, discloses in example 36 process for the prepration of 4-bromo-1-chloro-2-(4-(2-cyclopropoxy (ethoxy-2,2-d2))-benzyl)benzene and further conversion to deuterated Bexagliflozin is as shown below:

Bioorganic & Medicinal Chemistry Letters (2011), 21(15), 4465-4470 discloses the process for the prepration of 4-bromo-1-chloro-2-(4-(2-cyclopropoxy(ethoxy-2,2-))-benzyl)benzene as shown below:

BBr3 usage in high volume is highly corrosive and costly, handling is also difficult further maintaining -78°C temperature is also a tough task.

US 9193751B2 discloses the process for the prepration of 2-(4-(2-Cyclopropoxyethoxy) Benzyl)-1-Chloro-4-Iodobenzene as shown below:

Above described processes make use of drastic reaction conditions, more unit operations;
which is not desirable for commercial manufacturing .

Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve more unit operations. Moreover, the process does not require critical workup procedure.

Further there is always a need for an alternative process, which for example, involves use of reagents/solvents that are less expensive and easier to handle, consume smaller amounts of solvents, and provide a higher yield of product with higher purity. Hence,the main objective of the present invention is to provide cost effective and commercially viable process for the preparation of Bexagliflozin and its intermediates.

OBJECTIVE OF THE INVENTION

An object of the present invention is to provide the process for preparation of Bexagliflozin Formula-I, by using Bexagliflozin intermediate of Formula-IV which is economically and industrially feasible.

An object of the present invention is to provide the process for preparation of Bexagliflozin intermediate of Formula-IV, having high purity and yield.

Yet another object of the present invention is to provide crystalline form of Bexagliflozin intermediate of Formula-IV.

BRIEF DESCRIPTION OF DRAWINGS:
FIG. 1. is a a X-ray powder diffraction spectrum of crystalline Form- HO of Bexagliflozin intermediate of Formula-IVa
POWDER X-RAY DIFFRACTION METHOD

X-ray powder diffraction spectrum was measured on a broker axs D8 advance X-ray powder diffractometer having a copper-Ka radiation. Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees two theta per step and a step time of 10.8 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

SUMMARY OF THE INVENTION:

In one aspect, the present invention provides a process for the preparation Bexagliflozin of formula I, which comprises:

---
Formula-I
Wherein X is Cl, Br or I

a) reacting (5- halo-2-chloro-phenyl) (4-fluorophenyl) methanone of formula II,

---
Formula-II
wherein X is Cl, Br or I
with 2-cyclopropoxy ethanol of formula III in presence of base to provide a compound of Formula IV,

---
Formula-IV
b) reducing the compound of formula IV with a suitable reducing agent to provide
a compound of formula V.

---
Formula-V
c) converting the compound of formula V into bexagliflozin of formula I.

In one aspect, the present invention provides a process for the preparation Bexagliflozin of formula I, which comprises:

---
Formula-I

a) reacting (5-halo-2-chloro-phenyl)(4- hydroxyl phenyl) methanone of formula-VI,

---
Formula-VI
wherein X is Cl, Br or I;
with 2-cyclopropoxy compound of formula IIIa in presence of base to provide a compound of Formula IV,

---
Formula-IIIa
Wherein R is OH, OMs or OTs;

---
Formula-IV
b) reducing the compound of formula IV with a suitable reducing agent to provide
a compound of formula V;

---
Formula-V
c) converting the compound of formula V into bexagliflozin of Formula I.

DETAILED DESCRIPTION OF THE INVENTION:
In an embodiment of the present invention provides an improved process for the prepration of Bexagliflozin of Formula-I by using 5- halo -2-chloro phenyl)(4-(-2-cyclo propoxy ethoxy) phenyl) methanone compound of Formula-IV, which comprises reacting (5- halo-2-chloro-phenyl) (4-fluorophenyl) methanone of formula II(wherein X is Cl, Br or I) with 2-cyclopropoxy ethanol of formula III in presence of base to provide a compound of Formula IV, followed by reducing the compound of formula IV with a suitable reducing agent and a suitable solvent to provide a compound of formula V. converting the compound of formula V into bexagliflozin of formula I.

In another embodiment of the present invention provides reacting (5- halo-2-chloro-phenyl) (4-fluorophenyl) methanone of formula II(wherein X is Cl, Br or I) with 2-cyclo propoxy ethanol of formula III in presence of suitable base and solvent at temperature in the range of 0-10°C to provide crude compound of Formula IV.

In another embodiment of the present invention provides crystalline form of compound of Formula IV which comprises, crude compound of Formula IV suspended in hydrocarbon solvents and optionally heated to 40-50°C, and cooled to 0-5°, stirred for 2-3 hrs at 0-5° and filtered. The crystalline form represented as Form- HO.

Accordingly, in an embodiment the present invention relates to a process for the preparation of compound of Formula IV, wherein purifying by treating with hydrocarbon solvent and/or aliphatic hydrocarbon solvent thereof to obtain formula IV having purity greater than 99%.

In an embodiment, the suitable solvent used in the process herein above is selected from the group hydrocarbons; wherein hydrocarbons is selected from the group consisting of aromatic hydrocarbon such as toluene, xylene, aliphatic hydrocarbon such as hexanes cyclohexane, n-hexane, heptanes and the like; or mixtures thereof.

In another embodiment of the present invention compound of formula IV represented as below:

---
Formula-IV
Wherein X is halogen such as Cl, Br or I.

In another embodiment of the present invention, wherein compoundof formula IV under goes reduction with suitable reducing agent in suitable solvent in presence of lewis acid at temperature in the range of 25°C and 60°C, preferably 35-40°C, to provide compound of Formula V.

In another embodiment of the present invention provides an improved process for the prepration of Bexagliflozin of Formula-I, by using 5- halo-2-chloro phenyl)(4-(-2-cyclo propoxy ethoxy) phenyl) methanone compound of Formula-IV, which comprises reacting (5- halo-2-chloro-phenyl) (4-hydroxy phenyl) methanone of formula VI(wherein X is Cl, Br or I) with 2-cyclopropoxy compound of formula IIIa in presence of base to provide a compound of Formula IV, followed by reducing the compound of formula IV with a suitable reducing agent and a suitable solvent to provide a compound of formula V. converting the compound of formula V into bexagliflozin of formula I.

1-chloro-2-( 4-(2-cyclopropoxyethoxy) benzyl)-4-bromo benzene (formula V) reacted with 3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one in presence of a solvent and n-BuLi, at -70°C to -75°C, followed by addition of Methane sulfonic acid solution. The above residue undergoes reduction with reducing agent in presence of lewis acid followed by treating with acetic anhydride inpresence of dimethylaminopyridine in a suitable solvent to get acetylated bexagliflozin. Acetylated Bexagliflozin treated with suitable solvent and base at temperature 25-30°C for 3-5 hrs to obtain bexagliflozin crude, which is further crystallised in suitable solvents to get pure bexagliflozin.

The term “suitable base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates”
such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like ammonia and organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (DMAP), morpholine or mixture thereof.

The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tertbutyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexanes, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water or mixtures thereof.

The reduction reaction used in the present invention carried out with a reducing agent in the presence of a Lewis acid. Suitable reducing agents include for example silanes such as e.g. triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride, or samarium iodide. Suitable Lewis acids are such as e.g. boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, or zinc iodide; or suitable Lewis acids are Brønsted acids such as e.g. hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, or acetic acid.

The process of the present invention as per the specific embodiment described above is
illustrated in the following Scheme A:

Wherein X is halogen such as Cl, Br or I.

Alternate process for preparing compound of formula V as per the specific embodiment described above is illustrated in the following Scheme B:

Wherein R is OH, OMs (OSO2CH3) or OTs(OSO2C6H4CH3).
The process for the preparation of Bexagliflozin from formula V illustrated in the following Scheme C:

The process details of the invention are provided in the examples given below, which
are provided by way of illustration only and therefore should not be construed to limit
the scope of the invention.

Examples:
Example 1: Preparation of (5-bromo-2-chloro phenyl)(4-(-2-cyclopropoxyethoxy) phenyl) methanone (Formula IVa, wherein halogen is bromo)
To a clean and round RBF, (5-bromo-2-chloro phenyl)(4-fluorophenyl)methanone (100 g), 2-cyclopropoxy ethanol (40 gm) and THF(400ml) were added and cooled to 0-5°C.To this potassium t-butoxide (45 g) was added lot wise at 0-5°C, and stirred for 3 hrs at the same temperature. After completion of the reaction,water(1000ml) and toluene(1000ml) were added to the reaction mass and separated the organic layer distilled off the under vacuum at 40 - 50°C. To this crude hexanes was added(300 ml) and stirred for 2 hrs at 0-5°C and filtered the solid and dried under vaccum to get the crystalline form of (5-bromo-2-chloro phenyl)(4-(-2-cyclopropoxyethoxy) phenyl) methanone and figure is depicted as shown in figure 1.
Yield: 87%
HPLC Purity:99.3%

Example 2: Preparation of (5-Iodo -2-chloro phenyl)(4-(-2-cyclopropoxyethoxy) phenyl) methanone (Formula IVb, wherein halogen is Iodo)
To a clean and round RBF, (5-Iodo-2-chloro phenyl)(4-fluorophenyl)methanone (100 g), 2-cyclopropoxy ethanol (38 gm) and THF(400ml) were added and cooled to 0-5°C.To this potassium t-butoxide (40 g) was added lot wise at 0-5°C, and stirred for 3 hrs at the same temperature. After completion of the reaction,water(1000ml) and toluene(1000ml) were added to the reaction mass and separated the organic layer distilled off the under vacuum at 40 - 50°C. To this crude methanol added(300 ml) and stirred for 2 hrs at 0-5°C and filtered the solid and dried under vaccum to get the titled crystalline form of (5-Iodo-2-chloro phenyl)(4-(-2-cyclopropoxyethoxy) phenyl) methanone .
Yield: 90%
HPLC Purity:99.5%

Example 3: Preparation of (5-bromo -2-chloro phenyl)(4-(-2-cyclopropoxyethoxy) phenyl) methanone (Formula IVa, wherein halogen is bromo)

To a clean and round RBF, (5-bromo -2-chloro phenyl)(4- hydroxyl phenyl)methanone (100 g), 2-cyclopropyloxyethyl 4-methylbenzenesulfonate (90 gm) and Acetonitrile (400ml) were added at 25-30°C. To this potassium carbonate(100 g) was added and heated to 75-80°C, stirred for 3 hrs at the same temperature. After completion of the reaction cooled to 25-30°C, water(1000ml) and ethylacetate(500ml) were added to the reaction mass and separated the organic layer. Organiclayer was washed with 10% NaCl(2x200ml) solution and distilled off the organic solvent under vacuum at 40 -50°C. To this crude hexanes added(300 ml) and stirred for 2 hrs at 0-5°C and filtered the solid and dried under vaccum to get the crystalline form of (5-bromo-2-chloro phenyl)(4-(-2-cyclopropoxyethoxy) phenyl) methanone and figure is depicted as shown in figure 1.
Yield: 88%
HPLC Purity:99.2%

Example 4: Preparation of (4-bromo-1-chloro -2-(4-(2-cyclopropoxy ethoxy)benzyl) benzene( formula V)
To a clean and round RBF (5-bromo-2-chloro phenyl)(4-(-2-cyclopropoxyethoxy) phenyl) methanone(50 gm) in dichloromethane(MDC) (200 ml) and acetonitrile (100ml) added at 25-30°C. To this reaction mass triethyl silane (45gm) added and temperature raised to 35-40°C. BF3.Et2O added to the above, after completion of the reaction, water(100 ml) and MDC (500ml) were added to the reaction mass pH of the reaction mass was adjusted to 7.0-7.5 with aq NaOH. Seperated the organic layer and distilled of the solvent completely under vacuum to get the title compound.

Example 5: Preparation of acetylated Bexagliflozin

To a clean RBF 1-chloro-2-( 4-(2-cyclopropoxyethoxy)benzyl)-4- bromo benzene (50 g, 0.131m), (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy) methyl) tetrahydro-2H-pyran-2-one (91.7, 0.196 moles) and Tetrahydrofuran (500 ml) was added and cooled to -70°C to -75°C. n-BuLi (33.5 g, as 100%, 0.523 moles, 2.5 M in Hexane) was added over a period of 1 hour 30 minutes under Nitrogen at temperature about -70°C to -75°C and stirred for 3 hours, followed by addition of Methane sulfonic acid solution (methane sulfonic acid dissolve in Methanol) over a period of 1 hour under nitrogen at same temperature and stirred for 4 hours. After completion of reaction, the reaction mass pH was adjusted to 7.0 – 8.0 with Sodium bicarbonate solution and distilled out under vacuum. To the obtained residue water was added and extracted with ethyl acetate. The combined ethyl acetate fractions are washed with brine and dried over sodium sulphate. The reaction mixture is concentrated. To this residue acetonitrile and methylene chloride was added and cooled to the temperature 0°C to 10°C. Added drop wise simultaneously Triethyl silane (22.9 g, 0.196 mole) and BF3-diethyletherate (26 g, 0.18 mole) into above solution over a period of 40-45 minutes and stirred for about 2 hrs. After completion of reaction, the reaction mass pH was adjusted to 7.0 – 8.0 with Sodium bicarbonate solution and distilled out under vacuum. To the obtained residue water was added and extracted with ethyl acetate. The combined ethyl acetate fractions are washed with brine and dried over sodium sulphate. The reaction mass was concentrated. To the obtained residue methylene chloride, acetic anhydride (66.8 g, 0.655 moles) and dimethylaminopyridine was added and stirred for 3-4hrs. Water was added to the reaction mass and layers were separated. The methylene chloride layer was distilled and methanol was added to it followed by heating to 55-60°C.The reaction mixture was cooled, filtered and dried to obtain acetylated Bexagliflozin.

Example-6: Preparation of Bexagliflozin (Formula I)

To the acetylated Bexagliflozin (50 g, 0.08 moles) methanol (250 mL), water (25 mL) and sodium hydroxide (6.32 g, 0.16 moles), was added at temperature 25-30°C and stirred for 4-5 hrs, distilled the methanol. To the residue water was added MTBE (300 ml) and adjusted the pH with Con. HCl to 6.0 - 6.5 at 15-25°C. Separated the layers and distilled the organic solvent.To the crude Charged ethanol (200 ml) and pidolic acid (0.096 moles), raised the reaction mass temeperature to 50-55°C, stirred for 1hr and distilled to get foam solid. To the solid water (200 ml) was added and adjusted pH 8-9 with Na2CO3 solution, extract into MTBE (200 ml) distilled the solvent to get Bexagliflozin.
HPLC Purity: 99.85%

,CLAIMS:We claim:

1. A process for the preparation Bexagliflozin of formula I, which comprising:

---

Formula-I
a) reacting (5-halo-2-chloro-phenyl)(4- hydroxyl phenyl) methanone of formula-VI,

---
Formula-VI
wherein X is Cl, Br or I;
with 2-cyclopropoxy compound of formula IIIa in presence of base to provide a compound of Formula IV,

---
Formula-IIIa
Wherein R is OH, OMs or OTs;

---
Formula-IV
b) reducing the compound of formula IV with a suitable reducing agent to provide
a compound of formula V;

---
Formula-V
c) converting the compound of formula V into bexagliflozin of Formula I.

2. A process for the preparation Bexagliflozin of formula I, which comprising:

---
Formula-I
Wherein X is Cl, Br or I;
a) reacting (5- halo-2-chloro-phenyl) (4-fluorophenyl) methanone of formula II,

---
Formula-II
wherein X is Cl, Br or I;
with 2-cyclopropoxy ethanol of formula III in presence of base to provide a compound of Formula IV,

---
Formula-IV
b) reducing the compound of formula IV with a suitable reducing agent to provide
a compound of formula V.

---
Formula-V
c) converting the compound of formula V into bexagliflozin of formula I.

3. The process according to claim 1 or 2, wherein base is selected from a group consisting of alkali metal alkoxides, alkali metal hydroxides and “alkali metal carbonates and mixtures thereof.

4. The process according to claim 1 or 2, wherein reducing agent is selected from a group consisting triethylsilane, tripropylsilane or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride mixtures thereof.

5. A process for preparation of Crystalline Form-HO of Bexagliflozin intermediate of Formula-IVa having purity greater than 99% comprising:

a) reacting (5-bromo-2-chloro-phenyl)(4- hydroxyl phenyl) methanone of formula-VI,

---
Formula-VI
with 2-cyclopropoxy compound of formula IIIa in presence of base to provide a compound of Formula IVa,

---
Formula-IIIa
Wherein R is OH, OMs or OTs;

---
Formula-IVa
b) treating the crude with aliphatic hydrocarbon solvent;
c) isolate the Form- HO of formula IVa.

6. The process according to claim 5, wherein aliphatic hydrocarbon selected from hexanes, cyclohexane, n-hexane, heptanes or mixtures thereof.

Dated this 5th day of March 2025.

Dr. RATHNAKAR REDDY KURA
DIRECTOR
HONOUR LAB LIMITED