CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian provisional patent application No. I N201841007569, filed on February 28, 2018, and Indian provisional patent application No. I N201841039224, filed on October 16, 2018, each of which are incorporated herein in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to a process for the preparation of sotagliflozin. The present invention also provides intermediates for the preparation of sotagliflozin.

BACKGROUND

Sotagliflozin is an orally bioavailable inhibitor of the sodium-glucose co transporter subtype 1 (SGLT1) and 2 (SGLT2), with potential anti-hyperglycemic activity. Upon oral administration, sotagliflozin binds to and blocks both SGLT1 in the gastrointestinal (Gl) tract and SGLT2 in the kidneys, thereby suppressing the absorption of glucose from the Gl tract and the reabsorption of glucose by the proximal tubule into the bloodstream, respectively. This decreases glucose uptake and enhances the urinary excretion of glucose, which lowers and/or normalizes blood glucose levels. SGLT1 is the primary transporter responsible for glucose absorption from the Gl tract. SGLT2, a transport protein exclusively expressed in the proximal renal tubules, mediates approximately 90% of renal glucose reabsorption from tubular fluid.

Sotagliflozin, also named (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxyphenyl) methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol, has the chemical structural shown as Formula 1 below:

SUMMARY OF THE INVENTION

The present disclosure relates generally to processes for the preparation of sotagliflozin, which may be used to treat diabetes.

Sotagliflozin may be prepared by a process that includes:

condensing a compound of formula (27) with a compound of formula (26) in the presence of a first base to obtain a compound of formula (25)

reducing the compound of formula (25) with a first reducing agent to obtain a compound of formula (24)

cyclizing the compound of formula (24) to obtain a compound of formula (23)

protecting the hydroxyl groups of the compound of formula (23) to obtain a compound of formula (22)

23 22 converting the compound of formula (22) to a compound of formula (21)

converting the compound of formula (21) to sotagliflozin or a pharmaceutically acceptable salt thereof,

Within the context of this disclosure, and in any embodiment,“X” is a halide, for example, chloro, bromo, or iodo. “L” is morpholine, N-methylpiperazine, N- ethylpiperazine, 1-(2-pyramidyl)piperazine, 1-(2-pyridyl)piperazine, or benzyl piperazine. “Pg” is a hydroxyl protecting group and “P” is O-R, dimethoxy, morpholine, or NR ¹ R ² , wherein R is Ci- ₄ alkyl, mesyl, or tosyl. R ¹ and R ² are, independently, a linear or branched alkyl group, a linear or branched alkenyl group, a cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or together, R ¹ and R ² with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein the heterocyclic ring is optionally substituted with an alkyl group.

The product of any of the reaction steps (i.e., condensing, reducing, cyclizing, protecting, converting the compound of formula 22 to the compound of formula 21) need not be isolated before proceeding to subsequent steps. Thus, the above disclosed reaction scheme may be a“one-pot process”.

The condensation and the reducing of the compound of formula (25) may be carried out in a first and a second solvent, respectively. Suitable first and second solvent include ether solvents, aromatic hydrocarbon solvents, alcohol solvents, and halogenated hydrocarbon solvents. The first and second solvent may be the same or may be different. Examples of suitable ether solvents include tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4- dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include dichloromethane, chloroethane, chloroform, and mixture thereof.

The first base used in the condensing step may be, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, sodium hydride, potassium hydride, isopropyl magnesium chloride-lithium chloride complex, sec-butylmagnesium chloride- lithium chloride complex, orisopropylmagnesium chloride-lithium chloride complex (trimethylsilyl)methyllithium.

The reducing step may be carried out with a first reducing agent, which may be, for example, triethylsilane, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium hydride, sodium cyanoborohydride, zinc borohydride, lithium aluminum hydride, diisobutylaluminum hydride, samarium iodide, cerium (III) chloride heptahydrate, or any combination thereof.

Cyclization may be carried out in the presence of an acid, which may be, for example, formic acid, acetic acid, trifluoroacetic acid, methane sulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, or mixtures thereof. Hydroxyl group protection may be carried out in the presence of a second base, which may be, for example, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methyl morpholine, piperidine, pyridine, or mixtures thereof

Examples of suitable hydroxyl protecting groups (“Pg”) include, but are not limited to, alkyl, allyl, pivaloyl, acetyl (Ac), tosyl (Ts), mesyl (Ms), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tertiary butyldimethylsilyl (TBS), benzyl (Bn), para-methoxybenzyl (PMB), trityl (Tr), para-bromobenzoyl, para- nitrobenzoyl, benzoyl (Bz), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), [(3,4-dimethoxybenzyl)oxy]methyl (DMBM), methoxymethyl (MOM), 2- methoxyethoxym ethyl (MEM), methylthiomethyl (MTM), and 2-(trimethylsilyl) ethoxymethyl (SEM).

The conversion of the compound of formula (22) to a compound of formula (21) may be carried out in the presence of a third base, which may be, for example, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N- methylmorpholine, piperidine, pyridine, and mixtures thereof.

The compound of formula (21) may be converted to sotagliflozin by:

reducing the “P” moiety of the compound of formula (21) to yield a compound of formula (19)

and

deprotecting the compound of formula (19) to yield sotagliflozin or a pharmaceutically acceptable salt thereof

Alternatively, the compound of formula (21) may be converted to sotagliflozin by:

deprotecting the compound of formula (21) to yield a compound of formula (20)

reducing the “P” moiety of the compound of formula (19) to yield sotagliflozin or a pharmaceutically acceptable salt thereof

In the conversion of the compound of formula 21 to sotagliflozin, deprotecting may be carried out the presence of a fourth base, which may be, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, or mixtures thereof. In the conversion of the compound of formula 21 to sotagliflozin, reducing of the“P” moiety may be carried out in the presence of a second reducing agent, which may be, for example, boron trifluoride diethyl etherate or palladium carbon/ammonium formate.

Sotagliflozin may alternatively be prepared by a process that includes:

condensing a compound of formula (18) with a compound of formula (17) in the presence of a first base to obtain a compound of formula (16)

reducing the compound of formula (16) with a first reducing agent to obtain a compound of formula (15)

cyclizing the compound of formula (15) in the presence of an acid to obtain a compound of formula (14)

reacting a compound of formula (14) with acetic anhydride in the presence of a second base to obtain a compound of formula (13)

converting a compound of formula (13) to a compound of formula (12) in the presence of a third base

13 12 ; and converting the compound of formula (12) to yield sotagliflozin or a pharmaceutically acceptable salt thereof,

wherein“X” is a halide (e.g., chloro, bromo, or iodo).

The product of any of the reaction steps (i.e., condensing, reducing, cyclizing, protecting, converting the compound of formula 13 to the compound of formula 12) need not be isolated before proceeding to subsequent steps. Thus, the above disclosed reaction scheme may be a“one-pot process”.

The condensation reaction and the reducing of the compound of formula (16) may be carried out in a first and a second solvent, respectively. Suitable first and second solvent include ether solvents, aromatic hydrocarbon solvents, alcohol solvents, and halogenated hydrocarbon solvents. The first and second solvent may be the same or may be different. Examples of suitable ether solvents include tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4- dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include dichloromethane, chloroethane, chloroform, and mixture thereof. The first base used in the condensing step may be, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, sodium hydride, potassium hydride, isopropyl magnesium chloride-lithium chloride complex, sec-butylmagnesium chloride- lithium chloride complex, orisopropylmagnesium chloride-lithium chloride complex (trimethylsilyl)methyllithium.

The reducing step may be carried out with a first reducing agent, which may be, for example, triethylsilane, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium hydride, sodium cyanoborohydride, zinc borohydride, lithium aluminum hydride, diisobutylaluminum hydride, samarium iodide, cerium (III) chloride heptahydrate, or any combination thereof.

Cyclization may be carried out in the presence of an acid, which may be, for example, formic acid, acetic acid, trifluoroacetic acid, methane sulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, or mixtures thereof.

Reacting the compound of formula 14 with acetic anhydride in the presence of a second base, which may be, for example, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methyl morpholine, piperidine, pyridine, or mixtures thereof.

The conversion of the compound of formula (13) to a compound of formula (12) may be carried out in the presence of a third base, which may be, for example, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N- methylmorpholine, piperidine, pyridine, and mixtures thereof.

The compound of formula (12) may be converted to sotagliflozin by:

reducing the morpholine moiety of the compound of formula (12) to yield a compound of formula (10)

12 10

and deprotecting the compound of formula (10) to yield sotagliflozin or a pharmaceutically acceptable salt thereof

Alternatively, the compound of formula (12) may be converted to sotagliflozin by: deprotecting the compound of formula (12) to yield a compound of formula

(1 1)

reducing the morpholine moiety of the compound of formula (11) to yield sotagliflozin or a pharmaceutically acceptable salt thereof

In the conversion of the compound of formula 12 to sotagliflozin, the reduction of the ketone moiety may be carried out in a reducing agent, which may be, for example, boron trifluoride diethyl etherate or palladium carbon/ammonium formate.

In another example, sotagliflozin may be prepared by a process that includes: condensing a compound of formula (9) with a compound of formula (17) in the presence of a base to obtain a compound of formula (8) reducing a compound of formula (8) in the presence of reducing agent to obtain a compound of formula (7)

cyclizing a compound of formula (7) in the presence of an acid to obtain a compound of formula (6)

reacting a compound of formula (6) with morpholine in the presence of a second base to obtain a compound of formula (5)

6 converting a compound of formula (5) to a compound of formula (4) in the presence of a third base

converting a compound of formula (4) to sotagliflozin or a pharmaceutically acceptable salt thereof.

The product of any of the reaction steps (i.e., condensing, reducing, cyclizing, protecting, converting the compound of formula 5 to the compound of formula 4) need not be isolated before proceeding to subsequent steps. Thus, the above disclosed reaction scheme may be a“one-pot process”.

The condensation reaction and the reducing of the compound of formula (8) may be carried out in a first and a second solvent, respectively. Suitable first and second solvent include ether solvents, aromatic hydrocarbon solvents, alcohol solvents, and halogenated hydrocarbon solvents. The first and second solvent may be the same or may be different. Examples of suitable ether solvents include tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4- dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include dichloromethane, chloroethane, chloroform, and mixture thereof.

The first base used in the condensing step may be, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, sodium hydride, potassium hydride, isopropyl magnesium chloride-lithium chloride complex, sec-butylmagnesium chloride- lithium chloride complex, orisopropylmagnesium chloride-lithium chloride complex (trimethylsilyl)methyllithium. The reducing step may be carried out with a first reducing agent, which may be, for example, triethylsilane, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium hydride, sodium cyanoborohydride, zinc borohydride, lithium aluminum hydride, diisobutylaluminum hydride, samarium iodide, cerium (III) chloride heptahydrate, or any combination thereof.

Cyclization may be carried out in the presence of an acid, which may be, for example, formic acid, acetic acid, trifluoroacetic acid, methane sulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, or mixtures thereof.

Hydroxyl group protection may be carried out in the presence of a second base, which may be, for example, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methyl morpholine, piperidine, pyridine, or mixtures thereof.

Examples of suitable hydroxyl protecting groups (“Pg”) include, but are not limited to, alkyl, allyl, pivaloyl, acetyl (Ac), tosyl (Ts), mesyl (Ms), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tertiary butyldimethylsilyl (TBS), benzyl (Bn), para-methoxybenzyl (PMB), trityl (Tr), para-bromobenzoyl, para- nitrobenzoyl, benzoyl (Bz), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), [(3,4-dimethoxybenzyl)oxy]methyl (DMBM), methoxymethyl (MOM), 2- methoxyethoxym ethyl (MEM), methylthiomethyl (MTM), and 2-(trimethylsilyl) ethoxymethyl (SEM).

The conversion of the compound of formula (5) to a compound of formula (4) may be carried out in the presence of a third base, which may be, for example, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N- methylmorpholine, piperidine, pyridine, and mixtures thereof.

The compound of formula (4) may be converted to sotagliflozin by:

reducing the morpholine moiety of the compound of formula (4) to yield a compound of formula (10)

deprotecting the compound of formula (10) to yield sotagliflozin or a pharmaceutically acceptable salt thereof

Alternatively, the compound of formula (4) may be converted to sotagliflozin by: deprotecting the compound of formula (4) to yield a compound of formula

(3)

; and reducing the morpholine moiety of the compound of formula (3) to yield sotagliflozin or a pharmaceutically acceptable salt thereof

In the conversion of the compound of formula 4 to sotagliflozin, the reducing of the morpholine moiety may be carried out in the presence of a second reducing agent, which may be, for example, boron trifluoride diethyl etherate or palladium carbon/ammonium formate.

The present disclosure provides a process for the preparation of a compound of formula 26a, which includes:

oxidizing a compound of formula (30) in the presence of an oxidizing agent to obtain a compound of formula (29)

reacting a compound of formula (29) with N-methylpiperazine to obtain a compound of formula (26a)

The oxidizing agent used in the oxidizing step may be, for example, trichloroisocyanuric acid, dipotassium hydrogen phosphate, or mixtures thereof.

The compound of formula (26a) may be converted to sotagliflozin or a pharmaceutically acceptable salt thereof, using the methods disclosed herein.

The present disclosure also provides a process for the preparation of a compound of formula (9) that includes:

converting a compound of formula (33) into a compound of formula (32) in the presence of a base

; and reacting a compound of formula (32) with morpholine to get a compound of formula (9)

wherein“X” is a halide (e.g., chloro, bromo, or iodo) and R is Ci- ₄ alkyl, mesyl, or tosyl.

The base may be, for example, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyridine, or mixtures thereof.

The compound of formula (9) may be converted to sotagliflozin or a pharmaceutically acceptable salt thereof, using the methods disclosed herein.

The present disclosure also provides a process for the preparation of a compound of formula (27a) which includes:

converting a compound of formula (33) into a compound of formula (32) in the presence of a base

33 32

; and reacting a compound of formula (32) with N-methylpiperazine to get a compound of formula (27a)

wherein“X” is a halide (e.g., bromo, chloro, or iodo) and“R” is Ci-4 alkyl, mesyl, or tosyl.

The base may be, for example, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyridine, or mixtures thereof.

The compound of formula (27a) may be converted to sotagliflozin or a pharmaceutically acceptable salt thereof, using the methods disclosed herein.

The present disclosure also provides a number of compounds useful in the preparation of sotagliflozin, listed below:

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention. The present disclosure relates generally to a process for the preparation of sotagliflozin including pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof, as well as the intermediates used in its preparation.

The present disclosure provides methods for preparing sotagliflozin.

For example, sotagliflozin may be prepared by a process that includes:

condensing a compound of formula 27 with a compound of formula 26 to obtain a compound of formula 25; reducing the compound of formula 25 to obtain a compound of formula 24;

cyclizing the compound of formula 24 to obtain a compound of formula 23;

protecting the hydroxyl groups of the compound of formula 23 to obtain a compound of formula 22; and

converting the compound of formula 22 to a compound of formula 21.

22 21

The compound of formula 21 may then be converted to sotagliflozin by a process that includes, in any order:

reducing the“P” moiety; and

hydrolyzing to deprotect the hydroxyl groups of the 6-methylsulfanyloxane- 3,4,5-triol moiety.

Pg = Hydroxyl protecting group

Sotagliflozin may be prepared by condensation of a compound of formula 27 with a compound of formula 26 to form a compound of formula 25. The starting material, the compound of formula 27, is well known, and may be prepared by any conventional methods reported in the art, for example, as reported in Angewandte chemie international edition, 52(6), 1777-1780, 2013, which is incorporated herein by reference with respect to the synthesis of the compound of formula 27. Example 10 also provides disclosure as to a useful method for preparing a compound of formula 27. As used herein and throughout this disclosure (unless indicated otherwise), an“X” moiety in a chemical structure represents chloro, bromo, or iodo. As used herein and through this disclosure (unless indicated otherwise), an“L” moiety represents a leaving group. Examples of suitable leaving groups include, but are not limited to, morpholine, N- methylpiperazine, N-ethylpiperazine, 1-(2-pyramidyl)piperazine, 1-(2- pyridyl)piperazine, and benzylpiperazine.

The compound of formula 26 may be prepared by methods disclosed herein below or as in Example 2.

As used herein and throughout this disclosure (unless indicated otherwise), a“P” moiety represents -OR, dimethoxy, morpholine, or NR ¹ R ² , wherein R is a Ci- ₄ alkyl, mesyl, or tosyl; Ri and R2 are, independently, a linear or branched alkyl group, a linear or branched alkenyl group, a cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group; or R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein the heterocyclic ring optionally contains, in addition to the nitrogen to which R1 and R2 are attached, an additional heteroatom selected from N and wherein the heterocyclic ring is optionally substituted with a C1-C4 alkyl group.

The condensation reaction may be carried out in the presence of a first base in a first solvent. The first base may be, but is not limited to, organic organolithium compounds (such as, but not limited to, n-butyllithium, sec-butyllithium or tert- butyllithium), sodium hydride, potassium hydride, isopropylmagnesium chloride- lithium chloride complex, sec-butylmagnesium chloride-lithium chloride complex, isopropylmagnesium chloride-lithium chloride complex, or (trimethylsilyl)methyllithium. The first solvent may be, but is not limited to, ether solvents, aromatic hydrocarbon solvents, alcohol solvents, halogenated hydrocarbon solvents, or mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixture thereof. The condensation reaction may be carried out at a reduced temperature, for example, at a temperature of about -80°C to about 10°C. The reaction may be allowed to proceed for a suitable period of time, for example, for about 1 hour to about 5 hours.

A compound of formula 24 may then be prepared by reducing the compound of formula 25. This reduction may be carried out in a second solvent with a first reducing agent. The second solvent may be, but is not limited to, ether solvents, aromatic hydrocarbon solvents, alcohol solvents, halogenated hydrocarbon solvents, or mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixture thereof. The first reducing agent may be, but is not limited to, silanes (such as, but not limited to, triethylsilane, tripropylsilane, triisopropylsilane, or diphenylsilane), hydrides (such as, but not limited to, sodium borohydride, sodium hydride, sodium cyanoborohydride, zinc borohydride, lithium aluminum hydride, or diisobutylaluminum hydride), samarium iodide, or a hydride (as listed above) in combination with cerium (III) chloride heptahydrate. The reduction reaction may be carried out at a temperature of 10°C to about 30°C for a suitable period of time, e.g., about 10 minutes to about 30 minutes.

A compound of formula 23 may be prepared by cyclization of the compound of formula 24. Cyclization may be carried out in the presence of an acid in a third solvent. Examples of suitable acids include, but are not limited to, organic acids (such as, but not limited to, formic acid, acetic acid, trifluoroacetic acid, and methanesulfonic acid) and inorganic acids (such as, but not limited to, hydrochloric acid, sulfuric acid, and nitric acid). Examples of suitable third solvents include, but are not limited to, halogenated hydrocarbon solvents, ether solvents, amide solvents, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable amide solvents include, but are not limited to, dimethyl formamide, dimethyl acetamide, and mixtures thereof. The reaction may be carried out at an elevated temperature (e.g., about 70°C to about 85°C) for a suitable period of time (e.g., about 3 to about 6 hours).

The compound of formula 23 may then be converted to a compound of formula 22 by protecting the hydroxyl moieties of the compound of formula 23. Protection may be carried out in the presence of a catalyst, a second base, and a source of a hydroxyl protecting group in a fourth solvent. The catalyst may be, for example, 4-dimethylaminopyridine. Examples of suitable second bases include, but are not limited to, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyridine, and mixtures thereof. Examples of suitable hydroxyl protecting groups include, but are not limited to, alkyl, allyl, pivaloyl, acetyl (Ac), tosyl (Ts), mesyl (Ms), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), benzyl (Bn), para-methoxybenzyl (PMB), trityl (Tr), para-bromobenzoyl, para- nitrobenzoyl, benzoyl (Bz), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), [(3,4-dimethoxybenzyl)oxy]methyl (DMBM), methoxymethyl (MOM), 2- methoxyethoxym ethyl (MEM), methylthiomethyl (MTM), and 2-(trimethylsilyl) ethoxymethyl (SEM) groups. One of skill in the art would readily recognize sources of hydroxyl protecting groups as well as conditions for their use. The fourth solvent may be, for example a chlorinated solvent (e.g., dichloromethane), a nitrile solvent (e.g., acetonitrile), or a mixture thereof. The protecting reaction may be carried out at a reduced temperature. For example, it may be carried out at a temperature of about -10°C to about -20°C for a suitable period of time (e.g., about 1 hour to about 2 hours). The compound of formula 22 may then be converted to a compound of formula 21. A compound of formula 22 may be reacted with thiourea and trimethylsilyl trifluoromethanesulfonate in a fifth solvent. The reaction may be carried out at an elevated temperature. For example, the temperature may be about 70°C to about 100°C for a suitable period of time (e.g., for about 3 to about 5 hours).

Methyl iodide and a third base may then be added. The third base may be, for example (but not limited to), triethylamine, N-ethylisopropylamine, diisopropylamine, N-diisopropylethylamine, N-methylmorpholine, piperidine, pyridine, and mixtures thereof. Examples of suitable fifth solvents include, but are not limited to, halogenated hydrocarbon solvents, ether solvents, amide solvents, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4- dioxane, and mixtures thereof.

The compound of formula 21 may then be converted to sotagliflozin, for example, by deprotecting the compound of formula 21 in the presence of a fourth base in a sixth solvent to yield a compound of formula 20. The reaction may be carried out at an elevated temperature, for example, at a temperature about 30°C to about 70°C for 3-5 hours. Examples of suitable fourth bases include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Examples of suitable sixth solvents include alcohol solvents. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof.

Sotagliflozin may be then be prepared by reducing the compound of formula 20 with a second reducing agent in a seventh solvent. Examples of suitable second reducing agents include, but are not limited to, triethylsilane, boron trifluoride diethyl etherate, and ammonium formate/palladium on carbon. Examples of suitable seventh solvents include, but are not limited to, dichloromethane, chloroform, acetonitrile, toluene, tetrahydrofuran, methanol, and mixtures thereof. The reaction may be carried out at ambient temperature, for example about 20°C to about 35°C. The reaction may be monitored by HPLC, but in any embodiment, will generally progress for about 3 hours to about 15 hours.

Alternatively, deprotection and reduction may be carried out in reverse order by first reducing the“P” moiety of the compound of formula 21 to yield a compound of formula 19 and then deprotecting to yield sotagliflozin. The reaction conditions for the reducing step and deprotecting step are as disclosed above.

In any embodiment, the“P” moiety of Formula 27 is dimethoxy, the“L” leaving group of Formula 26 is a morpholine moiety, and the hydroxyl protecting group of Formula 22 is an acetyl group. Thus, sotagliflozin may be prepared by a process that includes:

condensing a compound of formula 18 with a compound of formula 17 to obtain a compound of formula 16;

reducing the compound of formula 16 to obtain a compound of formula 15;

cyclizing the compound of formula 15 to obtain a compound of formula 14;

reacting the compound of formula 14 with acetic anhydride to obtain a compound of formula 13; and

converting the compound of formula 13 to a compound of formula 12.

13 12

The compound of formula 12 may then be converted to sotagliflozin by a process that includes, in any order:

deprotecting the hydroxyl groups of the 6-methylsulfanyloxane-3,4,5-triol moiety; and

reducing to remove the ketone moiety.

As described above, sotagliflozin may be prepared by condensation of a compound of formula 18 with a compound of formula 17 to form a compound of formula 16. The starting material, the compound of formula 18, is well known, and may be prepared by any conventional methods reported in the art, for example, as described in Example 4.“X” is as previously described above.

The condensation reaction may be carried out in the presence of a first base in a first solvent. The first solvent may be, but is not limited to, ether solvents, aromatic hydrocarbon solvents, alcohol solvents, halogenated hydrocarbon solvents, or mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. The first base may be, but is not limited to, organolithium compounds (such as, but not limited to, n-butyllithium, sec-butyllithium or tert-butyllithium), sodium hydride, potassium hydride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride-lithium chloride complex, isopropylmagnesium chloride-lithium chloride complex, or (trimethylsilyl)methyllithium. The condensation reaction may be carried out at a reduced temperature, for example, at a temperature of about -80°C to about 10°C. The reaction may be allowed to proceed for a suitable period of time, for example, for about 1 hour to about 5 hours.

The compound of formula 15 may then be prepared by reducing the compound of formula 16. This reduction may be carried out in a second solvent with a first reducing agent. The second solvent may be, but is not limited to, ether solvents, aromatic hydrocarbon solvents, alcohol solvents, halogenated hydrocarbon solvents, or mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. The first reducing agent may be, but is not limited to, silanes (such as, but not limited to, triethylsilane, tripropylsilane, triisopropylsilane, and diphenylsilane), hydrides (such as, but not limited to, sodium borohydride, sodium hydride, sodium cyanoborohydride, zinc borohydride, lithium aluminum hydride, and diisobutylaluminum hydride), samarium iodide, and a hydride (as listed above) in combination with cerium (III) chloride heptahydrate. The reduction reaction may be carried out at a temperature of 10°C to about 30°C for a suitable period of time, e.g., about 10 minutes to about 30 minutes.

The compound of formula 14 may be prepared by cyclization of the compound of formula 15. Cyclization may be carried out, for example, in the presence of an acid in a third solvent. Examples of suitable acids include, but are not limited to, organic acids (such as, but not limited to, formic acid, acetic acid, trifluoroacetic acid, and methanesulfonic acid) and inorganic acids (such as, but not limited to, hydrochloric acid, sulfuric acid, and nitric acid). Examples of suitable third solvents include, but are not limited to, halogenated hydrocarbon solvents, ether solvents, amide solvents, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable amide solvents include, but are not limited to, dimethyl formamide, dimethyl acetamide, and mixtures thereof. The reaction may be carried out at an elevated temperature (e.g., about 70°C to about 85°C) for a suitable period of time (e.g., about 3 to about 6 hours).

The compound of formula 14 may be converted to a compound of formula 13 by protecting the hydroxyl moieties of the compound of formula 14. Protection may be carried out in the presence of a catalyst, a second base, and a source of an acetyl protecting group in a fourth solvent. The source of an acetyl group may be, for example, acetic anhydride. The catalyst may be, for example, 4- dimethylaminopyridine. Examples of suitable second bases include, but are not limited to, triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methylmorpholine, piperidine, pyridine, and mixtures thereof. The fourth solvent may be, for example a chlorinated solvent (e.g., dichloromethane), a nitrile solvent (e.g., acetonitrile), or a mixture thereof. The protecting reaction may be carried out at a reduced temperature. For example, it may be carried out at a temperature of about -10°C to about -20°C for a suitable period of time (e.g., about 1-2 hours).

The compound of formula 13 may then be converted to a compound of formula 12. The compound of formula 13 may be reacted with thiourea and trimethylsilyl trifluoromethanesulfonate in a fifth solvent. The reaction may be carried out at an elevated temperature. For example, the temperature may be about 70°C to about 100°C for a suitable period of time (e.g., for about 3 to about 5 hours).

Examples of suitable fifth solvents include, but are not limited to, halogenated hydrocarbon solvents, ether solvents, amide solvents, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, and 1 ,4- dioxane, and mixtures thereof.

Methyl iodide and a third base may then be added. Examples of suitable third bases include, but are not limited to, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyridine, and mixtures thereof.

The compound of formula 12 may then be converted to sotagliflozin, for example, by first deprotecting the compound of formula 12 in the presence of a fourth base in a sixth solvent. The conversion may be carried out at an elevated temperature, for example, at a temperature about 30°C to about 70°C for 3-5 hours. Examples of suitable fourth bases include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Examples of suitable sixth solvents include alcohol solvents. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof.

Sotagliflozin may be then be prepared by reducing the compound of formula 11 with a second reducing agent in a seventh solvent until the reaction is complete. The reaction may be carried out at ambient temperature, for example about 20°C to about 35°C. Examples of suitable second reducing agents include, but are not limited to, triethylsilane, boron trifluoride diethyl etherate, and ammonium formate/palladium on carbon. Examples of suitable seventh solvents include, but are not limited to, dichloromethane, chloroform, acetonitrile, toluene, tetrahydrofuran, methanol, and mixtures thereof. Reaction progress may be monitored by HPLC.

Alternatively, the deprotection and reduction may be carried out in reverse order by first reducing the ketone moiety of the compound of formula 12 to yield a compound of formula 10 and then deprotecting to yield sotagliflozin. The reaction conditions for the reducing step and deprotecting step are as disclosed above. In another example, both the“P” moiety in Formula 27 and the“L” leaving group in Formula 26 are morpholine moieties and the hydroxyl protecting group on Formula 22 is an acetyl group. Thus, sotagliflozin may be prepared a process that includes:

condensing a compound of formula 9 with a compound of formula 17 to obtain a compound of formula 8;

reducing the compound of formula 8 to obtain a compound of formula 7;

cyclizing the compound of formula 7 to a compound of formula 6;

reacting the compound of formula 6 with acetic anhydride to obtain a compound of formula 5; and

converting the compound of formula 5 to a compound of formula 4.

The compound of formula 4 may then be converted to sotagliflozin by a process that includes, in any order:

deprotecting the hydroxyl groups of the 6-methylsulfanyloxane-3,4,5-triol moiety; and

reducing to remove the morpholine moiety.

Sotagliflozin may be prepared by condensation of the compound of formula 9 with a compound of formula 17 to form a compound of formula 8. The starting material, compound 9, may be prepared by methods reported in the prior art or by methods disclosed herein (below).“X” is as described above.

In any embodiment, the“X” in Formula 9 is Br (formula 9a), and a compound of formula 9a may be prepared, for example, according to Example 11. The condensation reaction may be carried out in the presence of a first base in a first solvent. The first base may be, but is not limited to, organolithium compounds (such as, but not limited to, n-butyllithium, sec-butyllithium, t- butyllithium), sodium hydride, potassium hydride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride lithium chloride complex, isopropylmagnesium chloride-magnesium chloride complex, or (trimethylsilyl)methyllithium. The first solvent may be, but is not limited to, ether solvents, aromatic hydrocarbon solvents, alcohol solvents, halogenated hydrocarbon solvents, or mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixture thereof. The condensation reaction may be carried out at a reduced temperature, for example, at a temperature of about -80°C to about 10°C. The reaction may be allowed to proceed for a suitable period of time, for example, for about 1 hour to about 5 hours.

A compound of formula 7 may then be prepared by reducing the compound of formula 8. This reduction may be carried out in a second solvent with a first reducing agent. The second solvent may be, but is not limited to, ether solvents, aromatic hydrocarbon solvents, alcohol solvents, halogenated hydrocarbon solvents, or mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixture thereof. The first reducing agent may be, but is not limited to, silanes (such as, but not limited to, triethylsilane, tripropylsilane, triisopropylsilane, and diphenylsilane), hydrides (such as, but not limited to, sodium borohydride, sodium hydride, sodium cyanoborohydride, zinc borohydride, lithium aluminum hydride, and diisobutylaluminum hydride), samarium iodide, and a hydride (as listed above) in combination with cerium (III) chloride heptahydrate. The reduction reaction may be carried out at a temperature of 10°C to about 30°C for a suitable period of time, e.g., about 10 minutes to about 30 minutes.

The compound of formula 6 may be prepared by cyclization of the compound of formula 7. Cyclization may be carried out in the presence of an acid in a third solvent at an elevated temperature (e.g., about 70°C to about 85°C) for a suitable period of time (e.g., about 3 to about 6 hours). Examples of suitable acids include, but are not limited to, organic acids (such as, but not limited to, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and mixtures thereof) and inorganic acids (such as, but not limited to, hydrochloric acid, sulfuric acid, nitric acid, and mixtures thereof). Examples of suitable third solvents include, but are not limited to, halogenated hydrocarbon solvents, ether solvents, amide solvents, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert- butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable amide solvents include, but are not limited to, dimethyl formamide, dimethyl acetamide, and mixtures thereof.

The compound of formula 6 may be converted to a compound of formula 5 by protecting the hydroxyl moieties of the compound of formula 6. Protection may be carried out in the presence of a catalyst, a second base, and a source of an acetyl protecting group in a fourth solvent. The source of an acetyl group may be, for example, acetic anhydride. The catalyst may be, for example, 4- dimethylaminopyridine. Examples of suitable second bases include, but are not limited to, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropyl ethylamine, N-methylmorpholine, piperidine, pyridine, and mixtures thereof. The fourth solvent may be, for example a chlorinated solvent (e.g., dichloromethane) or a nitrile solvent (e.g., acetonitrile). The reaction may be carried out at a reduced temperature. For example, it may be carried out at a temperature of about -10°C to about -20°C for a suitable period of time (e.g., about 1-2 hours).

The compound of formula 5 may then be converted to a compound of formula 4 by reacting the compound of formula 5 with thiourea and trimethylsilyl trifluoromethanesulfonate in a fifth solvent. The reaction may be carried out at an elevated temperature. For example, the temperature may be about 70°C to about 100°C for a suitable period of time (e.g., for about 3 to about 5 hours).

Examples of suitable fifth solvents include, but are not limited to, halogenated hydrocarbon solvents, ether solvents, amide solvents, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, and 1 ,4- dioxane, and mixtures thereof.

Methyl iodide and a third base may then be added. Examples of suitable third bases include, but are not limited to, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyridine, and mixtures thereof.

The compound of formula 4 may then be converted to sotagliflozin, for example, by first deprotecting the compound of formula 4 in the presence of a fourth base in a sixth solvent to yield a compound of formula 3. The reaction maybe carried out at an elevated temperature, for example, the reaction may be carried out at a temperature about 30°C to about 70°C for 3-5 hours. Examples of suitable fourth bases include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Examples of suitable sixth solvents include alcohol solvents. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof.

Sotagliflozin may be then be prepared by reducing the compound of formula 3 with a second reducing agent in a seventh solvent. This reaction may be carried out at ambient temperature, for example about 20°C to about 35°C, until the reaction is complete. Examples of suitable second reducing agents include, but are not limited to, triethylsilane, boron trifluoride diethyl etherate, and ammonium formate/palladium on carbon.

Examples of suitable seventh solvents include, but are not limited to, dichloromethane, chloroform, acetonitrile, toluene, tetrahydrofuran, methanol, and mixtures thereof. The progress of the reaction may be monitored by HPLC, but generally, in any embodiment, may proceed for about 3 hours to about 15 hours.

Alternatively, the deprotection and reduction may be carried out in reverse order by first reducing the morpholine moiety of the compound of formula 4 to yield a compound of formula 10 and then deprotecting to yield sotagliflozin. The reaction conditions for the reducing step and deprotecting step are as disclosed above.

As noted above, the present disclosure provides methods for preparing a compound of formula 26. In any embodiment, the“L” moiety of formula 26 may be N-methylpiperazine (i.e. , formula 26a, shown below.

26a

For example, the compound of formula 26a may be prepared by a process that includes: oxidizing a compound of formula 30 to obtain a compound of formula 29; and

reacting the compound of formula 29 with N-methylpiperazine to obtain a compound of formula 26a.

Within the context of this embodiment, a compound of formula 30 (1 ,2-0- isopropylidene-a-D-xylofuranose) may be oxidized with an oxidizing agent in the presence of a base in a first solvent to obtain a compound of formula 29. The reaction mixture may also contain a buffer. This reaction may be carried out at room temperature, for example, at a temperature of about 20°C to about 35°C for a suitable time period, (e.g., about 20 hours to about 30 hours). Examples of suitable oxidizing agents include, but are not limited to, trichloroisocyanuric acid (TCCA), dipotassium hydrogen phosphate, (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO), and the like. Examples of suitable bases include, but are not limited to, alkoxides, hydroxides, carbonates, bicarbonates, amines, and mixtures thereof. Examples of suitable hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, and mixtures thereof. Examples of suitable alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. Examples of suitable carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Examples of suitable bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Examples of suitable amines include, but are not limited to, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and mixtures thereof. Examples of suitable buffers include, but are not limited to, sodium bromide, sodium iodide, and the like. Examples of suitable first solvents include ketone solvents, alcohol solvents, water, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n- propanol or t-butanol, and mixtures thereof.

The compound of formula 29 may then be converted to a compound of formula 28 by reacting the compound of formula 29 with N-methylpiperazine in the presence of boric acid and a second solvent. This reaction may be carried out at an elevated temperature, for example, at a temperature of about 100°C to about 120°C for a suitable period of time, for example, for about 20 hours to about 15 hours. Examples of suitable second solvents include, but are not limited to, ether solvents, aromatic hydrocarbon solvents, alcohol solvents, halogenated hydrocarbon solvents, and mixtures thereof. Examples of suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Examples of suitable aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, t-butanol, and mixtures thereof. Examples of suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof.

As noted above, the present disclosure provides methods for preparing a compound of formula 9. For example, the compound of formula 9 may be prepared by a process that includes:

converting a compound of formula 33 to a compound of formula 32 in the presence of a base; and

Oil OR

33 32 reacting the compound of formula 32 with morpholine to get a compound of formula 9.

Within the context of this embodiment, a compound of formula 30 may be oxidized with an oxidizing agent in the presence of a base in a first solvent to obtain a compound of formula 29. “X” and “R” are as described above. This reaction may be carried out at room temperature, for example, at a temperature of about 20°C to about 35°C for a suitable time period, (e.g., about 20 hours to about 30 hours).

Examples of suitable oxidizing agents include, but are not limited to, trichloroisocyanuric acid (TCCA), dipotassium hydrogen phosphate, and the like. Examples of suitable bases include, but are not limited to, alkoxides, hydroxides, carbonates, bicarbonates, amines, and mixtures thereof. Examples of suitable hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, and mixtures thereof; Examples of suitable alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. Examples of suitable carbonates include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Examples of suitable bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Examples of suitable amines include, but are not limited to, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and mixtures thereof. Examples of suitable first solvents include ketone solvents, alcohol solvents, water, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof. Examples of suitable alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol or t-butanol, and mixtures thereof.

The compound of formula 32 may then be reacted with morpholine to yield a compound of formula 9. This reaction may be carried out in the presence of boric acid and second solvent. This reaction may be carried out at an elevated temperature, for example, at a temperature of about 100°C to about 120°C for a suitable period of time, for example, for about 20 hours to about 15 hours. The second solvent may be, for example, xylene, 1 ,4-dioxane, or a mixture thereof. Sotagliflozin may be optionally converted into a pharmaceutically acceptable salt of sotagliflozin. Methods for converting compounds into their acid salt forms are well known in the art, and may be carried out, for example, by reacting a free base moiety on the compound with a suitable reagent.

Examples of suitable acids include, for example, inorganic acids or organic acids. Examples of suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Suitable organic acids include, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. A pharmaceutically acceptable salt may alternatively be prepared by other methods well known in the art, for example, ion exchange. Additional examples of suitable salts include, for example, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, (R,S)-malate, (S)-malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, phthalate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.

As noted above, the present disclosure provides methods for preparing a compound of formula 27. In any embodiment, the“P” moiety in formula 27 may be 1-methylpiperazine (i.e. , formula 27a, shown below.

27a

The compound of formula 27a may be used to synthesize sotagliflozin.“X” is as previously disclosed above. In one embodiment, the compound of formula 27a may be prepared by a process that includes:

converting a compound of formula 33 to a compound of formula 32 in the presence of a base; and

33 32 reacting the compound of formula 32 with N-methylpiperazine to get a compound of formula 27a.

“X” and“R” are as previously described above. A compound of formula 33 may be converted to a compound of formula 32 in the presence of a base in a first solvent. Examples of suitable bases include, but are not limited to, triethylamine, N-ethylisopropylamine, diisopropylamine, diisopropylethylamine, N- methylmorpholine, piperidine, pyridine, and mixtures thereof. The first solvent may be, but is not limited to, halogenated hydrocarbon solvents, ether solvents, amide solvents, nitrile solvents, and mixtures thereof. Suitable halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, chloroethane, chloroform, and mixtures thereof. Suitable ether solvents include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane, and mixtures thereof. Suitable amide solvents include, but are not limited to, dimethylformamide, dimethylacetamide, and mixtures thereof. One example of a suitable nitrile solvent is acetonitrile. This reaction may be carried out at a room temperature (e.g., at about 20°C to about 35°C) for a suitable time (e.g., for about 12 to about 18 hours).

The compound of formula 32 may then be converted to a compound of formula 27a by reacting a compound of formula 32 with N-methylpiperazine in a second solvent. This reaction may be carried out at an elevated temperature (e.g., at about 50°C to about 55°C) for a suitable time period (e.g., for about 4 hours). The second solvent may be, for example (but is not limited to), acetonitrile.

In one embodiment, “X” in formula 33 is Br (i.e. , formula 33a) and may be prepared, for example, according to Example 9. The conversion of the compound of formula 33a to a compound of formula 27a (where“X” is Br, i.e., formula 27b) may be carried out, for example, according to Example 10.

The methods disclosed herein above result in the synthesis of novel intermediates not previously disclosed to be useful in the synthesis of sotagliflozin. These novel intermediates are identified in Table 1 below. Table 1

Samples of intermediates identified above were characterized by NMR analysis. The analyses were performed on a Bruker 300MHz Avance NMR spectrometer equipped with 5mm BBI probe. Samples were dissolved in DMSO-d6. The data were collected and processed by Topsin-NMR software. Sotagliflozin, prepared as described herein, may be useful for incorporating into a pharmaceutical dosage form, for example, an oral dosage form such as a capsule or tablet. Sotagliflozin may be useful in the treatment of type 1 diabetes and may optionally be administered in combination with insulin. The dosage form may include, in addition to sotagliflozin, other pharmaceutically acceptable excipients such as fillers, binders, lubricants, anti-adherents, coatings, colors, glidants, flavors, preservatives, sorbents, and combinations thereof. Dosage forms may have any amount of sotagliflozin incorporated therein, for example from 50 mg to 400 mg, including 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, and 350 mg. Preferably, 400 mg/day of sotagliflozin are administered.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the disclosure as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions, and formulations according to the present disclosure. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES

Example 1 : Preparation of a compound of formula 29

Sodium bicarbonate (132.5 g), sodium bromide (10.8 g), and (2, 2,6,6- tetramethylpiperidin-1-yl)oxyl (TEMPO, 1.6 g) were added sequentially to 1 ,2-0- isopropylidene-a-D-xylofuranose (compound 30, 100 g) in mixture of acetone (1000 mL) and water (500 mL) at 25-30°C and stirred for 30 minutes. After cooling the reaction mixture to 0-5°C, trichloroisocyanuric acid (122 g) was added lot wise. Thereafter, the reaction mixture temperature was slowly raised to 25- 30°C and the reaction mixture was stirred for 24 hours. After completion of the reaction, the reaction was quenched with methanol (100 ml_) and salts were vacuum filtered out of the reaction mixture. The obtained filtrate was distilled under vacuum to concentrate the mixture, diluted with ethyl acetate (500 ml_) and water (200 ml_), and stirred for 15 minutes at 25-30°C. The organic layer was concentrated by vacuum distillation and dissolved in acetonitrile (200 ml_). N- Methylpiperazine (40.4 g) was added and the resultant reaction mixture was stirred for 15 hours at 25-30°C. The solid was obtained by filtering the reaction mixture, then dried under vacuum to yield a compound of formula 29 as a yellow solid (42 g). ¹ H-NMR (DMSO-de): 8.21 (bs,1 H), 5.84 (d, 1 H), 4.37 (d, 1 H), 4.21 (d, 1 H), 4.03 (d, 1 H), 2.94 (t, 4H), 2.50 (t, 4H), 2.18 (s, 3H), 1.36 (s, 3H), 1.22 (s, 3H)

Example 2: Preparation of a compound of formula 26a

N-Methylpiperazine (3.2 g) and boric acid (0.4 g) were added to an N- methylpiperazine salt of a compound of formula 30 (10 g) in toluene (100 ml_). The temperature of the reaction mixture was increased to 108-110°C and the reaction mass was stirred for 12 hours. After reaction completion, the reaction mass was concentrated to obtain a compound of formula 29 as a residue, which was isolated in heptane to afford a compound of formula 28 as a yellow solid.

¹ H-NMR (CDCb): 6.0 (d, 1 H), 5.56 (bs, 1 H), 4.62 (d, 1 H), 4.56 (s, 1 H), 4.44 (s, 1 H), 3.79 (m, 2H), 3.54 (m, 2H), 2.94 (t, 4H), 2.50 (t, 4H), 2.18 (s, 3H), 1.36 (s,

3H), 1.22 (s, 3H)

Example 3: Preparation of a compound of formula 34a

34a A/,/\/-dimethylformamide (3 mL) and oxalyl chloride (65.2 g) were added sequentially to a solution of 5-bromo-2-chlorobenzoic acid (100 g) in dichloromethane (700 mL) at 25-30°C and stirred for 2 hours. After reaction completion, the reaction mass was concentrated then diluted with dichloromethane (200 mL). In a separate vessel, aluminum chloride (65.2 g) was taken in dichloromethane (500 mL) under nitrogen atmosphere at 0-5°C. The contents of the first vessel containing the solution of 5-bromo-2-chlorobenzoyl chloride were added to a solution of ethoxybenzene (51.8 g) in dichloromethane at 0-5°C. Thereafter, the reaction mass was quenched with cooled (0-5°C) hydrochloric acid (1N, 500 mL). The organic layer was separated, washed with 5% w/v aqueous sodium bicarbonate (300 mL), and concentrated to obtain a residue. The obtained residue was taken in methanol and isolated to afford a compound of formula 34a as an off-white solid (100 g). The compound of formula 34a may be used, for example, to prepare a compound of formula 33a. ¹ H-NMR (DMSO-de): 7.91 (dd, 1 H), 7.83 (d, 1 H), 7.68 (t, 2H), 7.40(d, 1 H), 7.07 (d, 2H), 4.15 (dd, 2H), 1.36 (t, 3H)

Example 4: Preparation of a compound of formula 18a

18a

(5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (25 g), trimethyl orthoformate (78 g) and p-toluenesulfonic acid (2.80 g) were taken in methanol (250 mL). The reaction mass was heated to 60-62°C and stirred for 12 hours. After reaction completion, the reaction mass was concentrated to yield a residue which was then dissolved in ethyl acetate. The obtained solution was washed with aqueous sodium bicarbonate and water, sequentially. The organic and aqueous layers were separated and the obtained organic layer was concentrated under vacuum to obtain a compound of formula 18a (24 g) as a white solid. ¹ H-NMR (DMSO-de): 8.18 (d, 1 H), 7.56(dd, 1 H), 7.30 (dd, 3H), 6.86(d, 2H), 4.0 (q, 2H), 2.98 (s, 6H), 1.31 (t, 3H)

Example 5: Preparation of a compound of formula 16

A compound of formula 17 (5 g) was taken in tetrahydrofuran (50 ml_) at -20 to - 30°C under nitrogen atmosphere. A mixture of a compound of formula 18 (7 g) and tert-butyl magnesium chloride in tetrahydrofuran (1M, 11.4 ml_) was added to the above solution at same temperature and reaction mass was cooled to -70 to - 75°C. n-Butyllithium in hexane (1.6M, 11 ml_) was then added to this solution and the resultant mixture was stirred at the same temperature for 30 minutes. Aqueous ammonium chloride (50 ml_) was added and the reaction mixture was stirred for 30 minutes at 0°C. After reaction completion, ethyl acetate (50 ml_) and water (25 ml_) were added to the reaction mass. The organic layer was separated and concentrated to get a compound of formula 16 (6 g) as a residue. This residue was taken in heptane and isolated as an off-white solid. ¹ H-NMR (DMSO-de): 8.5 (d, 1 H), 7.94 (dd, 1 H), 7.49 (d, 1 H), 7.26 (d, 2H), 6.85(d, 2H), 6.05 (d, 1 H), 5.66 (d, 1 H), 5.53(d, 1 H), 4.5 (t, 2H), 4.0 (q, 2H), 3.56 (s, 2H), 3.3 (s, 6H), 3.0 (s, 6H), 1.31 (t, 3H).

Example 6: Preparation of a compound of formula 12

A compound of formula 16 (5.50 g) was taken in mixture of methanol (82.5 ml_) and tetrahydrofuran (27.5 ml_) after which cerium (III) chloride heptahydrate (4.10 g) was added at 25-30°C. Thereafter, sodium borohydride (0.16 g) in aqueous sodium hydroxide (1 N, 0.5 ml_) was added at 15-20°C and stirred for 15 minutes. After completion, the reaction mass was diluted with 20% w/v ammonium chloride (27.5 ml_), water (5.5 ml_), and dichloromethane (55 ml_). The separated organic layer was washed with water (11 ml_) and concentrated to get a compound of formula 15 as a residue. The obtained compound of formula 15 was dissolved in acetonitrile (11 ml_). Dilute sulfuric acid (0.45 g sulfuric acid mixed with 22.5 ml_ of water) was added and the mixture was stirred at 75-80°C for 4 hours. Thereafter, the reaction mass was cooled to 25°C and quenched with 10% w/v aqueous potassium carbonate solution and ethyl acetate (25 ml_). The organic layer was separated and concentrated to get a compound of formula 14 as a residue. The residue was again dissolved in dichloromethane (55 ml_) to which 4- dimethylaminopyridine (0.1 g), triethylamine (4.7 g), and acetic anhydride (4.3 g) were added sequentially at -5 to -15°C and stirred for one hour. After reaction completion, water (25 ml_) was added. The organic layer was separated and concentrated to yield a compound of formula 13 as a residue. After dissolving the compound of formula 13 in 1 ,4-dioxane (30 ml_), thiourea (1.6 g), and trimethylsilyl trifluoromethanesulfonate (4.6 g) were added at 25-30°C.

Thereafter, the reaction mass was heated to 80°C and stirred for 3 hours. After cooling the reaction mass to 20°C, methyl iodide (3.7 g) and diethylisopropylamine (6.7 g) were added sequentially and stirred for 15 hours at 25°C. After reaction completion, ethyl acetate (25 ml_) and water (55 ml_) were added to the reaction mass. The separated organic layer was concentrated to obtain a compound of formula 12 as a residue, which was taken in methanol and isolated as an off-white solid (3g).

¹ H-NMR (DMSO-de): 7.64 (d, 2H), 7.57 (s, 2H), 7.49 (s, 1 H), 5.40 (t, 1 H), 5.21 (m, 2H), 4.91 (d, 1 HO, 4.81(d, 1 H), 4.15 (q, 2H), 2.10 (s, 3H), 2.03 (s, 3H), 1.95 (s, 3H), 1.81 (s, 3H), 1.36 (t, 3H)

Example 7: Preparation of a compound of formula 11

A compound of formula 12 (2 g) was taken in methanol (20 ml_) at 25-30°C. Potassium carbonate (0.25 g) was added at same temperature, the reaction mass was heated to 60°C, and stirred for 3 hours. After reaction completion, the reaction mass was concentrated and diluted with dichloromethane (20 ml_), methanol (2 ml_), and water (4 ml_). The organic layer was separated and concentrated to afford a compound of formula 11 (1.5 g) as a white solid. ¹ H-NMR (DMSO-de): 7.70 (d, 2H), 7.56 (d, 1 H), 7.51 (d, 1 H), 7.35 (s, 1 H), 4.57 (s, 1 H), 4.38 (d, 1 H), 4.22 (d, 2H), 4.15 (q, 2H), 3.30 (t, 1 H), 3.21 (m, 2H), 2.06 (s, 3H), 1.36 (t, 3H)

Example 8: Preparation of sotagliflozin Triethylsilane (2.5 ml_) and boron trifluoride diethyl etherate (5 ml_) were added sequentially to a solution of a compound of formula 12 (1.0 g) in dichloromethane (20 ml_) at 25-30°C and the reaction mass was stirred for 12 hours at 25-30°C. After reaction completion, the reaction mass was quenched with 5% w/v aqueous sodium bicarbonate (10 ml_). The organic layer was separated and concentrated to afford sotagliflozin (0.5 g) as a white solid.

¹ H-NMR (CDCIs): 7.32(d, 1 H), 7.26(s, 2H), 7.06 (d, 2H), 6.78(d, 2H), 4.29 (d, 1 H), 4.15 (d, 1 H), 4.10-3.95 (m, 3H), 3.64 (t, 1 H), 3.50 (m, 2H), 2.73 (br s, 3H), 1.40(t, 3H)

Example 9: Preparation of a compound of formula 33a Sodium borohydride (3.3 g) was added lot wise to (5-bromo-2-chlorophenyl)(4- ethoxyphenyl)methanone (formula 34a, e.g., from example 3; 30 g) in methanol (300 ml_) at 15-20°C and stirred for 2 hours. After reaction completion, the reaction mass was quenched with 20 % w/v aqueous ammonium chloride solution (150 ml_) and stirred for 10 minutes at 25-30°C. Thereafter, the reaction mass was concentrated and diluted/stirred with ethyl acetate (200 ml_), water (150 ml_), and aqueous hydrochloride (5N, 10 ml_) at 25-30°C. The organic layer was separated, concentrated, and a compound of formula 33a was isolated as a white solid (30 g) using dichloromethane.

¹ H-NMR (DMSO-de): 7.83 (d, 1 H), 7.48 (dd, 1 H), 7.35 (dd, 1 H), 6.86 (d, 2H), 6.11 (d, 2H), 5.87(d, 1 H), 3.99 (q, 2H), 1.3 (t, 3H) Example 10: Preparation of a compound of formula 27b

(5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol (formula 33a, 10 g) was taken in a mixture of dichloromethane (50 ml_) and tetrahydrofuran (50 ml_) at room temperature. Triethylamine (7.9 g) was added to this solution, the reaction mass was cooled to -2°C, and methanesulfonyl chloride (6.6 g) was added slowly at 0-5°C. The reaction mass temperature was raised to 25-30°C and stirred for 15 hours. After reaction completion, salts were removed by filtration and the filtrate was concentrated. The resulting residue was dissolved in acetonitrile (50 ml_) and N-methylpiperazine (13.1 g) was added at 25-30°C. The reaction mixture was again heated to 50-55°C and stirred for 4 hours. After reaction completion, the contents were concentrated and the obtained residue was dissolved in dichloromethane (50 ml_) and water (25 ml_). Again, the organic layer was separated, concentrated, and a compound of formula 31a was isolated in acetonitrile (50 ml_) as an off-white solid (7.5 g). ¹ H-NMR (DMSO-de): 7.91 (d, 1 H), 7.45 (dd, 1 H), 7.35 (d, 1 H), 7.26 (d, 2H), 6.87 (d, 2H), 4.59 (s, 1 H), 3.98 (q, 2H), 2.5 (s, 3H), 2.20 (t, 8H), 2.20 (t, 2H), 1.30 (t, 3H)

Example 11 : Preparation of a compound of formula 9a

Triethylamine (4.4 g) was added to 4-[(5-bromo-2-chlorophenyl)(4- ethoxyphenyl)methyl]morpholine (5 g) in mixture of dichloromethane (25 ml_) and tetrahydrofuran (25 ml_). The reaction mass was cooled to -2°C after which methanesulfonyl chloride (6.6 g) was added slowly at 0-5°C. The reaction temperature was raised to 25-30°C and the mixture was stirred for 15 hours. After reaction completion, the reaction mixture was filtered to collect the salts, which were washed with tetrahydrofuran (5 ml_). The filtrate was concentrated to obtain a residue, which was dissolved in acetonitrile (50 ml_). Potassium carbonate (10 g) and morpholine (6.3 g) were added sequentially at 25-30°C. The reaction mixture was heated to 50-55°C and stirred for 2 hours. After reaction completion, inorganic salts were filtered out, the filtrate was concentrated, and the obtained residue was dissolved in dichloromethane (50 ml_) and water (25 ml_). The organic layer was separated and concentrated. Finally, a compound of formula 9a was isolated in acetonitrile (10 ml_) as white solid (4.2 g).

¹ H-NMR (DMSO-de): 7.94 (d, 1 H), 7.45 (dd, 1 H), 7.35 (d, 1 H), 7.26 (d, 2H), 6.87 (d, 2H), 4.59 (s, 1 H), 3.98 (q, 2H), 3.59 (t, 4H), 2.30 (d, 2H), 2.20 (t, 2H), 1.30 (t,

3H)

Example 12: Preparation of a compound of formula 8 t-Butylmagnesium chloride in tetrahydrofuran (1 M, 16.6 ml_) was added to a solution of a compound of formula 17 (7.3 g) in tetrahydrofuran (50 ml_) under nitrogen atmosphere at -20 to -30°C and stirred for 30 minutes. Compound 9 (7.3 g) was added at -20 to -30°C, after which n-butyllithium in hexane (1.6 M, 30 ml_) at -70 to -75°C. The reaction mixture was stirred for 30 minutes at same temperature after which 25% w/v aqueous ammonium chloride (50 ml_) was added. The mixture was stirred for 30 minutes at 0°C. The reaction mass was diluted with ethyl acetate (70 ml_) at 25-30°C then sequentially washed with water and brine. The separated organic layer was concentrated and a compound of formula 8 (10 g) was isolated in heptane as an off-white solid.

¹ H-NMR (DMSO-de): 7.76 (dd, 1 H), 7.51 (d, 1 H), 7.29 (dd, 2H), 6.87 (d, 2H), 6.06 (q, 1 H), 5.66 (d, 1 H), 5.47 (d, 1 H), 4.64 (d, 1 H), 4.53 (q, 1 H), 4.4 (q, 1 H), 3.98 (q, 2H), 3.61 (m, 4H), 2.33 (s, 2H), 2.20 (s, 2H), 1.30 (t, 3H), 1.29 (s, 6H)

Example 13: Preparation of a compound of formula 4

Cesium trichloride heptahydrate (4.10 g) was added to a compound of formula 8 (5.50 g) in a mixture of methanol (37 ml_) and tetrahydrofuran (37 ml_) at 25- 30°C. Sodium borohydride (0.1 g) in aqueous sodium hydroxide (1 N, 0.4 ml_) was added at 15-20°C and the mixture was stirred for 15 minutes. After diluting the reaction mass with 20% w/v ammonium chloride (40 ml_), water (5.5 ml_), and dichloromethane (55 ml_), the organic layer was washed with water (1 1 ml_) and concentrated to get a compound of formula 7 as a residue. The residue was then dissolved in acetonitrile (11 ml_) after which dilute sulfuric acid solution (0.45 g sulfuric acid mixed with 22.5 ml_ of water) was added at 75-80°C and stirred for 4 hours. The reaction mass was cooled to 25°C and quenched with 10% w/v aqueous potassium carbonate solution and ethyl acetate. The organic layer was separated and concentrated to get a compound of formula 6 as a residue. After dissolving the compound of formula 6 in dichloromethane (55 ml_), 4- dimethylaminopyridine (0.1 g), triethylamine (4.7 g), and acetic anhydride (4.3 g) were added sequentially at -5 to -15°C and the reaction mass was stirred. After reaction completion, water (25 ml_) was added to the reaction mass and the organic layer was separated and concentrated to yield a compound of formula 5 as a residue. The obtained a compound of formula 5 was dissolved in 1 ,4- dioxane (30 ml_) at 25-30°C. Thiourea (1.6g) and trimethylsilyl trifluoromethanesulfonate (4.6 g) were added at the same temperature and the reaction mass was heated to 80°C and stirred. After 3 hours the reaction mass was slowly cooled to 20°C. Methyl iodide (3.7 g) and diethylisopropylamine (6.7 g) were added and the reaction mass was stirred for 15 hours at 25°C. After reaction completion, ethyl acetate (25 ml_) and water (55 ml_) were added to the reaction mass. The separated organic layer was concentrated to obtain a residue of a compound of formula 4, which was taken in methanol and isolated as an off- white solid (3 g).

1 H-NMR (DMSO-d6) 7.64 (d, 2H), 7.57 (s, 2H), 7.49 (s, 1 H), 7.29 (dd, 2H), 5.40 (t, 1 H), 5.21 (m, 2H), 4.91 (d, 1 H), 4.81 (d, 1 H), 5.59 (s, 1 H), 4.15 (q, 2H), 3.59 (t, 4H), 2.30 (d, 2H), 2.20 (t, 2H), 2.10 (s, 3H), 2.03 (s, 3H), 1.95 (s, 3H), 1.81 (s, 3H), 1.36 (t, 3H)

Example 14: Preparation of a compound of formula 3

A compound of formula 3 (2 g) and potassium carbonate (0.25 g) were taken in methanol (20 ml_) and heated and stirred at 60°C for 3 hours. After reaction completion, the reaction mass was concentrated to get a residue which was diluted with dichloromethane (20 ml_), methanol (2 ml_), and water (4 ml_). The organic layer was separated then concentrated to yield a compound of formula 3 (1.5 g) as a white solid.

1 H-NMR (DMSO-d6) 7.64 (d, 2H), 7.56 (d, 2H), 7.51 (d, 1 H), 7.29 (dd, 2H), 5.14 (s, 1 H), 4.88 (1 H), 4.64 (1 H), 4.51 (s, 1 H), 4.37 (d, 2H), 4.05 (q, 2H), 4.64(1 H), 3.97 (1 H), 3.70 (1 H) 3.59 (t, 4H), 2.67 (t, 4H), 3.21 (m, 2H), 2.06 (s, 3H), 1.36 (t,

3H)

Example 15: Preparation of sotagliflozin

Triethylsilane (2.5 ml_) and boron trifluoride diethyl etherate (5 ml_) were added to a solution of a compound of formula 3 (1.0 g) in dichloromethane (20 ml_). The reaction mixture was stirred for 12 hours at 25-30°C. Thereafter, the reaction mass was quenched with 5% w/v aqueous sodium bicarbonate (10 ml_\L). The organic layer was separated and concentrated to afford sotagliflozin (0.5 g) as a white solid.

1 H-NMR (CDC ): 7.32(d, 1 H), 7.26(s, 2H), 7.06 (d, 2H), 6.78(d, 2H), 4.29 (d, 1 H), 4.15 (d, 1 H), 4.10-3.95 (m, 3H), 3.64 (t, 1 H), 3.50 (m, 2H), 2.73 (br s, 3H),

1.40(t, 3H)