# US 2019/0169152 A1 · Process for the preparation of DL-proline co-crystal of Dapagliflozin

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- Number: US 2019/0169152 A1
- Document ID: US20190169152A1
- Status: Published application
- Kind: A1
- Application number: 16/097,777
- Filed: 2017-04-28
- Published: 2019-06-06
- Earliest claimed: 2016-05-02
- Assignees: Aurobindo Pharma Ltd
- Applicants: Aurobindo Pharma Limited
- Inventors: Senthilkumar NATRAJAN; Kishore KARUMANCHI; Vittal TANGIRALA; Sivakumaran MEENAKSHISUNDERAM
- Web page: https://patentgrep.com/patent/US20190169152A1

## CPC

- C07D 309/10: Oxygen atoms
- C07C 31/10: containing three carbon atoms
- C07C 31/205: {1,3-Propanediol; 1,2-Propanediol}
- C07D 207/12: Oxygen or sulfur atoms
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to a process For the preparation of Dapagliflozin DL—Proline co-crystal and its use in the preparation/purification of Dapagliflozin. The invention also provides a process for the preparation of Dapagliflozin (R,S)-1.2-propanediol monohydrate.

## Claims

### Claim 1

A process for the preparation of crystalline Dapagliflozin DL-proline co-crystals, comprising the steps of:
a) providing a solution or suspension of Dapagliflozin and DL-proline in a solvent or mixture of solvents;
b) optionally heating and concentrating the reaction mass; and
c) isolating Dapagliflozin DL-proline co-crystals.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the solvent used in step (a) is selected from the group consisting of esters selected from ethyl acetate, and isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons selected from toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride; dialkyl formamides selected from dimethyl formamide; ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, dimethyl ether, and methyl butyl ether; cyclic ethers selected from tetrahydrofuran, and 1,4-dioxane; substituted cyclic ethers selected from 2-methyl tetrahydrofuran; alcohols selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, and diethylene glycol; ketones selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides selected from dimethyl sulfoxide; dialkylacetamides selected from N,N-dimethyl acetamide; nitrites selected from acetonitrile, and propionitrile; ionic liquids, hexamethylphosphorous triamide, hexamethylphosphoramide; water and/or mixtures thereof.

### Claim 3

A process for preparation of amorphous Dapagliflozin (I), comprising the steps of:
a) providing a solution of Dapagliflozin DL-proline co-crystal in a solvent or mixture of solvents;
b) treating the reaction mass obtained in step (a) with a base;
c) optionally separating the organic layer;
d) optionally removing the solvent;
e) adding antisolvent; and
f) isolating amorphous Dapagliflozin.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the solvent used in step (a) is selected from the group consisting of esters selected from ethyl acetate, and isopropyl acetate; ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, dimethyl ether, and methyl butyl ether; alcohols such as methanol, ethanol, isopropanol, n-butanol; ketones such as methyl isobutyl ketone, acetone; chlorinated solvents such as methylene chloride; water and/or mixtures thereof.

### Claim 5 (depends on 3)

The process according to claim 3, wherein the base used in step (b) may be organic or inorganic base; the organic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,5-diazabicyclo[4.3.0]non-5-ene; primary amines such as methylamine, propyl amine, 2-propyl amine, butyl amine; secondary amines N,N-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine; tertiary amines such as triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine; pyridine or substituted pyridine such as 2,6-lutidine, 2,4-lutidine, 3,5-lutidine; pyrimidine and N,N-dimethylethyl amine; tetra alkyl ammonium and phosphonium hydroxides; metal alkoxides and inorganic bases such as alkali metal carbonates such as potassium carbonate, sodium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; metal hydrides; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert butoxide; metal amides or liquor ammonia.

### Claim 6 (depends on 3)

The process according to claim 3, wherein the antisolvent used in step (e) is selected from group consisting of hydrocarbons such as hexane, heptane, cyclohexane, and pentane.

### Claim 7

(canceled)

### Claim 8

(canceled)

### Claim 9

(canceled)

### Claim 10

A Crystalline DL-proline Dapagliflozin co-crystal characterized by an x-ray diffraction pattern (XRD) as shown in FIG. 3.