WO2021245253A1

WO2021245253A1 - Preparation of highly pure amorphous dapagliflozin

Info

Publication number: WO2021245253A1
Application number: PCT/EP2021/065044
Authority: WO
Inventors: Aleš POLOVIC; Primoz Benkic; Nika OSTERMAN; Mateja GRUBAR; Jernejka VOVKO; Tjaž KOBAL; Monika KUFNER
Original assignee: Krka, D.D., Novo Mesto
Priority date: 2020-06-05
Filing date: 2021-06-04
Publication date: 2021-12-09
Also published as: CN115867538A; EP4161912A1

Abstract

A novel and improved process for the preparation of amorphous dapagliflozin is disclosed. The present invention further provides pharmaceutical compositions containing amorphous dapagliflozin, optionally in a combination with one or more other active substances and methods for making the same.

Description

PREPARATION OF HIGHLY PURE AMORPHOUS DAPAGLIFLOZIN

1. Technical field of the invention

The present invention relates to novel and improved processes for the preparation of SGLT2 inhibitor dapagliflozin, particularly dapagliflozin in amorphous form. The present invention further provides pharmaceutical compositions containing amorphous dapagliflozin optionally in a combination with one or more other active substances and methods for making the same.

2. Background of the invention

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a group of oral medicines used for treating diabetes that have been approved since 2013. SGLT2 inhibitors prevent the kidneys from re-absorbing glucose back into the blood by passing into the bladder. Glucose is re-absorbed back into the blood via the renal proximal tubules. SGLT2 is a protein predominantly expressed in the renal proximal tubules and is likely to be major transporter responsible for this uptake. Glucose-lowering effect of SGLT-2 inhibitors occurs via an insulin-independent mechanism mostly through glucosuria by increasing the urinary excretion of glucose.

It has been shown that the treatment with SGLT2 inhibitors in patients with type II diabetes lowers HbAlc, reduces body weight, lowers systemic blood pressure (BP) and induces a small increase in LDL- C and HDL-C levels.

SGLT2 inhibitors inhibit the reabsorption of sodium and glucose from the tubule and hence, more sodium is delivered in the macula densa causing arteriole dilation, reduced intraglomerular pressure and decreased hyperfiltration. SGLT2 inhibitors cause natriuresis and volume depletion, and an increase in circulating levels of renin, angiotensin and aldosterone. They also reduce albuminuria and slow GFR loss through mechanisms that appear independent of glycemia.

Dapagliflozin as shown in formula below is a highly potent and reversible SGLT2 inhibitor, which increases the amount of glucose excreted in the urine and improves both fasting and post-prandial plasma glucose levels in patients with type 2 diabetes. Dapagliflozin has also been shown to tend to reduce liver fat content in some studies in a diabetic population.

Dapagliflozin is available on the market in the form of dapagliflozin propanediol monohydrate and is sold under trade name Forxiga or Farxiga in the form of fdm-coated tablets. Further it is available on the market as a combination product with metformin hydrochloride which is sold under trade name Xigduo IR or Xigduo XR in the form of film-coated tablets. In addition, it is available on the market as a combination product with saxagliptin hydrochloride which is sold under trade name Qtem in the form of film-coated tablets. Moreover, it is available on the market as a combination product with saxagliptin hydrochloride and metformin hydrochloride which is sold under trade name Qtemmet XR in the form of film-coated tablets.

Dapagliflozin as a monotherapy and in a combination with other active substances has demonstrated its efficacy in improving glycaemic control and reducing body weight and blood pressure in a broad spectrum of patients with type II diabetes, including those with high baseline HbAlc and the elderly. A sustained reduction in serum uric acid concentration was also observed. Dapagliflozin provides significant improvement in HbAlc, reduction in insulin dose and reduction in body weight in patients with type 1 diabetes as adjunct therapy to adjustable insulin.

Dapagliflozin can be in its free form or any stereoisomer or any pharmaceutically acceptable salt or co crystal complex or a hydrate or a solvate thereof and in any polymorphic forms and any mixtures thereof.

Dapagliflozin as a substance was first disclosed in US 6,515,117. The process for the preparation of dapagliflozin involves the reaction of 4-bromo- 1 -chloro-2-(4-ethoxybenyl)benzene with 2,3,4,6-tetra- O-trimethyl silyl -D-gluconolactone, the obtained compound 3 on demethoxylation yields diastereomeric mixture of Dapagliflozin. Hie diastereomeric mixture of dapagliflozin is further acetylated with acetic anhydride in the presence of pyridine and dimethylaminopyridine yields, then recrystallized from absolute ethanol to yield the desired tetra-acetyJated b-C-glucoside as a white solid. Compound tetra- acetylated b-C-glucoside is treated with lithium hydroxide hydrate which undergoes deprotection to yield the compound dapagliflozin. Several other documents, patents and applications disclose the process for the preparation of dapagliflozin such as for example WOO 127128, WO03099836, W02004063209, W02006034489,

W02010022313, WO2012019496, W02013064909, W02013068850, W02013079501, WO2014094544, WO2014159151, WO2014206299, W02015040571, WO2015044849, WO2015063726, WO2015132803, WO2015155739, W02016098016, WO2016128995, WO2016178148, WO2017042683, WO2017063617, W02018029611, WO2018029264, WO2018142422.

Prior art documents already provided some compositions of SGLT2 inhibitor dapagliflozin.

W02008116179 discloses immediate release formulation in the form of a stock granulation or in the form of a capsule or a tablet which comprises dapagliflozin propylene glycol hydrate, one or more bulking agent, one or more binder and one or more disintegrant.

WO2011060256 describes the bilayer tablet comprising dapagliflozin having sustained release profde in one layer and metformin in another layer while WO2011060290 describes immediate release formulation of dapagliflozin and metformin.

WO2012163546 discloses the pharmaceutical composition comprising cyclodextrin and dapagliflozin. Co-crystals of dapagliflozin with lactose are described in WO2014178040.

Solid dispersion compositions comprising amorphous dapagliflozin and at least one polymer are disclosed in W02015011113 and in WO2015128853.

CN103721261 discloses the combination of SGLT2 inhibitor with vitamins such as vitamin B.

Pharmaceutical composition preparation comprising dapagliflozin L-proline and metformin and/or DPP-IV inhibitor is disclosed in WO2018124497.

EP2252289A1 provides a combination of SGLT inhibitor with DPP4 inhibitor showing synergistic effect in increasing plasma active GLP-1 level in a patient over that provided by administration of the SGLT inhibitor or the DPP4 inhibitor alone.

EP2395983A1 relates to a pharmaceutical composition comprising a SGLT2 inhibitor, a DPP4 inhibitor and a third antidiabetic agent which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia. Regardless of these various known manufacturing processes, there still exists a need for an efficient synthesis of amorphous dapagliflozin which provides dapagliflozin substance in high degree of purity and which does not require cumbersome purification steps. Amorphous dapagliflozin prepared according to the process of the present invention is used in a pharmaceutical composition that exhibits excellent chemical and physical stability, that is stable under normal storage conditions and at the same time it provides improved content uniformity.

3. Summary of the invention

One embodiment of the present invention is a process for the preparation of amorphous dapagliflozin comprising the steps of:

(optionally purifying dapagliflozin), i) dissolving (optionally purified) dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic or polar protic solvents (and mixtures thereof), and filtration of the obtained solution, ii) combining the solution with an antisolvent selected from the group consisting of non- aqueous and non-protic solvents (and mixtures thereof) at temperature between 0 to 25 °C (under stirring), preferably at stirring rate in the range of power number P/V ("power number P/V" being also referred to herein as "agitation power per (unit) volume P/V") between 2 W/m³ to 250 W/m³, iii) stirring the suspension at crystallization temperature between 0 °C to 25 °C , preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³ , iv) cooling until temperature between -15 °C to 15 °C is achieved (under stirring), preferably at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³ and v) isolation of the product followed by washing and drying.

This process is also referred to herein as "process (A)". Before step i) of "process (A)", "process (A)" can comprise an optional step of purifying dapagliflozin, preferably purifying dapagliflozin by acid- base extraction, more preferably purifying dapagliflozin by acid-base extraction by the addition of alkaline water solution and additional washing with water.

The product obtained in step v) comprises or consists of amorphous dapagliflozin. Advantageously, the process of the present invention provides a product which comprises or consists of amorphous dapagliflozin, and which can be free of impurity IMP A or comprises impurity IMP A in low amount, such as in an amount of less than 0.02 % by weight, based on the total weight of dapagliflozin, (as obtained after step v) in the washed and dried product), especially based on the total weight of amorphous dapagliflozin, (as obtained after step v) in the washed and dried product). In an embodiment, in steps ii), iii), iv), the stirring is at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³. P/V being an abbreviation for power/volume. As used herein, the terms "power number P/V", and "agitation power per unit volume P/V", and "agitation power per volume P/V", and "P V" all can be used interchangeably herein. The term "agitation power per volume P/V" can in particular be the agitation power per volume of mixture (said mixture can be e.g. the suspension of step iii) or iv) of "process (A)" or the suspension of step iv) or v) of "process (B)" or e.g. the combination of step ii) of "process (A)" or the combination of step iii) of "process (B)") subjected to stirring.

The term "a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic or polar protic solvents (and mixtures thereof)" as used herein can be in particular "a solvent selected from the group consisting of non-aqueous and aprotic solvents and mixtures thereof', or can be in particular "a solvent selected from the group consisting of aprotic solvents; non-aqueous, polar protic solvents; and mixtures thereof'. An aprotic solvent can be in particular a polar aprotic solvent. A polar protic solvent can be in particular a non-aqueous polar protic solvent.

As used herein, the terms "between x and y" and "between x to y", respectively, describe ranges including both range ends values x and y. For example, the range "between 0 to 25°C" includes the range end values 0°C and 25°C. The terms "between x to y" and "from x to y" can be used interchangeably herein. As used herein, the term "crystallization temperature" can in particular encompass the term "temperature of formation of solid amorphous material".

Another embodiment of the present invention is the process for the preparation of amorphous dapagliflozin comprising the steps of: i) purifying dapagliflozin, preferably purifying dapagliflozin by acid-base extraction, more preferably purifying dapagliflozin by acid-base extraction by the addition of alkaline water solution and additional washing with water, ii) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic solvents and polar protic solvents (and mixtures thereof), and filtration of the obtained solution, iii) combining the solution with an antisolvent selected from the group consisting of non- aqueous and non-protic solvents (and mixtures thereof) at temperature between 0 to 25 °C (under stirring), preferably at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³, iv) stirring the suspension at crystallization temperature between 0 °C to 25 °C , preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³, v) cooling until temperature between -15 °C to 15 °C is achieved (under stirring), preferably at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³ and vi) isolation of the product followed by washing and drying.

This process is also referred to herein as "process (B)".

The product obtained in step vi) comprises or consists of amorphous dapagliflozin. Advantageously, the process of the present invention provides a product which comprises or consists of amorphous dapagliflozin, and which can be free of impurity IMP A or comprises impurity IMP A in low amount, such as in an amount of less than 0.02 % by weight, based on the total weight of dapagliflozin, (as obtained after step vi) in the washed and dried product), especially based on the total weight of amorphous dapagliflozin, (as obtained after step vi) in the washed and dried product).

In another embodiment of the present invention dapagliflozin used in step i) of the above disclosed processes for the preparation of amorphous dapagliflozin is prepared by the following process comprising (schematic presentation Figure 1): reaction of 5-bromo-2-chlorobenzoic acid compound of formula 3 with oxalyl chloride in dichloromethane to provide 5-bromo-2-chlorobenzoyl chloride, reaction of the obtained compound with ethoxybenzene in the presence of AICT, in dichloromethane, optionally purifying the obtained compound, preferably purifying the obtained compound by crystalizing, more preferably purifying the obtained compound by crystalizing with seeding, to provide (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone, reaction of the obtained compound with AICT, and NaBFb in THF, optionally purifying the obtained compound, preferably purifying the obtained compound by crystalizing, more preferably purifying the obtained compound by crystalizing with seeding, to provide 4-bromo- l-chloro-2-(4-ethoxybenzyl)benzene, reaction of the obtained compound with compound of (3R,4S,5R,6R)-3,4,5- tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one in the presence of n-butyl lithium in THF and toluene, followed by treating (the obtained mixture) with methane sulfonic acid in methanol, optionally purifying the obtained compound using extraction with heptane to provide 3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol, reaction of the obtained compound in-situ with triethylsilane and boron trifluoride etherate in dichloromethane to provide (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl) tetrahydro2H-pyran-3,4,5-triol, reaction of the obtained compound in-situ with acetic anhydride in the presence of dimethylamino pyridine in dichloromethane, optionally purifying the obtained compound, preferably purifying the obtained compound by crystalizing, more preferably purifying the obtained compound by crystalizing with seeding, to provide (2R,3R,4R,5S,6S)-2- (acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate, treating the obtained compound with sodium hydroxide in aqueous methanol to provide dapagliflozin, which can be used in steps i) to v) (of "process (A)") or i) to vi) (of "process (B)") as disclosed above, in particular to prepare amorphous dapagliflozin.

In an embodiment of the present invention dapagliflozin used in step i) of the above disclosed processes for the preparation of amorphous dapagliflozin is prepared by the following process (schematic presentation Figure 1) (comprising): reaction of 5-bromo-2-chlorobenzoic acid compound of formula 3 with oxalyl chloride in dichloromethane to provide 5-bromo-2-chlorobenzoyl chloride, reaction of the obtained compound with ethoxybenzene in the presence of AlCh in dichloromethane, purifying the obtained compound by crystalizing with seeding to provide (5- bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone, reaction of the obtained compound with AlCh and NaBFb in THF, purifying the obtained compound with seeding to provide 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene, reaction of the obtained compound with compound of (3R,4S,5R,6R)-3,4,5- tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one in the presence of n-butyl lithium in THF and toluene, followed by treating with methane sulfonic acid in methanol, purifying the obtained compound using extraction with heptane to provide 3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3 ,4,5 -triol, reaction of the obtained compound in-situ with triethylsilane and boron trifluoride etherate in dichloromethane to provide (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl) tetrahydro2H-pyran-3,4,5-triol, reaction of the obtained compound in-situ with acetic anhydride in the presence of dimethylamino pyridine in dichloromethane, purifying the obtained compound crystalizing with seeding to provide (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate, treating the obtained compound with sodium hydroxide in aqueous methanol to provide dapagliflozin which can be used in steps i) to v) (of "process (A)") or i) to vi) (of "process (B)") as disclosed above, in particular to prepare amorphous dapagliflozin.

The term "purifying by crystalizing" can comprise dissolving the compound to be purified in a solvent to obtain a solution, allowing or inducing crystallization of the compound to be purified in the solution, and optionally isolating the crystallized compound to be purified. The term "purifying by crystalizing with seeding" can comprise dissolving the compound to be purified in a solvent to obtain a solution, and inducing crystallization of the compound to be purified in the solution by adding seeding material, especially seeding crystals, to the solution, and optionally isolating the crystallized compound to be purified. The seeding crystals can be seeding crystals comprising or consisting of the compound to be purified by crystallization or seeding material can be silica particles. Silica particles can be in particular used for initially preparing seeding crystals comprising or consisting of the compound to be purified by crystallization.

Especially, the following items are provided: 1. A process for the preparation of amorphous dapagliflozin comprising the steps of: i) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic or polar protic solvents and filtration of the obtained solution, ii) combining the solution with an antisolvent selected from the group consisting of non- aqueous and non-protic solvents at temperature between 0 to 25 °C at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³, iii) stirring the suspension at crystallization temperature between 0 °C to 25 °C at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³ , iv) cooling until temperature between -15 °C to 15 °C is achieved at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³ and v) isolation of the product followed by washing and drying.

2. The process for the preparation of amorphous dapagliflozin according to item 1 wherein the solvent used in step i) is selected from aromatic carbohydrates, esters, eters, alcohols, preferably from toluene, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, ethanol, more preferably from toluene, ethyl acetate, tert-butyl methyl ether and even more preferably toluene.

3. The process for the preparation of amorphous dapagliflozin according to item 1 wherein the antisolvent used in step ii) is selected from alkanes and cyclohexane, preferably from heptane and hexane and more preferably heptane.

4. The process for the preparation of amorphous dapagliflozin according to item 1 wherein temperature used in step ii) is between 0 to 25 °C, preferably between 5 and 20°C and more preferably between 10 and 15°C.

5. The process for the preparation of amorphous dapagliflozin according to item 1 wherein crystallization temperature used in step iii) is between 0 to 25 °C, preferably between 5 to 20 °C and more preferably between 10 to 15 °C.

6. The process for the preparation of amorphous dapagliflozin according to item 1 wherein cooling temperature of step iv) is between -15 to 15 °C, preferably between -10 and 10°C and more preferably between -5 and 5°C.

7. The process for the preparation of amorphous dapagliflozin according to item 1 wherein stirring rate of step ii), step iii) and step iv) is in the range of power number P V between 2 to 250W/m³, preferably from 2W/m³ to 120W/m³ and more preferably from 2 to 60 W/m³.

8. A process for the preparation of amorphous dapagliflozin comprising the steps of: i) purifying dapagliflozin by acid-base extraction by the addition of alkaline water solution and additional washing with water, ii) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic solvents and polar protic solvents and fdtration of the obtained solution, iii) combining the solution with an antisolvent selected from the group consisting of non- aqueous and non-protic solvents at temperature between 0 to 25 °C at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³, iv) stirring the suspension at crystallization temperature between 0 °C to 25 °C at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³, v) cooling until temperature between -15 °C to 15 °C is achieved at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³ and vi) isolation of the product followed by washing and drying.

9. The process for the preparation of amorphous dapagliflozin according to item 8 wherein acid base extraction of step i) is performed by the addition of alkaline water solution selected from NaOH, KOH or any other basic species with pH value between 8 and 14, preferably between 10 and 14 and more preferably between 12.5 and 13.5.

10. The process for the preparation of amorphous dapagliflozin according to item 8 wherein the solvent used in step ii) is selected from aromatic carbohydrates, esters, eters, alcohols, preferably from toluene, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, ethanol, more preferably from toluene, ethyl acetate, tert-butyl methyl ether and even more preferably toluene.

11. The process for the preparation of amorphous dapagliflozin according to item 8 wherein the antisolvent used in step iii) is selected from alkanes and cyclohexane, preferably from heptane and hexane and more preferably heptane.

12. The process for the preparation of amorphous dapagliflozin according to item 8 wherein temperature used in step iii) is between 0 to 25 °C, preferably between 5 and 20°C and more preferably between 10 and 15°C.

13. The process for the preparation of amorphous dapagliflozin according to item 8 wherein crystallization temperature used in step iv) is between 0 to 25 °C, preferably between 5 to 20 °C and more preferably between 10 to 15 °C.

14. The process for the preparation of amorphous dapagliflozin according to item 8 wherein cooling temperature of step v) is between -15 to 15°C, preferably between -10 and 10°C and more preferably between -5 and 5°C.

15. The process for the preparation of amorphous dapagliflozin according to item 8 wherein stirring rate of step iii), step iv) and step v) is in the range of power number P V between 2 W/m³ to 250 W/m³, preferably from 2 W/m³ to 120 W/m³ and more preferably from 2 W/m³ to 60 W/m³.

16. A process for the preparation of amorphous dapagliflozin comprising the steps of: reaction of 5-bromo-2-chlorobenzoic acid compound of formula 3 with oxalyl chloride in dichloromethane to provide 5-bromo-2-chlorobenzoyl chloride, reaction of the obtained compound with ethoxybenzene in the presence of AlCb in dichloromethane, purifying the obtained compound by crystalizing with seeding to provide (5- bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone, reaction of the obtained compound with AlCb and NaBH_t in THF, purifying the obtained compound using ethanol with seeding to provide 4-bromo-l-chloro-2-(4- ethoxybenzyl)benzene, reaction of the obtained compound with compound of (3R,4S,5R,6R)-3,4,5- tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one in the presence of n-butyl lithium in THF and toluene, followed by treating with methane sulfonic acid in methanol, purifying the obtained compound using extraction with heptane to provide 3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3 ,4,5 -triol, reaction of the obtained compound in-situ with triethylsilane and boron trifluoride etherate in dichloromethane to provide (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl) tetrahydro2H-pyran-3,4,5-triol, reaction of the obtained compound in-situ with acetic anhydride in the presence of dimethylamino pyridine in dichloromethane, purifying the obtained compound crystalizing with seeding to provide (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate, treating the obtained compound with sodium hydroxide in aqueous methanol to provide dapagliflozin used in any previous items from 1 to 15.

4. Brief description of the drawing

Figure 1 describes the process for the preparation of dapagliflozin

5. Detailed description of the invention

It is well known that formulation comprising pharmaceutical active substance shows technological problem of re-agglomeration causing lower dissolution profdes of active substance. Therefore, amorphous form is advantage to increase dissolution profde to overcome problem of reduction of dissolution profdes due to unwanted re-agglomeration. It is generally known that it is difficult to obtain amorphous material in chemically pure form which means substance that complies with ICH requirements. During the preparation of amorphous dapagliflozin according to the state of the art literature the substance or impurity with chemical name (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (below marked as impurity IMP A) and chemical structure formula 1 (impurity IMP A) is identified which could not be easily eliminated from the final amorphous dapagliflozin.

The content of impurity IMP A and residual solvents were determined by HPLC method disclosed in Example A.

Therefore one embodiment of the present intention was to develop the process for the preparation of amorphous dapagliflozin that does not contain any detectable level of impurity IMP A. Another embodiment of the present invention was to develop the process for the preparation of amorphous dapagliflozin wherein the impurity IMP A can be purified or eliminated to below 0.02 %. We surprisingly found out that by using extraction process in the final step of the synthesis of amorphous dapagliflozin the impurity IMP A can be purified with high yields. The extraction process is advantageous in comparison to generally known processes such as crystallisation, formation of co crystals and similar that can all result in enormous loss of material when purification factor of this particular impurity is low. The processes according to the present invention provide amorphous dapagliflozin that does not contain any detectable level of impurity IMP A and also achieves ICH requirements for residual solvents in the final substance.

The present invention relates to a novel and improved process for the preparation of amorphous dapagliflozin as shown in formula below

and reaction intermediates suitable for manufacturing the same wherein the obtained amorphous dapagliflozin does not contain any detectable level of the impurity IMP A or below 0.02 %.

Therefore, one embodiment of the present invention is a process for the preparation of amorphous dapagliflozin comprising the steps of: i) dissolving dapagliflozin in a solvent and filtration of the obtained solution, ii) combining the solution with an antisolvent at defined temperature and stirring rate to obtain suspension, iii) stirring the suspension at crystallization temperature, iv) cooling and v) isolation of the product.

The inventors of the present invention surprisingly found out that in order to obtain amorphous dapagliflozin that complies with ICH Guidelines requirements the formation of the impurity IMP A in the final amorphous dapagliflozin can be minimized by thorough control of process parameters of each process step of the preparation of amorphous dapagliflozin. By such thorough process control it can be assured that final amorphous dapagliflozin is substantially free of the impurity IMP A which means that the content of impurity IMP A in amorphous dapagliflozin is below 0.02 % and that the obtained amorphous dapagliflozin also achieves ICH requirements for residual solvents in the final substance.

Therefore, one embodiment of the present invention is the process for the preparation of amorphous dapagliflozin wherein the starting dapagliflozin has a content of impurity IMP A below 0.02% comprising the steps of: i) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic or polar protic solvents (and mixtures thereof), and filtration of the obtained solution, ii) combining the solution with an antisolvent selected from the group consisting of non- aqueous and non-protic solvents (and mixtures thereof) at temperature between 0 to 25 °C (under stirring), preferably at stirring rate in the range of power number P/V ("power number P/V" being also referred to herein as "agitation power per (unit) volume P/V") between 2 W/m³ to 250 W/m³, iii) stirring the suspension at crystallization temperature between 0 °C to 25 °C, preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³ , iv) cooling until temperature between -15 °C to 15 °C is achieved (under stirring), preferably at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³ , and v) isolation of the product followed by washing and drying.

Power number P V is generally accepted scale-up parameter that depends on stirring rate and geometry of the reaction vessel and stirrer. It is defined by the following equation

P N_p p n³ d⁵ v V where p represents density of reaction mass, n represents stirrer speed, d is diameter of stirrer, V is volume of reaction mass. N_p represent power number that can be calculated by computational fluid dynamic or empirically estimated from the literature data based on the shape of stirrer and geometry of reaction vessel (Rushton, J. H.; Costich, E. W.; Everett, J. J. "Power characteristics of mixing impellers Part 2." Chem. Eng. Prog. 46 (1950): 467-476.)

Solvent used in step i) can be selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; preferably from toluene, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, ethanol, and mixtures thereof; more preferably solvent can be selected from toluene, ethyl acetate, tert- butyl methyl ether; and even more preferably solvent can be toluene.

Antisolvent used in step ii) can be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably antisolvent can be heptane.

Solvent used in step i) can be selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; and antisolvent used in step ii) can be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably antisolvent can be heptane.

Solvent used in step i) can be selected from toluene, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, ethanol, and mixtures thereof; more preferably solvent can be selected from toluene, ethyl acetate, tert-butyl methyl ether; and antisolvent used in step ii) can be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably antisolvent can be heptane.

Solvent used in step i) can be toluene; and antisolvent used in step ii) can be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably antisolvent can be heptane.

Temperature used in step ii) can be between 0 to 25 °C, preferably between 5 and 20°C and more preferably between 10 and 15°C.

Crystallization temperature used in step iii) can be between 0 to 25 °C, preferably between 5 to 20 °C and more preferably between 10 to 15 °C.

Cooling temperature of step iv) can be between -15 to 15°C, preferably between -10 and 10°C and more preferably between -5 and 5°C. Stirring rate of step ii), step iii) and step iv) can be in the range of power number P/V between 2 W/m³ to 250 W/m³, preferably from 2 W/m³ to 120 W/m³ and more preferably from 2 W/m³ to 60 W/m³.

The inventors of the present invention found out that all above defined process steps should be performed in carefully pre-defined temperature range and preferably carefully defined stirring rates. By such thorough process control it can be assured that the obtained substance achieves ICH requirements for residual solvents in the final substance and that the process is applicable on industrial scale without problem of slow filtration of final substance that is in general often the case with amorphous materials.

The inventors of the present invention surprisingly found out that temperature of precipitation of step ii) is extremely important to achieve fast filtration of the product. It is important that agglomeration during the precipitation is performed within the specific temperature range which provides appropriate agglomerated particles that assure good filtration properties of the product. If the precipitation temperature is lower than the limits specified above the filtration is too slow. If temperature is higher agglomeration due to ‘glass transition’ of amorphous material in preferred solvent combination will be too intense leading to oiling of the product that cannot be isolated at all. Moreover, higher temperature of precipitation has strong influence on residual solvents in the final amorphous dapagliflozin substance. If material is precipitated at higher temperatures as defined above the so obtained material will result in residual solvents trapped into the material that cannot be reduced by drying even though material showed good filtration speed.

In addition, the inventors of the present invention surprisingly found out that stirring rate and temperature of steps iii) and iv) is more critical for fast filtration rate as average expert in the field could expect. With too high power input and too low temperature of suspension amorphous particles are crashed due to power input by stirring what leads to extremely high resistance of filtration cake as demonstrated but not limited with examples. Filtration rate in meters per second is defined as volume of mother liquor in cubic meters that passes through defined filter area in square meters in measured time in seconds at 1 bar pressure difference on the filtration cake.

The product obtained by the above-defined steps i) to v) can be isolated at any industrial equipment which means that no special and expensive devices are required. For example, pressure filter or filter dryer can be used. To perform complete isolation step followed by washing step and drying step the isolation step can be preferably performed in filter dryer. Filtered material should be thoroughly washed with antisolvent such as heptane to wash residual solvents from the wet cake to achieve efficient removal of solvents during drying. Optionally material can be slurried in antisolvent to improve residual solvent removal from the cake before drying. The inventors of the present invention found out that remaining solvents in wet cake is critical to achieve efficient drying of the product. If for example solvent like toluene is present in the wet cake (in considerable amounts), it will initiate low ‘glass transition’ of amorphous dapagliflozin resulting in additional agglomeration and consequently failure in achieving ICH requirements for residual solvents on final product for solvent and antisolvent used in the process.

Dapagliflozin used in step i) of the above disclosed process for the preparation of amorphous dapagliflozin can be in any form as a solid in any polymorphic form or dissolved in a solvent and can be prepared according to any process that provides dapagliflozin with the content of impurity IMP A below 0.02 %.

In another embodiment of the present invention dapagliflozin used in step i) of the above disclosed process for the preparation of amorphous dapagliflozin is prepared by the following process (schematic presentation on Figure 1):

Step 1: Reaction of 5-bromo-2-chlorobenzoic acid compound of formula 3 with oxalyl chloride in dichloromethane to provide 5-bromo-2-chlorobenzoyl chloride compound of formula 4.

Step 2: Reaction of compound of formula 4 with ethoxybenzene in the presence of AlCl, in dichloromethane, purifying the obtained compound by crystalizing with seeding to provide (5- bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone compound of formula 5. Reaction temperature during addition of compound of formula 4 is between -20°C to 0°C. Crystallization solvent is a mixture of methanol and ethyl acetate in the range of methanol/ethyl acetate=10: 1 to 4: 1. Temperature of seeding is between 35°C to 45°C.

Step 3: Reaction of compound of formula 5 with AlCh and NaBFfl in THF, purifying the obtained compound using ethanol with seeding to provide 4-bromo-l-chloro-2-(4- ethoxybenzyl)benzene compound of formula 6. Reaction temperature during addition of compound of AlCfl is between -10°C to 5°C. Reaction temperature after addition of AICF is between 60°C to 65°C. Temperature of seeding is between 25°C to 30°C.

Step 4: Reaction of compound of (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6- (((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (compound 7) with compound of formula 6 in the presence of n-butyl lithium in tetrahydrofuran and toluene, followed by treating with methane sulfonic acid in methanol, purifying the obtained compound using extraction with heptane to provide 3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)- 2-methoxytetrahydro-2H-pyran-3,4,5-triol compound of formula 8. Reaction temperature during addition of n-Buli is between -90°C to -65°C. Reaction temperature during addition of compound of 7 is between -90°C to -70°C.

Step 5: Reaction of compound of formula 8 in-situ with triethylsilane and boron trifluoride etherate in dichloromethane to provide (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro2H-pyran-3,4,5-triol compound of formula 2. Reaction temperature during addition of boron trifluoride etherate is between -50°C to -20°C.

Step 6: Reaction of compound of formula 2 in-situ with acetic anhydride in presence of dimethylamino pyridine in dichloromethane, purifying the obtained compound by crystalizing from ethanol with seeding to provide (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate compound of formula 9. Temperature of seeding is between 60°C to 65 °C.

Step 7: Treating the compound formula 9 with sodium hydroxide in aqueous methanol to provide compound 2.

Step 8: Preparation of solid amorphous dapagliflozin according to steps i) to v) as disclosed above.

Another embodiment of the present invention is the process for the preparation of amorphous dapagliflozin wherein the starting dapagliflozin can have a content of impurity IMP A above 0.02 % which means that there is no need to control the content of impurity IMP A during the synthesis of dapagliflozin. Therefore another embodiment of the present invention is the process for the preparation of amorphous dapagliflozin comprising the steps of: i) purifying dapagliflozin, preferably purifying dapagliflozin by acid-base extraction, more preferably purifying dapagliflozin by acid-base extraction by the addition of alkaline water solution and additional washing with water, ii) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic solvents and polar protic solvents (and mixtures thereof), and filtration of the obtained solution, iii) combining the solution with an antisolvent selected from the group consisting of non- aqueous and non-protic solvents (and mixtures thereof) at temperature between 0 to 25 °C (under stirring), preferably at stirring rate in the range of power number P/V ("power number P/V" being also referred to herein as "agitation power per (unit) volume P/V") between 2 W/m³ to 250 W/m³, iv) stirring the suspension at crystallization temperature between 0 °C to 25 °C , preferably at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³, v) cooling until temperature between -15 °C to 15 °C is achieved (under stirring), preferably at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³ and vi) isolation of the product followed by washing and drying.

Power number P V is generally accepted scale-up parameter that depends on stirring rate and geometry of the reaction vessel and stirrer. It is defined by the following equation P N_p p n³ d⁵

V V where p represents density of reaction mass, n represents stirrer speed, d is diameter of stirrer, V is volume of reaction mass. N_p represent power number (" power number N_p ") that can be calculated by computational fluid dynamic or empirically estimated from the literature data based on the shape of stirrer and geometry of reaction vessel ((Rushton, J. H.; Costich, E. W.; Everett, J. J. "Power characteristics of mixing impellers Part 2." Chem. Eng. Prog. 46 (1950): 467-476.)

Stirring at stirring rate in the range of power number P/V ("power number P/V" being also referred to herein as "agitation power per (unit) volume P/V") transfers power (agitation power) into the stirred fluid (e.g. suspension or solution) per (unit) volume. For example, stirring at stirring rate in the range of power number P V between 2 W/m³ to 250 W/m³ transfers power (agitation power) into a mixture (e.g. a suspension or a combination of a solution comprising dapagbflozin with antisolvent) subjected to stirring in the range between 2 W/m³ to 250 W/m³ (2 to 250 W per m³ of volume of mixture subjected to stirring).

In particular, stirring at stirring rate in the range of power number P V between 2 W/m³ to x W/m³ (x W/m³ can be e.g. 250 W/m³ or 120 W/m³ or 60 W/m³) can transfer power (agitation power) into a suspension subjected to stirring (e.g. the suspension of step iii) or iv) of "process (A)" or the suspension of step iv) or v) of "process (B)" in the range between 2 to x W per m³ of suspension subjected to stirring. In particular, stirring at stirring rate in the range of power number P V between 2 W/m³ to x W/m³ (x W/m³ can be e.g. 250 W/m³ or 120 W/m³ or 60 W/m³) can transfer power (agitation power) into a combination of a solution comprising dapagbflozin with antisolvent (e.g. the combination of step ii) of "process (A)" or the combination of step iii) of "process (B)") subjected to stirring in the range between 2 to x W per m³ of combination subjected to stirring.

The power (agitation power) can be transferred by a stirring device (e.g. a stirred vessel, a stirred reactor, or any other stirring device) into the stirred suspension or solution. The most common techniques for determining the power transfer into a stirred fluid (e.g. suspension or solution) per (unit) volume are based on electrical power draw, calorimetry or the torque upon the agitator. "Agitation power" can be in particular "stirring power".

In case of a stirring device (e.g. stirred vessel or stirred reactor) provided with an agitator, the "power number N_p " can be in particular calculated after having determined the effective torque (T_eff ) (e.g. by using a torque meter) upon the agitator, as described e.g. by S. C. Kaiser, S. Werner, V. Jossen, K. Blaschczok, D. Eibl, "Power Input Measurements in Stirred Bioreactors at Laboratory Scale", J. Vis. Exp. (135) e56078, doi: 10.3791/56078 ((May) 2018), especially in the introduction thereof. For taking into account losses occurring in the agitation, the effective torque (T_eff ) can be in particular determined as the difference between the torque value measured in the device filled with liquid (e.g. heptane) (TL ) and the torque value measured in the empty device (TD ) (T_eff = TL -TD).

Acid base extraction of step i) can be performed by the addition of alkaline water solution that can be selected from NaOH, KOH or any other basic species with pH value between 8 and 14, preferably between 10 and 14 and more preferably between 12.5 and 13.5.

Acid base extraction of step i) can be performed by the addition of alkaline water solution (that can comprise a basic species selected from NaOH, KOH, any other basic species, and mixtures thereof) with pH value between 8 and 14, preferably between 10 and 14 and more preferably between 12.5 and 13.5.

The terms "alkaline water solution" and "aqueous alkaline solution" can be used interchangeably herein. Preferably, the alkaline water solution comprises a basic species selected from NaOH, KOH and mixtures thereof.

Acid base extraction of step i) can comprise: providing a mixture comprising dapagliflozin, water and optionally a first organic solvent, such as methanol, extracting said mixture with a second organic solvent, such as tert-butyl methyl ether, to obtain a solution comprising dapagliflozin and said second organic solvent, optionally washing said solution comprising dapagliflozin and said second organic solvent with water, isolating dapagliflozin from said (optionally washed) solution comprising dapagliflozin and said second organic solvent. Said second organic solvent can be a solvent capable of providing a solution comprising dapagliflozin, and said second organic solvent can be furthermore not or not completely miscible with water.

Solvent used in step ii) can be selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; preferably solvent(s) can be selected from toluene, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, ethanol, more preferably from toluene, ethyl acetate, tert-butyl methyl ether, and mixtures thereof; and even more preferably solvent used in step ii) can be toluene.

Antisolvent used in step iii) can be selected from alkanes and cyclohexane, and mixtures thereof; preferably heptane and hexane, and mixtures thereof; and more preferably antisolvent used in step iii) can be heptane.

Solvent used in step ii) can be selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; and antisolvent used in step iii) can be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably antisolvent can be heptane.

Solvent used in step ii) can be selected from toluene, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, ethanol, and mixtures thereof; more preferably solvent can be selected from toluene, ethyl acetate, tert-butyl methyl ether; and antisolvent used in step iii) can be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably antisolvent can be heptane.

Solvent used in step ii) can be toluene; and antisolvent used in step iii) can be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably antisolvent can be heptane.

Temperature used in step iii) can be between 0 to 25 °C, preferably between 5 and 20°C and more preferably between 10 and 15°C.

Crystallization temperature used in step iv) can be between 0 to 25 °C °C, preferably between 5 to 20 °C and more preferably between 10 to 15 °C.

Cooling temperature of step v) can be between -15 to 15°C, preferably between -10 and 10°C and more preferably between -5 and 5°C.

Stirring rate of step iii), step iv) and step v) can be in the range of power number P/V between 2 W/m³ to 250 W/m³, preferably from 2 W/m³ to 120 W/m³ and more preferably from 2 W/m³ to 60 W/m³.

The inventors of the present invention surprisingly found out that impurity IMP A is very easy to be purified with extraction process as defined in above steps i) to vi). Dapagliflozin has a poorly solubility in water (<lmg/ml) so extraction is excellent process for purification because of a high yield. Beside high yield, extraction has a very good purification potential that is required since. Impurity IMP A is not purified during the isolation of amorphous dapagliflozin. Also precursors of impurity IMP A in previous steps have poor purification potential. Purification with extraction in last step is extremely effective procedure in terms of purification impurities, easy to perform and also time efficient with excellent yield much better then could be obtained by e.g. standard crystallization procedures.

Dapagliflozin used in step i) of the above disclosed process for the preparation of amorphous dapagliflozin can be in any form as a solid in any polymorphic form or dissolved in a solvent and can be prepared according to any process known from the state of the art that provides dapagliflozin with the content of impurity IMP A above 0.02 %.

In one embodiment of the present invention dapagliflozin used in step i) of the above disclosed process for the preparation of amorphous dapagliflozin is prepared by the following process (schematic presentation Figure 1):

Step 2: Reaction of compound of formula 4 with ethoxybenzene in the presence of AlCl, in dichloromethane, purifying the obtained compound by crystalizing with seeding to provide (5- bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone compound of formula 5. Reaction temperature during addition of compound of formula 4 is between -20°C to 10°C. Solvent for purification may be selected from the group consisting of methanol, ethanol, ethyl acetate or mixture of them. Temperature of seeding is between 20°C to 50°C.

Step 3: Reaction of compound of formula 5 with AICT and NaBFb in THF, purifying the obtained compound using ethanol, ethanol/water mixture, methanol, methanol/water mixture with seeding to provide 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene compound of formula 6. Reaction temperature during addition of AICT, is between -20°C to 30°C. Reaction temperature after addition of AICT, is between 40°C to 65°C. Temperature of seeding is between 20°C to 35°C.

Step 4: Reaction of compound of formula 7 with compound of formula 6 in presence of n-butyl lithium in THF and toluene, followed by treating with methane sulfonic acid in methanol, purifying the obtained compound using extraction with heptane to provide 3R,4S,5S,6R)-2-(4- chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5- triol compound of formula 8. Reaction temperature during addition of n-Buli («-Butyl lithium) is between -100°C to -60°C. Reaction temperature during addition of compound of 7 is between -100°C to -60°C.

Step 5: Reaction of compound of formula 8 in-situ with triethylsilane and boron trifluoride etherate in dichloromethane to provide (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro2H-pyran-3,4,5-triol compound of formula 2. Reaction temperature during addition of boron trifluoride etherate is between -60°C to 0°C.

Step 6: Reaction of compound of formula 2 in-situ with acetic anhydride in presence of dimethylamino pyridine in dichloromethane, purifying the obtained compound crystalizing with seeding to provide (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate compound of formula 9. Solvent for purification may be selected from the group consisting of methanol, ethanol, isopropanol, toluen or mixture of them. Temperature of seeding is between 50°C to 70°C.

Step 8: Preparation of solid amorphous dapagliflozin according to steps i) to vi) as disclosed above.

The inventors of the present invention found out that all above disclosed reaction steps 1-8 should be performed in preferably carefully pre-defmed reaction parameters such as reaction temperature, pH, seeding temperature and also materials for process should be carefully selected, such as solvents for crystallization of intermediates. By such thorough process control it can be assured that the obtained active substances achieves requirements, wherein the impurity IMP A is below 0.02%.

The inventors of the present invention surprisingly found out that used solvent for crystallization of compound 5 is also critical for proper quality. It is important that ratio between two solvents is properly defined. In case where only one solvents is used, the quality of isolated compound of formula 5 is lower than in cases where two solvents are used. Beside this also temperature of seeding is important for proper quality. If temperature of seeding is lower that the limits specified above the nucleation is fast and beside product, also impurities crystallized.

In step 3, inventors found out that reaction temperature during addition of AlCfi is important to achieve proper quality and yield. If reaction temperature is higher, additional impurities are formed, which effect on final quality and yield. If reaction temperature is lower that the limits specified above, reaction mixture become sticky and less appropriate for scale up. Beside this also temperature of seeding is important for proper quality. If temperature of seeding is lower that the limits specified above the nucleation is fast and beside product, also impurities crystallized.

In step 4, reaction temperature is critical for final quality and yield. If temperature is higher than the limits specified above, additional impurities are formed.

In step 5 inventors found out that reaction temperature during addition of boron trifluoride etherate is important to achieve proper quality and yield. If reaction temperature is higher, additional impurities are formed. If reaction temperature is lower, reaction mixture become very viscous and less appropriate for scale up.

In step 6 temperature of seeding is important for proper quality. If temperature of seeding is lower that the limits specified above the nucleation is spontaneous and fast. The suspension become thick and difficult to stir. With seeding we achieve gradual nucleation, which has a good effect on the impurity profile.

Following the above disclosed process for the synthesis of dapagliflozin it can be assured that dapagliflozin with extremely low content of impurity IMP A is prepared, which means it can be assured that final amorphous dapagliflozin does not contain any detectable level of impurity IMP A. At last when dapagliflozin is converted to amorphous form according to the processes of the present invention it will be also pure with respect to residual solvents.

Seeding crystals can be obtainable from a crystallisation solvent mixture comprising the compound to be crystallized, which crystallisation solvent mixture is subjected to a slow evaporation under magnetic stirring or seeding material can be silica particles. Silica particles can be in particular used for initially preparing seeding crystals comprising or consisting of the compound to be purified by crystallization.

In particular, seeding crystals of formula 5, formula 6 and formula 9 were obtained from a crystallisation solvent mixture (comprising the compound to be crystallized) by slow evaporation under magnetic stirring, in particular followed by cooling heating cycling. Solution can be optionally inoculated by silica particles to initiate crystallisation. Optionally, oily residue after reaction can be purified by flash chromatography before preparation of first seeding crystals. So obtained crystals are used for inoculation in crystallisation of formula 5, 6 and 9 to obtain pure seeding material. Pure material as obtained by routine crystallization or manufacture can be used for seeding.

In yet another embodiment the present invention relates to a pharmaceutical compositions containing dapagliflozin in amorphous form prepared according to the process of the present invention optionally in a combination with one or more other active substances. The pharmaceutical compositions according to the present invention are disclosed in co-pending Slovenian patent application P-202000042.

Preferred specific embodiments of the present invention are described in the following examples. It is, however, to be understood that the present invention is not limited to these examples.

Example A: HPLC method

The purity of Dapagliflozine in general may be determined with the following HPLC method: column: XBridge C18, 150x4.6mm, 3.5; flow-rate: 0.9ml/min; column temperature: 50°C, wavelength: UV 225 nm; mobile phase: eluent A: 0.1% H3PO4, Eluent B: methanol; gradient:

Sample preparation: Accurately weigh about 40mg of sample and dissolve in 50 ml of solvent. Calculation: Use area per cent method. Do not integrate solvent peaks.

Example 1: Preparation of 5-bromo-2-chlorobenzoyl chloride

5-bromo-2-chlorobenzoic acid (450 g) was suspended in dichloromethane (2.25 L) and dimethylformamide (0.74 ml). At 15 - 30°C oxalyl chloride (180.3 ml) was slowly added. During addition gas evolution of HC1 and CO2 occurred. The reaction was performed at 20-30°C. The reaction was considered to be complete if 2-chloro-5-bromobenzoic acid was below 1% (area percent purity). The mixture was concentrated at elevated temperature until oily residue was obtained.

Example 2: Preparation of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone

Dichloromethane (900 ml) was charged into reactor and then aluminum chloride (267.6 g) was added. The reaction mixture was cooled below 5°C and ethoxybenzene (256.1 ml) was slowly added. After complete addition, the mixture was gradually cooled below -5°C. In a separate reactor, 5-bromo-2- chlorobenzoyl chloride (485g) was dissolved in dichloromethane (900 ml). This solution was slowly added to the mixture of aluminum chloride and ethoxybenzene with such rate that temperature was kept below -5°C. After complete addition the mixture was stirred below -5°C until reaction was finished. The reaction was considered to be complete if methyl ester was below 1 % (the reaction mixture is sampled in methanol). After reaction was completed the reaction mixture was slowly added into cooled 1M HC1 solution and flushed with of dichloromethane (450 ml). The organic phase was separated and water phase was washed again with dichloromethane. Organic phases were combined and washed with water and NaHC0₃ solution. So obtained organic phase was concentrated to oily residue and dissolved in methanol ethyl acetate mixture in 10 to 1 ratio at reflux temperature. The clear solution was gradually cooled down to 35-45 °C and seeded with pure 5-bromo-2-chlorophenyl(4-ethoxyphenyl)methanone. The reaction mass was gradually cooled down to 0-10°C and stirred at that temperature up to 4 hours. The precipitate was isolated and washed with precooled methanol. The product was dried to a final LOD (Loss on drying) content of less than 1.0% with a yield of 564g (87% mass yield).

Example 3: Preparation of 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene

5-bromo-2-chlorophenyl(4-ethoxyphenyl)methanone (400g) was dissolved in 1.62L tetrahydrofuran. Into solution NaBTL (53.5g ) was added. After addition, the mixture was stirred at ambient temperature for 30-60 min followed by cooling of reaction mixture below -5°C. Aluminum chloride (314g) was added in portion and reaction mixture maintained below 5°C. After addition, the reaction mixture was gradually heated to reflux temperature and stirred until reaction was complete. Reaction mixture was cooled to ambient temperature and mixture of THF/water was slowly added into reaction mixture followed by addition of water and stirred at ambient temperature. Organic phase was collected and washed with saturated NaCl solution. Organic phase was concentrated to oily residue and dissolved in ethanol (800ml) at elevated temperature. Solution was cooled to 25-30°C and seeded with pure 4-bromo- l-chloro-2-(4-ethoxybenzyl)benzene. The reaction mass was gradually cooled to -2 to 10°C and stirred at that temperature. The product was isolated and washed with precooled ethanol and dried until final LOD (Loss on drying) content was less than 1.0%. Yield was 322 g (89%).

Example 4: Preparation of 3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-

(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene (97.5g ) and toluene (1.46L) was charge into reactor. Solution was heated to reflux temperature and approximately half of the solvent was distilled out. Tetrahydrofuran (195 mL) was charged into the solution and mixture was cooled below -70°C. Solution of 15% «-Buli in hexane (227.5 ml) was slowly added and temperature was kept below -70°C. After complete addition solution was stirred at temperature below -70°C to complete reaction. Solution of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (182 g) in toluene (243 mL) was added into reaction mixture at temperature below -70°C. After complete addition, the mixture was stirred below -70°C, warmed to approximately -65°C and then mixture of 57.6 g methanesulfonic acid in 488 ml methanol was added. After addition, the mixture was gradually warmed to ambient temperature and stirred until reaction was complete. After reaction was finished reaction mixture was slowly added into saturated NaHCCL solution (630ml) and stirred. Into quenched mixture 975 ml of heptane and 585 ml methanol was added. The mixture was stirred for additional 15 min. Organic phase was washed with water/methanol mixture several times. Water phases were combined and distilled to remove organic solvents. Into the residual water phase, toluene was added to perform extraction. Organic phases were combined and washed with water. Organic phase was distillated at elevated temperature until oily residue was obtained.

Example 5: Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl) tetrahydro2H-pyran-3,4,5-triol - Dapagliflozin

Dichloromethane (656 mL) was charged into oily residue from step 4 and stirred at ambient temperature until clear solution was obtained. Triethysilane (122 mL) was added into the so obtained solution. Reaction mixture was cooled below -30°C and 94.2 mL of boron trifluoride etherate was slowly added at temperatures below -30°C. After complete addition, the mixture was stirred below -30°C for one hour and gradually warmed to -5 to 0°C until reaction was completed. After reaction was finished saturated NaHCCL solution (468 mL) was slowly added. Reaction mixture was distilled to remove organic solvents followed by addition ethyl acetate into the residue. Organic phase was collected and washed again with saturated NaHC0₃ and water. So obtained organic phase was distillated at elevated temperature until oily residue is obtained.

Example 6: Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate.

Oily residual from example 5 was dissolved in dichloromethane (602 mL) at ambient temperature followed by addition of DMAP (6.22g). Reaction mixture was cooled to 0 - 10°C and 144.3 mL of acetic anhydride was added at temperatures below 10°C. Reaction mixture was gradually warmed to ambient temperature and stirred until reaction was completed. Reaction mass was washed with water with saturated NaHC0₃. Organic phase was collected and concentrated to oily residue to which ethanol (1.68L) was charged and approximately 300 ml ethanol was removed by distillation. The clear solution was gradually cooled to 60-65 °C and seeded. The reaction mass was gradually cooled to 20-25 °C and product was isolated. The product was dried at 50°C in vacuum until LOD (Loss on drying) below 1.0% 123g of product was obtained with yield 71%. HPLC purity: 99.97 %.

Formula 9 Formula 2 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran- 3,4,5-triyl triacetate (740 g) as prepared according to process described in examples 1 to 6 was charged into solution of methanol (2.27L), water (0.74L) and NaOH (23 lg) at 35-45°C and stirred at 35-45°C until reaction was completed. After reaction was finished 1M HC1 (1.63L) was slowly added. Reaction mass was distilled to remove organic solvents and product was extracted by tert-butyl methyl ether. Combined organic phases were washed with water and concentrated at elevated temperature until oily residue was obtained. Content of impurity IMP A was below 0.02%.

Example 7a: Preparation of amorphous dapagliflozin.

Oily residue as prepared according to example 7 comprising approximately 262 g of dapagliflozin was dissolved in toluene (2.5L) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (5.3L) at temperature between 10 to 15°C and stirring rate with P/V at 4 W/m³. After complete addition, the suspension was cooled to 0°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Filtration rate was 14 · 10⁴ m/s. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of impurity IMP A was below 0.02% and residual heptane and toluene were 1673 ppm and below 89 ppm.

(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) tetrahydro-2H-pyran- 3,4,5-triyl triacetate (30 g) of 4 different qualities obtained by the process known in the prior art was charged into solution of methanol (90 mL), water (30 mL) and NaOH (9.36 g) and stirred at 35-45°C until reaction was completed and sampled for HPLC analysis (Sample 1).

After reaction was finished 1M HC1 (66 mL) was slowly added. Reaction mass was distilled to remove organic solvents and product was extracted by tert-butyl methyl ether. To the combined organic phases 68ml of 1M NaOH was added and pH was set to 12.5 to 13.5. Phases were separated and organic phase is washed again with 68ml of water without pH correction. So obtained organic phase was sampled for HPLC analysis (Sample 2) and concentrated at elevated temperature until oily residue was obtained. Oily residue comprising approximately 21 g of dapagliflozin was dissolved in toluene (210 mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (420 mL) at temperature between 10 to 15°C and stirring rate with P/V as defined in Table 1. After complete addition, the suspension was cooled to 0°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Filtration rate was as defined in Table 1. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Amorphous dapagliflozin with content of impurity IMP A as shown in Table 1 and residual heptane and toluene as shown in Table 1 was obtained for each cases. Table 1 : Process parameters used in the preparation of four different starting materials (cases).

As it is evident from Table 2 the final amorphous dapagliflozin prepared by the extraction process according to the present invention contains less than 0.02% of impurity IMP A irrespective of the level of impurity IMP A present in the starting material. Table 2: Content of impurity IMP A in the final amorphous dapagliflozin obtained with and without extraction.

Example 9

Oily residue, as obtained by the procedure described in example 8 case 1, containing approximately 2 g of dapagliflozin was dissolved in 1.5ml of isopropyl acetate and 6ml of tert-butyl methyl ether at temperature 50-55 °C. So prepared solution was charged into 25 mL of heptane at 0°C. After complete addition the suspension was stirred at -10 to 0°C. Suspension was isolated and washed with precooled heptane at temperatures between 25°C to 50 °C. 1.5 g of dapagliflozin was obtained with content of impurity IMP A was below 0.02%. Example 10

Oily residue, as obtained by the procedure described in example 8 case 1, containing approximately 2 g of dapagliflozin was dissolved in 1.5ml of isopropyl acetate and 6ml of tert-butyl methyl ether at temperature 50-55 °C. So prepared solution was charged into 40 mL of heptane at 0°C. After complete addition the suspension was stirred at -10 to 0°C. Suspension was isolated and washed with precooled heptane at temperatures between 25°C to 50 °C. 1.5 g of dapagliflozin was obtained with content of impurity IMP A was below 0.02%.

Example 11

Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at 5°C and stirring rate with P/V at 16 W/m³. After complete addition, the suspension was cooled to -10°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 1480 ppm and 732 ppm.

Example 12

Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at 20°C and stirring rate with P/V at 16 W/m³. After complete addition, the suspension was cooled to 5°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled hcptanc Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 2873 ppm and 639 ppm.

Comparative Example 1

Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at -5°C and stirring rate with P/V at 16 W/m³. After complete addition, the suspension was cooled to -15°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 1940 ppm and 1557 ppm.

Comparative Example 2

Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at 25°C and stirring rate with P V at 16 W/m³. After complete addition, the suspension was cooled to 20°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 3663 ppm and 2047 ppm.

Comparative Example 3 Dapagliflozin (30g) was dissolved in toluene (285mL) at temperature 60-70 °C. Solution of dapagliflozin in toluene was slowly added into heptane (600mL) at 30°C and stirring rate with P/V at 16 W/m³. After complete addition, the suspension was cooled to 15°C and stirred with unchanged stirring rate. Suspension was isolated and washed with precooled heptane. Isolated product was dried in vacuum dryer at temperatures between 25 °C to 50 °C. Content of residual heptane and toluene were 2425 ppm and 1812 ppm.

Claims

1. A process for the preparation of amorphous dapagliflozin comprising the steps of: i) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic or polar protic solvents and mixtures thereof, and fdtration of the obtained solution, ii) combining the solution with an antisolvent selected from the group consisting of non- aqueous and non-protic solvents and mixtures thereof at temperature between 0 to 25 °C under stirring, preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³, iii) stirring the suspension at crystallization temperature between 0 °C to 25 °C , preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³ , iv) cooling until temperature between -15 °C to 15 °C is achieved under stirring, preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³ , and v) isolation of the product followed by washing and drying.

2. The process for the preparation of amorphous dapagliflozin according to claim 1, wherein the solvent used in step i) is selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; preferably from toluene, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, ethanol, and mixtures thereof; more preferably from toluene, ethyl acetate, tert-butyl methyl ether; and even more preferably the solvent used in step i) is toluene.

3. The process for the preparation of amorphous dapagliflozin according to claim 1 or 2, wherein the antisolvent used in step ii) is selected from alkanes and cyclohexane, and mixtures thereof; preferably from heptane and hexane and mixtures thereof; and more preferably the antisolvent used in step ii) is heptane.

4. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims, wherein temperature used in step ii) is between 0 to 25 °C, preferably between 5 and 20°C and more preferably between 10 and 15°C.

5. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims, wherein crystallization temperature used in step iii) is between 0 to 25 °C °C, preferably between 5 to 20 °C and more preferably between 10 to 15 °C.

6. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims, wherein cooling temperature of step iv) is between -15 to 15°C, preferably between -10 and 10°C and more preferably between -5 and 5°C.

7. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims, wherein stirring rate of step ii), step iii) and step iv) is in the range of power number P/V between 2 to 250W/m³, preferably from 2 W/m³ to 120W/m³ and more preferably from 2 to 60W/m³.

8. A process for the preparation of amorphous dapagliflozin comprising the steps of: i) purifying dapagliflozin, preferably purifying dapagliflozin by acid-base extraction, more preferably purifying dapagliflozin by acid-base extraction by the addition of alkaline water solution and additional washing with water, ii) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic solvents and polar protic solvents and mixtures thereof, and fdtration of the obtained solution, iii) combining the solution with an antisolvent selected from the group consisting of non- aqueous and non-protic solvents and mixtures thereof at temperature between 0 to 25 °C under stirring, preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³, iv) stirring the suspension at crystallization temperature between 0 °C to 25 °C , preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³, v) cooling until temperature between -15 °C to 15 °C is achieved under stirring, preferably at stirring rate in the range of power number P/V between 2 W/m³ to 250 W/m³ , and vi) isolation of the product followed by washing and drying.

9. The process for the preparation of amorphous dapagliflozin according to claim 8 wherein acid base extraction of step i) is performed by the addition of alkaline water solution, preferably alkaline water solution comprising a basic species selected from NaOH, KOH or any other basic species, with pH value between 8 and 14, preferably between 10 and 14 and more preferably between 12.5 and 13.5.

10. The process for the preparation of amorphous dapagliflozin according to claim 8 or 9, wherein the solvent used in step ii) is selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; preferably from toluene, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, ethanol, and mixtures thereof; more preferably from toluene, ethyl acetate, tert-butyl methyl ether; and even more preferably the solvent used in step ii) is toluene.

11. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims 8 to 10, wherein the antisolvent used in step iii) is selected from alkanes and cyclohexane, and mixtures thereof; preferably from heptane and hexane and mixtures thereof; and more preferably heptane.

12. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims 8 to 11, wherein temperature used in step iii) is between 0 to 25 °C, preferably between 5 and 20°C and more preferably between 10 and 15°C.

13. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims 8 to 12, wherein crystallization temperature used in step iv) is between 0 to 25 °C °C, preferably between 5 to 20 °C and more preferably between 10 to 15 °C.

14. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims 8 to 13, wherein cooling temperature of step v) is between -15 to 15°C, preferably between -10 and 10°C and more preferably between -5 and 5°C.

15. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims 8 to 14, wherein stirring rate of step iii), step iv) and step v) is in the range of power number P/V between 2 W/m³ to 250 W/m³, preferably from 2 W/m³ to 120 W/m³ and more preferably from 2 W/m³ to 60 W/m³.

16. A process for the preparation of dapagliflozin, optionally for the preparation of amorphous dapagliflozin, said process comprising the steps of: reaction of 5-bromo-2-chlorobenzoic acid compound of formula 3 with oxalyl chloride in dichloromethane to provide 5-bromo-2-chlorobenzoyl chloride, reaction of the obtained compound with ethoxybenzene in the presence of AlCh in dichloromethane, optionally purifying the obtained compound by crystalizing with seeding, to provide (5 -bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone, reaction of the obtained compound with AICI₃ and NaBTh in THF, optionally purifying the obtained compound using ethanol with seeding, to provide 4-bromo-l-chloro-2-(4- ethoxybenzyl)benzene, reaction of the obtained compound with compound of (3R,4S,5R,6R)-3,4,5- tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one in the presence of n-butyl lithium in THF and toluene, followed by treating with methane sulfonic acid in methanol, optionally purifying the obtained compound using extraction with heptane, to provide 3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3 ,4,5 -triol, reaction of the obtained compound in-situ with triethylsilane and boron trifluoride etherate in dichloromethane to provide (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl) tetrahydro2H-pyran-3,4,5-triol, reaction of the obtained compound in-situ with acetic anhydride in the presence of dimethylamino pyridine in dichloromethane, optionally purifying the obtained compound crystalizing with seeding, to provide (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4- ethoxybenzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate, - treating the obtained compound with sodium hydroxide in aqueous methanol to provide dapagliflozin, optionally subjecting the dapagliflozin to a process for the preparation of amorphous dapagliflozin according to any one of preceding claims 1 to 15.