CN115867538A

CN115867538A - Preparation of highly pure amorphous dapagliflozin

Info

Publication number: CN115867538A
Application number: CN202180049664.5A
Authority: CN
Inventors: 阿莱斯·波洛维奇; 普利莫斯·本基奇; 尼卡·奥斯特曼; 马泰加·格鲁巴尔; 杰内伊卡·沃夫科; 贾兹·科巴尔; 莫妮卡·库夫纳
Original assignee: KRKA dd
Current assignee: KRKA dd
Priority date: 2020-06-05
Filing date: 2021-06-04
Publication date: 2023-03-28
Also published as: EP4161912A1; WO2021245253A1

Abstract

Novel and improved processes for preparing amorphous dapagliflozin are disclosed. The invention also provides pharmaceutical compositions comprising amorphous dapagliflozin, optionally in combination with one or more other active substances, and methods for making the same.

Description

Preparation of highly pure amorphous dapagliflozin

Technical Field

The present invention relates to a new and improved process for the preparation of the SGLT2 inhibitor dapagliflozin (dapagliflozin), in particular in amorphous form. The invention also provides pharmaceutical compositions comprising amorphous dapagliflozin, optionally in combination with one or more other active substances, and processes for the preparation thereof.

Background

Sodium-glucose cotransporter-2 (SGLT 2) inhibitors are a group of oral drugs used for the treatment of diabetes, approved since 2013. SGLT2 inhibitors prevent the kidneys from reabsorbing glucose back into the blood by passing into the bladder. Glucose is withdrawn back into the blood via the renal proximal tubule. SGLT2 is a protein that is expressed primarily in the renal proximal tubule and may be the major transporter responsible for this absorption. The hypoglycemic effect of SGLT-2 inhibitors occurs through diabetes primarily by increasing the urinary excretion of glucose via a non-insulin dependent mechanism.

Treatment with SGLT2 inhibitors in type II diabetic patients has been shown to reduce HbAlc, reduce body weight, reduce systemic Blood Pressure (BP) and cause small increases in LDL-C and HDL-C levels.

SGLT2 inhibitors inhibit reabsorption of sodium and glucose by the tubules, so more sodium is transported to the dense plaque, causing dilation of the arterioles, a decrease in intraglomerular pressure, and a decrease in ultrafiltration. SGLT2 inhibitors cause natriuresis and volume depletion, as well as elevated circulating levels of renin, angiotensin and aldosterone. They also reduce albuminuria and slow GFR loss by mechanisms that appear to be unrelated to glycemia.

Dapagliflozin, shown below, is a highly potent and reversible SGLT2 inhibitor that increases the amount of glucose excreted in the urine and improves fasting and postprandial plasma glucose levels in type 2 diabetic patients. In some studies in the diabetic population, dapagliflozin has also been shown to tend to reduce liver fat content.

Dapagliflozin is commercially available in the form of dapagliflozin propylene glycol monohydrate, sold under the trade name Forxiga or Farxiga in the form of a film coated tablet. Furthermore, it is commercially available as a combination product with metformin hydrochloride, which is sold under the trade name Xigduo IR or Xigduo XR in the form of film-coated tablets. Furthermore, it is commercially available as a combination product with saxagliptin hydrochloride, which is sold under the trade name Qtern in the form of film-coated tablets. Furthermore, it is commercially available as a combination product with saxagliptin hydrochloride and metformin hydrochloride, which is sold under the trade name Qternmet XR in the form of film-coated tablets.

Dapagliflozin, as a monotherapy and in combination with other active substances, has demonstrated efficacy in improving glycemic control as well as reducing body weight and blood pressure in a wide range of type II diabetic patients, including those with high baseline HbAlc and the elderly. A sustained decrease in serum uric acid concentration was also observed. Dapagliflozin provides a significant improvement in HbAlc, reduction in insulin dosage and reduction in body weight in type 1 diabetic patients as an adjunctive therapy to the modulation of insulin.

Dapagliflozin may be in its free form or in any of its stereoisomers or in any of its pharmaceutically acceptable salts or co-crystal complexes or hydrates or solvates thereof, as well as in any polymorphic form and in any mixture thereof.

Dapagliflozin is disclosed for the first time in US 6,515,117 as a substance. The process for preparing dapagliflozin comprises reacting 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain compound 3 which upon demethoxylation produces a diastereomeric mixture of dapagliflozin. The diastereomeric mixture of dapagliflozin is further acetylated with acetic anhydride in the presence of pyridine and dimethylaminopyridine, then recrystallized from anhydrous ethanol to yield the desired tetraacetylated β -C-glucoside as a white solid. The compound tetraacetylated β -C-glucoside was treated with lithium hydroxide hydrate, which underwent deprotection to give the compound dapagliflozin.

Several other documents, patents and applications disclose methods for the preparation of dapagliflozin, such as for example WO0127128, WO03099836, WO2004063209, WO2006034489, WO2010022313, WO2012019496, WO2013064909, WO2013068850, WO2013079501, WO2014094544, WO2014159151, WO2014206299, WO2015040571, WO2015044849, WO2015063726, WO 92 zxft 3292, WO2015155739, WO2016098016, WO2016128995, WO2016178148, WO 3725 zxft 3225, WO 4235, WO 42526258, WO 42xzft 4258, WO 4258 zxft 5258.

The prior art literature has provided some compositions of SGLT2 inhibitor dapagliflozin.

WO2008116179 discloses an immediate release formulation comprising dapagliflozin propylene glycol hydrate, one or more fillers, one or more binders and one or more disintegrants in the form of a blank granulation or in the form of a capsule or tablet.

WO2011060256 describes a bilayer tablet comprising dapagliflozin having a sustained release profile in one layer and metformin in the other layer, whilst WO2011060290 describes an immediate release formulation of dapagliflozin and metformin.

WO2012163546 discloses pharmaceutical compositions comprising cyclodextrin and dapagliflozin.

Cocrystals of dapagliflozin and lactose are described in WO 2014178040.

Solid dispersion compositions comprising amorphous dapagliflozin and at least one polymer are disclosed in WO2015011113 and WO 2015128853.

CN103721261 discloses combinations of SGLT2 inhibitors with vitamins such as vitamin B.

Pharmaceutical composition formulations comprising dapagliflozin L-proline and metformin and/or a DPP-IV inhibitor are disclosed in WO 2018124497.

EP2252289A1 provides combinations of SGLT inhibitors and DPP4 inhibitors that exhibit synergistic effects in increasing plasma active GLP-1 levels in patients relative to those provided by administration of either SGLT inhibitor or DPP4 inhibitor alone.

EP2395983A1 relates to a pharmaceutical composition comprising an SGLT2 inhibitor, a DPP4 inhibitor and a third antidiabetic agent, which is suitable for treating or preventing one or more conditions selected from the group consisting of type 1 diabetes, type 2 diabetes, impaired glucose tolerance and hyperglycemia.

Regardless of these various known manufacturing methods, there remains a need for efficient synthesis of amorphous dapagliflozin that provides a high purity dapagliflozin material and does not require cumbersome purification steps. Amorphous dapagliflozin prepared according to the method of the present invention is used in a pharmaceutical composition, which exhibits excellent chemical and physical stability, which is stable under normal storage conditions, while it provides improved content uniformity.

Disclosure of Invention

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

(optionally purifying dapagliflozin),

i) (optionally purified) dapagliflozin is dissolved 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 the obtained solution is filtered,

ii) at a temperature of from 0 ℃ to 25 ℃ (with stirring), preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of the power number P/V ("power number P/V" is also referred to herein as "stirring power per (unit) volume P/V"), combining the solution with an anti-solvent selected from non-aqueous and aprotic solvents (and mixtures thereof),

iii) At a crystallization temperature of 0 ℃ to 25 ℃, preferably at 2W/m ³ To 250W/m ³ Stirring the suspension at a stirring rate in the range of P/V,

iv) cooling (under stirring) until a temperature of-15 ℃ to 15 ℃ is achieved, preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of the power number P/V, and

v) the product is isolated, then washed and dried.

This process is also referred to herein as "process (a)". Prior to step i) of "method (a)", "method (a)" may comprise an optional step of purifying dapagliflozin, preferably by acid-base extraction, more preferably by acid-base extraction via addition of an alkaline aqueous solution and additional washing with water.

The product obtained in step v) comprises or consists of amorphous dapagliflozin. Advantageously, the process of the invention provides a product which: it comprises or consists of amorphous dapagliflozin and it may be free of the impurity IMP a or comprise a small amount of the impurity IMP a, for example in an amount of less than 0.02 wt. -%, based on the total weight of dapagliflozin (as obtained in the washed and dried product after step v)), in particular based on the total weight of amorphous dapagliflozin (as obtained in the washed and dried product after step v)). In one embodiment, in steps ii), iii), iv), the stirring rate of the stirring is 2W/m ³ To 250W/m ³ Within the range of P/V.

P/V is 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" may be used interchangeably herein. The term "stirring power per volume P/V" may in particular be the stirring power per volume of the mixture subjected to stirring (which mixture may be, for example, a suspension of step iii) or iv) of "method (a)" or a suspension of step iv) or V) of "method (B)", or, for example, a combination of step ii) of "method (a)" or a combination of step iii) of "method (B)").

The term "solvent selected from non-aqueous and aprotic solvents or polar aprotic or polar protic solvents (and mixtures thereof)" as used herein may especially be "a solvent selected from non-aqueous and aprotic solvents and mixtures thereof", or may especially be "selected from aprotic solvents; a non-aqueous polar protic solvent; and solvents for mixtures thereof ". The aprotic solvent may in particular be a polar aprotic solvent. The polar protic solvent may in particular be a non-aqueous polar protic solvent.

As used herein, the terms "between x and y" and "x to y" describe a range that includes the two range ends x and y, respectively. For example, a range of "0 ℃ to 25 ℃" includes the range endpoints of 0 ℃ and 25 ℃. The terms "between x and y" and "x to y" are used interchangeably herein. As used herein, the term "crystallization temperature" may specifically encompass the term "temperature at which a solid amorphous material is formed".

Another embodiment of the present invention is a process for preparing amorphous dapagliflozin, comprising the steps of:

i) Purifying dapagliflozin, preferably purifying dapagliflozin by acid-base extraction, more preferably purifying dapagliflozin by acid-base extraction via addition of a basic aqueous solution and further washing with water,

ii) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic and polar protic solvents (and mixtures thereof), and filtering the obtained solution,

iii) At a temperature of 0 ℃ to 25 ℃ (with stirring), preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of power numbers P/V, combining the solution with an anti-solvent selected from non-aqueous and aprotic solvents (and mixtures thereof),

iv) a crystallization temperature of from 0 ℃ to 25 ℃, preferably at 2W/m ³ To 250W/m ³ Stirring the suspension at a stirring rate within the range of power number P/V,

v) cooling (under stirring) until a temperature of-15 ℃ to 15 ℃ is achieved, preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of power number P/V and

vi) the product is isolated, then washed and dried.

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 invention provides a product which: it comprises or consists of amorphous dapagliflozin and it may be free of the impurity IMP a or comprise a small amount of the impurity IMP a, for example in an amount of less than 0.02 wt. -%, based on the total weight of dapagliflozin (as obtained in the washed and dried product after step vi)), in particular based on the total weight of amorphous dapagliflozin (as obtained in the washed and dried product after step vi)).

In another embodiment of the present invention, the dapagliflozin used in step i) of the method disclosed above for preparing amorphous dapagliflozin is prepared by a method comprising:

-reacting the 5-bromo-2-chlorobenzoic acid compound of formula 3 with oxalyl chloride in dichloromethane to provide 5-bromo-2-chlorobenzoyl chloride,

reacting the compound obtained with ethoxybenzene in AlCl ₃ Optionally purifying the obtained compound, preferably by crystallization, more preferably by crystallization with seed crystals, to provide (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone,

reacting the compound obtained with AlCl ₃ And NaBH ₄ Reaction in THF, optionally purification of the obtained compound, preferably by crystallization, more preferably by crystallization with seed crystals, to give 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene,

-reacting the obtained compound with a compound of (3R, 4S,5R, 6R) -3,4,5-tris ((trimethylsilyl) oxo) -6- (((trimethylsilyl) oxo) methyl) tetrahydro-2H-pyran-2-one in the presence of n-butyllithium in THF and toluene, followed by treatment with methanesulfonic acid in methanol (the obtained mixture), optionally purifying the obtained compound using heptane extraction to provide 3R,4S,5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol,

-reacting 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) tetrahydro 2H-pyran-3,4,5-triol,

-reacting the obtained compound in situ with acetic anhydride in the presence of dimethylaminopyridine in dichloromethane, optionally purifying the obtained compound, preferably purifying the obtained compound by crystallization, more preferably purifying the obtained compound by crystallization with seed crystals, to provide (2R, 3R,4R,5S, 6S) -2- (acetoxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triyltriacetate,

-treating the obtained compound with sodium hydroxide in aqueous methanol solution to provide dapagliflozin, which may be used in particular in steps i) to v) or i) to vi) as disclosed above ("of method (a)") to prepare amorphous dapagliflozin.

In one embodiment of the present invention, the dapagliflozin used in step i) of the method disclosed above for preparing amorphous dapagliflozin is prepared by (schematic figure 1) (comprising):

reacting the compound obtained with ethoxybenzene in AlCl ₃ In dichloromethane, and purifying the obtained compound by crystallization with seed crystals to provide (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone,

reacting the compound obtained with AlCl ₃ And NaBH ₄ Reacting in THF, purifying the obtained compound with seed crystals to provide 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene,

-reacting the obtained compound with a compound of (3R, 4S,5R, 6R) -3,4,5-tris ((trimethylsilyl) oxo) -6- (((trimethylsilyl) oxo) methyl) tetrahydro-2H-pyran-2-one in the presence of n-butyllithium in THF and toluene, followed by treatment with methanesulfonic acid in methanol and purification of the obtained compound using heptane extraction to afford 3R,4S,5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol,

-reacting the obtained compound in situ with acetic anhydride in the presence of dimethylaminopyridine in dichloromethane, purifying the obtained compound with seed crystallization to provide (2R, 3R,4R,5S, 6S) -2- (acetoxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triyltriacetate,

-treating the obtained compound with sodium hydroxide in aqueous methanol solution to provide dapagliflozin, which can be used in particular in steps i) to v) or i) to vi) as disclosed above ("of method (B)") to prepare amorphous dapagliflozin.

The term "purification by crystallization" may include dissolving a compound to be purified in a solvent to obtain a solution, allowing or causing crystallization of the compound to be purified in the solution, and optionally isolating the crystalline compound to be purified. The term "purification by crystallization with seed crystals" may comprise dissolving the compound to be purified in a solvent to obtain a solution and causing the compound to be purified to crystallize in the solution by adding seeding material, in particular seed crystals, to the solution and optionally isolating the crystalline compound to be purified. The seed may be a seed comprising or consisting of the compound to be purified by crystallization, or the seeding material may be silica particles. The silica particles can be used in particular for the initial preparation of seeds comprising or consisting of the compound to be purified by crystallization.

Specifically, the following items are provided: 1. a process for preparing 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 filtering the obtained solution,

ii) at a temperature of from 0 ℃ to 25 ℃ at 2W/m ³ To 250W/m ³ With an anti-solvent selected from the group consisting of non-aqueous and aprotic solvents at a stirring rate in the range of a power number P/V,

iii) At a crystallization temperature of 0 ℃ to 25 ℃ at 2W/m ³ To 250W/m ³ Stirring the suspension at a stirring rate in the range of P/V,

iv) at 2W/m ³ To 250W/m ³ Is cooled at a stirring rate in the range of the power number P/V until a temperature of-15 ℃ to 15 ℃ is achieved, and

v) the product is isolated, then washed and dried.

2. The process for the preparation of amorphous dapagliflozin according to entry 1, wherein the solvent used in step i) is selected from the group consisting of aromatic carbohydrates, esters, ethers, 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 entry 1, wherein the anti-solvent used in step ii) is selected from the group consisting of alkanes and cyclohexane, preferably from heptane and hexane, and more preferably heptane.

4. The process for preparing amorphous dapagliflozin according to item 1, wherein the temperature used in step ii) is from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃, and more preferably from 10 ℃ to 15 ℃.

5. The process for preparing amorphous dapagliflozin according to item 1, wherein the crystallization temperature used in step iii) is from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃, and more preferably from 10 ℃ to 15 ℃.

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

7. The process for preparing amorphous dapagliflozin according to item 1, wherein the stirring rate of step ii), step iii) and step iv) is at 2W/m ³ To 250W/m ³ Preferably 2W/m ³ To 120W/m ³ And more preferably 2W/m ³ To 60W/m ³ Within the range of power number P/V.

8. A process for preparing amorphous dapagliflozin, comprising the steps of:

i) Dapagliflozin is purified by acid-base extraction via addition of an alkaline aqueous solution and additional washing with water,

ii) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or a polar aprotic solvent and a polar protic solvent, and filtering the obtained solution,

iii) At a temperature of 0 ℃ to 25 ℃ at 2W/m ³ To 250W/m ³ At a stirring rate in the range of P/V, with an anti-solvent selected from non-aqueous and aprotic solvents,

iv) crystallization temperature of 0 ℃ to 25 ℃ at 2W/m ³ To 250W/m ³ Stirring the suspension at a stirring rate in the range of power number P/V,

v) at 2W/m ³ To 250W/m ³ Until a temperature of-15 ℃ to 15 ℃ is achieved, at a stirring rate in the range of the power number P/V, and

vi) the product is isolated, then washed and dried.

9. The process for preparing amorphous dapagliflozin according to entry 8, wherein the acid-base extraction of step i) is carried out by adding an aqueous alkaline solution having a pH value of from 8 to 14, preferably from 10 to 14, and more preferably from 12.5 to 13.5, selected from NaOH, KOH or any other alkaline substance.

10. The process for the preparation of amorphous dapagliflozin according to entry 8, wherein the solvent used in step ii) is selected from aromatic carbohydrates, esters, ethers, 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 entry 8, wherein the anti-solvent used in step iii) is selected from the group consisting of alkanes and cyclohexane, preferably from heptane and hexane, and more preferably heptane.

12. The process for preparing amorphous dapagliflozin according to entry 8, wherein the temperature used in step iii) is from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃, and more preferably from 10 ℃ to 15 ℃.

13. The process for preparing amorphous dapagliflozin according to entry 8, wherein the crystallization temperature used in step iv) is from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃, and more preferably from 10 ℃ to 15 ℃.

14. The process for preparing amorphous dapagliflozin according to entry 8, wherein the cooling temperature of step v) is from-15 ℃ to 15 ℃, preferably from-10 ℃ to 10 ℃, and more preferably from-5 ℃ to 5 ℃.

15. The method for preparing amorphous dapagliflozin according to item 8, wherein the stirring rate of step iii), step iv) and step v) is at 2W/m ³ To 250W/m ³ Preferably 2W/m ³ To 120W/m ³ And more preferably 2W/m ³ To 60W/m ³ Within the range of power number P/V.

16. A process for preparing amorphous dapagliflozin, comprising the steps of:

reacting the compound obtained with AlCl ₃ And NaBH ₄ Reacting in THF, purifying the obtained compound with seed crystals using ethanol to provide 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene,

-treating the obtained compound with sodium hydroxide in aqueous methanol to provide dapagliflozin for use in any of the preceding entries 1 to 15.

Drawings

FIG. 1 depicts a process for preparing dapagliflozin

Detailed Description

It is well known that formulations containing a pharmaceutically active substance exhibit technical problems of re-agglomeration, resulting in a reduced dissolution profile of the active substance. Thus, the amorphous form is advantageous for increasing the dissolution profile to overcome the problem of decreased dissolution profile due to undesirable re-agglomeration. It is well known that it is difficult to obtain amorphous materials in chemically pure form, meaning substances that meet ICH requirements. During the preparation of amorphous dapagliflozin according to the prior art document, a substance or impurity is identified which is chemically named (2s, 3r,4r,5s, 6r) -2- (4-chloro-3- (4-hydroxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (hereinafter labeled as impurity IMP a) and which has a chemical structure which cannot be easily removed from the final amorphous dapagliflozin.

The contents of impurities IMP a and residual solvent were determined by the HPLC method disclosed in example a.

Accordingly, one embodiment of the present invention is to develop a process for preparing amorphous dapagliflozin that does not comprise any detectable level of the impurity IMP a. Another embodiment of the present invention is to develop a process for preparing amorphous dapagliflozin, wherein the impurity IMP a may be purified or eliminated to below 0.02%. We have unexpectedly found that by using an extraction process in the final step of the synthesis of amorphous dapagliflozin, the impurity IMP a can be purified in high yield. Given the low purification coefficient of this particular impurity, the extraction method is advantageous compared to commonly known methods such as crystallization, eutectic formation and the like, all of which can result in significant material loss. The method according to the invention provides amorphous dapagliflozin that does not contain any detectable level of impurity IMP a and also meets ICH requirements for residual solvent in the final material.

The present invention relates to a new and improved process for the preparation of amorphous dapagliflozin represented by the following formula and reaction intermediates suitable for the manufacture thereof, wherein the amorphous dapagliflozin obtained does not comprise any detectable level of impurity IMP a or less than 0.02%.

Accordingly, one embodiment of the present invention is a process for preparing amorphous dapagliflozin, said process comprising the steps of:

i) Dissolving dapagliflozin in a solvent and filtering the obtained solution,

ii) combining the solution with an anti-solvent at a defined temperature and stirring rate to obtain a suspension, iii) stirring the suspension at a crystallization temperature,

iv) cooling, and

v) isolating the product.

The inventors of the present invention have unexpectedly found that by fully controlling the process parameters of each process step for preparing amorphous dapagliflozin, the formation of the impurity IMP a in the final amorphous dapagliflozin can be minimized, in order to obtain amorphous dapagliflozin meeting the requirements of ICH guidelines. By such complete process control it can be ensured that the final amorphous dapagliflozin is substantially free of the impurity IMP a, which means that the content of the impurity IMP a in the amorphous dapagliflozin is below 0.02% and that the amorphous dapagliflozin obtained also meets ICH requirements for residual solvents in the final material.

Accordingly, one embodiment of the present invention is a process for the preparation of amorphous dapagliflozin, wherein the starting dapagliflozin has an impurity IMP a content of less than 0.02%, said process 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 filtering the obtained solution,

v) the product is isolated, then washed and dried.

The power number P/V is a generally accepted amplification parameter which depends on the stirring rate and the geometry of the reaction vessel and stirrer. Which is defined by the following formula

Where ρ represents the density of the reaction mass, n represents the stirrer speed, d is the diameter of the stirrer, and V isVolume of reaction mass. N is a radical of _p Represents the number of such powers: it can be calculated by computational fluid dynamics or estimated empirically from literature data based on stirrer shape and reaction vessel geometry (Rushton, J.H.; costicich, E.W.; everett, J.J. "Power characteristics of mixing imprners Part 2." chem.Eng.prog.46 (1950): 467 to 476.)

The solvent used in step i) may be selected from aromatic carbohydrates, esters, ethers, alcohols and mixtures thereof; preferably selected from the group consisting of toluene, ethyl acetate, isopropyl acetate, t-butyl methyl ether, ethanol, and mixtures thereof; more preferably, the solvent may be selected from toluene, ethyl acetate, t-butyl methyl ether; and even more preferably, the solvent may be toluene.

The anti-solvent used in step ii) may be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably, the anti-solvent can be heptane.

The solvent used in step i) may be selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; the anti-solvent used in step ii) may be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably, the anti-solvent may be heptane.

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

The solvent used in step i) may be toluene; the anti-solvent used in step ii) may be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably, the anti-solvent may be heptane.

The temperature used in step ii) may be from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃ and more preferably from 10 ℃ to 15 ℃.

The crystallization temperature used in step iii) may be from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃ and more preferably from 10 ℃ to 15 ℃.

The cooling temperature of step iv) may be from-15 ℃ to 15 ℃, preferably from-10 ℃ to 10 ℃ and more preferably from-5 ℃ to 5 ℃.

The stirring rate of step ii), step iii) and step iv) may be 2W/m ³ To 250W/m ³ Preferably 2W/m ³ To 120W/m ³ And more preferably 2W/m ³ To 60W/m ³ Within the range of P/V.

The inventors of the present invention have found that all the above defined process steps should be carried out within a carefully predefined temperature range and preferably at a carefully defined stirring rate. By such a complete process control it is possible to ensure that the obtained material reaches the ICH requirements for residual solvent in the final material and that the process is suitable for industrial scale without the problem of slow filtration of the final material (which is often the case with amorphous materials).

The inventors of the present invention have surprisingly found that the precipitation temperature of step ii) is extremely important to achieve a fast filtration of the product. It is important that the agglomeration during precipitation is carried out within a specific temperature range, which provides suitably agglomerated particles, ensuring good filtration characteristics of the product. If the precipitation temperature is below the limits specified above, the filtration is too slow. If the temperature is higher, the agglomeration due to the "glass transition" of the amorphous material in the preferred solvent combination will be too strong, causing oiling of the product, making separation impossible at all. Furthermore, higher precipitation temperatures have a strong influence on the residual solvent in the final amorphous dapagliflozin substance. If the material is allowed to precipitate at a higher temperature as defined above, even if the material thus obtained exhibits a good filtration rate, the material will result in residual solvent being trapped in the material and not being reduced by drying.

Furthermore, the inventors of the present invention have unexpectedly found that the stirring rate and temperature of steps iii) and iv) are more critical for fast filtration rates, as can be expected by the expert in the field. At too high a power input and too low a suspension temperature, the amorphous particles break up due to the power input by stirring, which results in a very high resistance of the filter cake, as shown in the examples but not limited to them. The filtration rate in meters per second is defined as the volume of mother liquor (in cubic meters) passing through a specified filtration area (in square meters) for the filter cake at a pressure difference of 1 bar over the measurement time (in seconds).

The products obtained by steps i) to v) defined above can be isolated in any industrial plant, which means that no special and expensive equipment is required. For example, a pressure filter or a filter dryer may be used. In order to perform the complete separation step followed by the washing step and the drying step, the separation step may preferably be performed in a filter dryer. The filtered material should be thoroughly washed with an anti-solvent, such as heptane, to wash residual solvent from the wet cake to achieve efficient removal of solvent during drying. Optionally, the material may be slurried in an anti-solvent to improve removal of residual solvent from the filter cake prior to drying. The inventors of the present invention have found that the residual solvent in the wet cake is critical to achieving effective drying of the product. If, for example, a solvent such as toluene is present in the wet cake (in substantial amounts), it will initiate a low "glass transition" of amorphous dapagliflozin, leading to additional agglomeration and thus, for the solvent and anti-solvent used in the process, not being able to reach the ICH requirements for residual solvent of the final product.

The dapagliflozin used in step i) of the process for preparing amorphous dapagliflozin disclosed above may be in any form (such as in any polymorphic form or as a solid dissolved in a solvent), and may be prepared according to any process that provides dapagliflozin with an impurity IMP a content of less than 0.02%.

In another embodiment of the present invention, dapagliflozin used in step i) of the method disclosed above for the preparation of amorphous dapagliflozin is prepared by the following method (schematic of fig. 1):

-step 1: the 5-bromo-2-chlorobenzoic acid compound of formula 3 is reacted with oxalyl chloride in dichloromethane to provide the 5-bromo-2-chlorobenzoyl chloride compound of formula 4.

-step 2: reacting a compound of formula 4 with ethoxybenzene in AlCl ₃ The reaction in methylene chloride in the presence of a solvent, and the obtained compound is purified by crystallization with a seed crystal to provide a (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone compound of formula 5. The reaction temperature during the addition of the compound of formula 4 is-20 ℃ to 0 ℃. The crystallization solvent is a mixture of methanol and ethyl acetate in the range of methanol/ethyl acetate =10 to 4:1. The seeding temperature is 35 ℃ to 45 ℃.

-a step 3: reacting a compound of formula 5 with AlCl ₃ And NaBH ₄ The obtained compound was purified by seeding with ethanol in THF to provide a 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene compound of formula 6. Adding compound AlCl ₃ The reaction temperature during this period was-10 ℃ to 5 ℃. Adding AlCl ₃ The reaction temperature thereafter was 60 ℃ to 65 ℃. The seeding temperature is 25 ℃ to 30 ℃.

-step 4: compound (3r, 4s,5r, 6r) -3,4,5-tris ((trimethylsilyl) oxo) -6- (((trimethylsilyl) oxo) methyl) tetrahydro-2H-pyran-2-one (compound 7) is reacted with a compound of formula 6 in the presence of n-butyllithium in tetrahydrofuran and toluene, then treated with methanesulfonic acid in methanol, and the resulting compound is purified using heptane extraction to provide the 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. The reaction temperature during the addition of n-Buli is from-90 ℃ to-65 ℃. The reaction temperature during the addition of compound 7 was-90 ℃ to-70 ℃.

-step 5: reacting the compound of formula 8 in situ with triethylsilane and boron trifluoride etherate in dichloromethane to provide a (2s, 3r,4r,5s, 6r) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro 2H-pyran-3,4,5-triol compound of formula 2. The reaction temperature during the addition of the boron trifluoride etherate is from-50 ℃ to-20 ℃.

-step 6: the compound of formula 2 is reacted in situ with acetic anhydride in the presence of dimethylaminopyridine in dichloromethane and the resulting compound is purified by crystallization from ethanol with seed crystals to provide (2r, 3r,4r,5s, 6s) -2- (acetoxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula 9. The seeding temperature is 60 ℃ to 65 ℃.

-step 7: compound of formula 9 is treated with sodium hydroxide in aqueous methanol to afford compound 2.

-step 8: solid amorphous dapagliflozin is prepared according to steps i) to v) as disclosed above.

Another embodiment of the present invention is a process for the preparation of amorphous dapagliflozin, wherein the starting dapagliflozin may have a content of impurity IMP a higher than 0.02%, which means that there is no need to control the content of impurity IMP a during the synthesis of dapagliflozin. Accordingly, another embodiment of the present invention is a process for preparing amorphous dapagliflozin, said process comprising the steps of:

iii) At a temperature of 0 ℃ to 25 ℃ (with stirring), preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of the power number P/V ("power number P/V" is also referred to herein as "stirring power per (unit) volume P/V"), combining the solution with an anti-solvent selected from non-aqueous and aprotic solvents (and mixtures thereof),

iv) a crystallization temperature of from 0 ℃ to 25 ℃, preferably at 2W/m ³ To 250W/m ³ Stirring the suspension at a stirring rate in the range of P/V,

v) cooling (under stirring) until a temperature of-15 ℃ to 15 ℃ is achieved, preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of the power number P/V, and

vi) the product is isolated, then washed and dried.

Where ρ represents the density of the reaction mass, n represents the stirrer speed, d is the diameter of the stirrer, and V is the volume of the reaction mass. N is a radical of _p Representing such a power number ("power number N) _p "): it can be calculated by computational fluid dynamics or estimated empirically from literature data based on stirrer shape and reaction vessel geometry ((Rushton, j.h.; costich, e.w.; everett, j.j. "Power characteristics of mixing imprners Part 2." chem.eng.prog.46 (1950): 467 to 476.)

Agitation delivers power (agitation power) into each (unit) volume of agitated fluid (e.g., suspension or solution) at an agitation rate in the range of a power number P/V ("power number P/V" is also referred to herein as "agitation power per (unit) volume P/V"). For example, at 2W/m ³ To 250W/m ³ Stirring at a stirring rate in the range of P/V of power transfers power (stirring power) to a stirring tank subjected to stirring at 2W/m ³ To 250W/m ³ In the range (per m) ³ Volumes 2W to 250W of the stirred mixture) of the stirred mixture (e.g., a suspension or a solution comprising dapagliflozin in combination with an anti-solvent).

In particular, at 2W/m ³ X W/m ³ (x W/m ³ May be, for example, 250W/m ³ Or 120W/m ³ Or 60W/m ³ ) May deliver power (agitation power) to a stirring tank subjected to stirring at a stirring rate in the range of P/V of power number of ³ Subjected to stirring in the range of from 2W to x W (e.g. the suspension of step iii) or iv) of "method (a)" or the suspension of step iv) or v) of "method (B)"). In particular, at 2W/m ³ X W/m ³ (x W/m ³ May be, for example, 250W/m ³ Or 120W/m ³ Or 60W/m ³ ) Of power number P/VStirring at a stirring rate in the range may deliver power (stirring power) to be subjected to stirring at every m ³ Subjected to agitation in the range of combination 2W to x W, and an anti-solvent (e.g., a combination of step ii) of "method (a)" or a combination of step iii) of "method (B)").

Power (agitation power) may be transferred to the agitated suspension or solution by an agitation device, such as an agitated vessel, an agitated reactor, or any other agitation device. The most common techniques for determining the power transferred per (unit) volume of agitated fluid (e.g. suspension or solution) are based on the power consumed, calorimetry or torque of the agitator. The "agitation power" may in particular be "stirring power".

In the case of a stirring apparatus provided with a stirrer (e.g. a stirred vessel or stirred reactor), "power number N _p "the effective torque (T) of the stirrer can be determined, in particular (for example by using a torque meter) _eff ) Thereafter, calculations are made, for example, as described in particular in the introduction to "Power Input Measurements in cultured Bioreactors at Laboratory Scale", J.Vis.Exp. (135) e56078, doi:10.3791/56078 ((May) 2018), by S.C. Kaiser, S.Werner, V.Jossen, K.Blachczk, D.Eibl. Effective torque (T) taking into account losses occurring during stirring _eff ) Can be determined in particular as the torque value (T) measured in a device filled with a liquid (for example heptane) _L ) With the torque value (T) measured in the empty device _D ) Difference between (T) _eff ＝T _L -T _D )。

The acid-base extraction of step i) may be carried out by adding an aqueous alkaline solution having a pH value of 8 to 14, preferably 10 to 14, and more preferably 12.5 to 13.5, which may be selected from NaOH, KOH or any other alkaline substance.

The acid-base extraction of step i) may be carried out by adding an aqueous alkaline solution (which may comprise an alkaline substance selected from NaOH, KOH, any other alkaline substance, and mixtures thereof) having a pH value of 8 to 14, preferably 10 to 14, and more preferably 12.5 to 13.5.

The terms "aqueous alkaline solution" and "aqueous alkaline solution" are used interchangeably herein. Preferably, the aqueous alkaline solution comprises an alkaline substance selected from the group consisting of NaOH, KOH, and mixtures thereof.

The acid-base extraction of step i) may comprise: providing a mixture comprising dapagliflozin, water and optionally a first organic solvent (e.g. methanol),

extracting the mixture with a second organic solvent (e.g. tert-butyl methyl ether) to obtain a solution comprising dapagliflozin and the second organic solvent,

optionally washing the solution comprising dapagliflozin and the second organic solvent with water, and isolating dapagliflozin from the (optionally washed) solution comprising dapagliflozin and the second organic solvent. The second organic solvent may be a solvent capable of providing a solution comprising dapagliflozin and further the second organic solvent may be immiscible or not fully miscible with water.

The solvent used in step ii) may be selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; preferably, the solvent may 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, the solvent used in step ii) may be toluene.

The anti-solvent used in step iii) may be selected from alkanes and cyclohexane, and mixtures thereof; preferably heptane and hexane and mixtures thereof; and more preferably, the anti-solvent used in step iii) may be heptane.

The solvent used in step ii) may be selected from aromatic carbohydrates, esters, ethers, alcohols, and mixtures thereof; the anti-solvent used in step iii) may be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably, the anti-solvent can be heptane.

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

The solvent used in step ii) may be toluene; the anti-solvent used in step iii) may be selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably, the anti-solvent may be heptane.

The temperature used in step iii) may be from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃ and more preferably from 10 ℃ to 15 ℃.

The crystallization temperature used in step iv) may be from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃ and more preferably from 10 ℃ to 15 ℃.

The cooling temperature of step v) may be from-15 ℃ to 15 ℃, preferably from-10 ℃ to 10 ℃ and more preferably from-5 ℃ to 5 ℃.

The stirring rate of step iii), step iv) and step v) may be at 2W/m ³ To 250W/m ³ Preferably 2W/m ³ To 120W/m ³ And more preferably 2W/m ³ To 60W/m ³ Within the range of P/V.

The inventors of the present invention have surprisingly found that the impurity IMP a is easily purified by the extraction process as defined in steps i) to vi) above. Dapagliflozin has poor solubility in water (< 1 mg/ml), so extraction is an excellent method for purification due to high yield. In addition to high yields, extraction has the very good purification potential required thereafter. During the isolation of amorphous dapagliflozin, the impurity IMP a was not purified. In addition, the precursor of impurity IMP a in the previous step also has poor purification potential. Purification with extraction in the last step is an extremely efficient procedure in terms of purifying impurities, easy to perform, and time-efficient, with superior yields much better than those obtainable by e.g. standard crystallization procedures.

The dapagliflozin used in step i) of the method for preparing amorphous dapagliflozin disclosed above may be in any form (such as in any polymorphic form or a solid dissolved in a solvent) and may be prepared according to any method known in the art to provide dapagliflozin having an impurity IMP a content of above 0.02%.

In one embodiment of the present invention, dapagliflozin used in step i) of the method disclosed above for preparing amorphous dapagliflozin is prepared by the following method (schematic figure 1):

-step 2: reacting a compound of formula 4 with ethoxybenzene in AlCl ₃ Reacting in dichloromethane in the presence of a solvent, and purifying the obtained compound by crystallization with a seed crystal to provide a (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone compound of formula 5. The reaction temperature during the addition of the compound of formula 4 is-20 ℃ to 10 ℃. The solvent used for purification may be selected from methanol, ethanol, ethyl acetate or mixtures thereof. The seeding temperature is 20 ℃ to 50 ℃.

-step 3: reacting a compound of formula 5 with AlCl ₃ And NaBH ₄ The resulting compound was purified by seeding in THF using ethanol, ethanol/water mixture, methanol/water mixture to provide 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene compound of formula 6. Adding AlCl ₃ The reaction temperature during this period was-20 ℃ to 30 ℃. Adding AlCl ₃ The reaction temperature thereafter was 40 ℃ to 65 ℃. The seeding temperature is 20 ℃ to 35 ℃.

-step 4: the compound of formula 7 is reacted with the compound of formula 6 in the presence of n-butyllithium in THF and toluene, followed by treatment with methanesulfonic acid in methanol and the resulting compound is purified by extraction with heptane to provide the 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. The reaction temperature during the addition of n-Buli (n-butyllithium) is from-100 ℃ to-60 ℃. The reaction temperature during the addition of compound 7 was-100 ℃ to-60 ℃.

-step 5: reacting the compound of formula 8 in situ with triethylsilane and boron trifluoride etherate in dichloromethane to provide a (2s, 3r,4r,5s, 6r) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro 2H-pyran-3,4,5-triol compound of formula 2. The reaction temperature during the addition of the boron trifluoride etherate is from-60 ℃ to 0 ℃.

-step 6: the compound of formula 2 is reacted in situ with acetic anhydride in the presence of dimethylaminopyridine in dichloromethane and the resulting compound is purified by seed crystallization to provide (2r, 3r,4r,5s,6 s) -2- (acetoxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triyltriacetate compound of formula 9. The solvent used for purification may be selected from methanol, ethanol, isopropanol, toluene or mixtures thereof. The seeding temperature is 50 ℃ to 70 ℃.

-step 8: the solid amorphous dapagliflozin is prepared according to steps i) to vi) as disclosed above.

The inventors of the present invention have found that all of the above disclosed reaction steps 1 to 8 should be carried out at reaction parameters such as reaction temperature, pH, seeding temperature, which are preferably carefully predefined, and that the materials used for the process, such as solvents for the crystallization of intermediates, should also be carefully selected. By such a complete process control it is ensured that the active substance obtained meets the requirements, wherein the impurity IMP a is below 0.02%.

The inventors of the present invention have surprisingly found that the solvent used for the crystallization of compound 5 is also critical for suitable quality. It is important to properly define the ratio between the two solvents. In the case of using only one solvent, the isolated compound of formula 5 is lower in quality than the case of using two solvents. In addition, the seeding temperature is also important for proper quality. If the seeding temperature is below the limit specified above, nucleation occurs rapidly and, in addition to the product, the impurities crystallize.

In step 3, the inventors found that AlCl was added ₃ The reaction temperature during this time is important to achieve suitable quality and yield. If the reaction temperature is higher, additional impurities are formed, which affect the final quality and yield. If the reaction temperature is below the limit value specified above, the reaction is carried outThe mixture becomes viscous and less suitable for scale-up. In addition, the seeding temperature is also important for proper quality. If the seeding temperature is below the limit specified above, nucleation occurs rapidly and, in addition to the product, the impurities crystallize.

In step 4, the reaction temperature is critical for the final quality and yield. If the temperature is above the limit value specified above, further impurities are formed.

In step 5, the inventors found that the reaction temperature during addition of the boron trifluoride etherate is important for achieving suitable quality and yield. If the reaction temperature is higher, additional impurities are formed. If the reaction temperature is lower, the reaction mixture becomes very viscous and less suitable for scale-up.

In step 6, the seeding temperature is important for proper quality. If the seeding temperature is below the limit specified above, nucleation is spontaneous and rapid. The suspension became viscous and difficult to stir. By seeding, we achieved gradual nucleation, which had a good effect on the impurity profile.

According to the above disclosed method for synthesizing dapagliflozin, it can be ensured that dapagliflozin having an extremely low content of IMP a as impurity is produced, which means that it can be ensured that the final amorphous dapagliflozin does not contain any detectable level of IMP a as impurity. Finally, when dapagliflozin is converted into an amorphous form according to the process of the present invention, it will also be pure with respect to residual solvents.

The seed crystals may be obtained from a crystallization solvent mixture containing the compound to be crystallized which is slowly evaporated under magnetic stirring, or the seeding material may be silica particles. The silica particles can be used in particular for the initial preparation of seeds containing or consisting of the compound to be purified by crystallization.

In particular, the seeds of formula 5, formula 6 and formula 9 are obtained from a crystallization solvent mixture (containing the compound to be crystallized) by slow evaporation under magnetic stirring, in particular followed by a cooling heating cycle. The solution may optionally be seeded with silica particles to initiate crystallization. Optionally, the oily residue after the reaction can be purified by flash chromatography before the first seed crystals are prepared. The crystals thus obtained were used for seeding in the crystals of formulae 5, 6 and 9 to obtain pure seeding materials. Pure materials, as obtained by conventional crystallization or fabrication, may be used for seeding.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising dapagliflozin in amorphous form, prepared according to the method of the present invention, optionally in combination with one or more other active substances. Pharmaceutical compositions according to the invention are disclosed in co-pending silowenia patent application P-202000042.

Preferred embodiments of the present invention are described in the following examples. However, it should be understood that the present invention is not limited to these examples.

Example A: HPLC method

The purity of dapagliflozin can generally be determined by the following HPLC method: column: xbridge C18, 150X 4.6mm,3.5; flow rate: 0.9 ml/min; column temperature: 50 ℃, wavelength: UV 225nm; mobile phase: eluent A:0.1% H ₃ PO ₄ And eluent B: methanol; gradient:

sample preparation: about 40mg of the sample was accurately weighed and dissolved in 50ml of the solvent. And (3) calculating: the area percentage method was used. The solvent peaks were not integrated.

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

5-bromo-2-chlorobenzoic acid (450 g) was suspended in dichloromethane (2.25L) and dimethylformamide (0.74 ml). Oxalyl chloride (180.3 ml) was added slowly at 15 ℃ to 30 ℃. HCl and CO occurred during the addition ₂ The gas of (2) is discharged. The reaction is carried out at a temperature of from 20 ℃ toAt 30 ℃. The reaction is considered complete if 2-chloro-5-bromobenzoic acid is less than 1% (area percent purity). The mixture was concentrated at elevated temperature until an oily residue was obtained.

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

Dichloromethane (900 ml) was added to the reactor followed by aluminium chloride (267.6 g). The reaction mixture was cooled to below 5 ℃ and ethoxybenzene (256.1 ml) was added slowly. After the addition was complete, the mixture was gradually cooled to below-5 ℃. In a separate reactor, 5-bromo-2-chlorobenzoyl chloride (485 g) was dissolved in dichloromethane (900 ml). The solution was slowly added to the mixture of aluminum chloride and ethoxybenzene at a rate such that the temperature remained below-5 ℃. After the addition was complete, the mixture was stirred below-5 ℃ until the reaction was complete. The reaction was considered complete if the methyl ester was below 1% (the reaction mixture was sampled in methanol). After completion of the reaction, the reaction mixture was slowly added to a cooled 1M HCl solution and rinsed with dichloromethane (450 ml). The organic phase was separated and the aqueous phase was washed again with dichloromethane. The organic phases are combined and treated with water and NaHCO ₃ And (4) washing the solution. The organic phase thus obtained was concentrated to an oily residue and dissolved in a 10:1 mixture of methanol and ethyl acetate at reflux temperature. The clear solution was gradually cooled to 35 ℃ to 45 ℃ and seeded with pure 5-bromo-2-chlorophenyl (4-ethoxyphenyl) methanone. The reaction mass was gradually cooled to 0 ℃ to 10 ℃ and stirred at this temperature for up to 4 hours. The precipitate was separated and washed with pre-cooled 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-1-chloro-2- (4-ethoxybenzyl) benzene

5-bromo-2-chlorophenyl (4-ethoxyphenyl) methanone (400 g) was dissolved in 1.62L tetrahydrofuran. Adding NaBH to the solution ₄ (53.5 g). After addition, the mixture was stirred at ambient temperature for 30 to 60 minutes, then the reaction mixture was cooled to below-5 ℃. Aluminum chloride (314 g) was added in portions and the reaction mixture was kept below 5 ℃. After addition, the reaction mixture was gradually heated to reflux temperature and stirred until the reaction was complete. The reaction mixture was cooled to ambient temperature and a THF/water mixture was slowly added to the reaction mixture, then water was added and stirred at ambient temperature. The organic phase was collected and washed with saturated NaCl solution. The organic phase was concentrated to an oily residue and dissolved in ethanol (800 ml) at elevated temperature. The solution was cooled to 25 ℃ to 30 ℃ and seeded with pure 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene. The reaction mass was gradually cooled to-2 ℃ to 10 ℃ and stirred at this temperature. The product was isolated and washed with pre-cooled ethanol and dried until the final LOD (loss on drying) content was less than 1.0%. Yield 322g (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-1-chloro-2- (4-ethoxybenzyl) benzene (97.5 g) and toluene (1.46L) were charged to the reactor. The solution was heated to reflux temperature and about half of the solvent was distilled off. Tetrahydrofuran (195 mL) was added to the solution and the mixture was cooled below-70 ℃. Slowly add 15% n-Buli solution in hexane (227.5 ml) and keep temperature below-70 ℃. After the addition was complete, the solution was stirred at a temperature below-70 ℃ to complete the reaction. A solution of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (182 g) in toluene (243 mL) was added to the reaction mixture at a temperature below-70 ℃. After the addition was complete, the mixture was stirred at less than-70 ℃ and warmed to about-6 ℃A mixture of 57.6g of methanesulfonic acid in 488ml of methanol was then added at 5 ℃. After addition, the mixture was gradually warmed to ambient temperature and stirred until the reaction was complete. After the reaction was complete, the reaction mixture was slowly added to saturated NaHCO ₃ Solution (630 ml) and stirred. To the quenched mixture was added 975ml heptane and 585ml methanol. The mixture was stirred for an additional 15 minutes. The organic phase is washed several times with a water/methanol mixture. The aqueous phases were combined and distilled to remove the organic solvent. Toluene was added to the residual aqueous phase for extraction. The organic phases were combined and washed with water. The organic phase is distilled at elevated temperature until an oily residue is obtained.

Example 5: preparation of (2S, 3R,4R,5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol-dapagliflozin

Dichloromethane (656 mL) was added to the oily residue from step 4 and stirred at ambient temperature until a clear solution was obtained. Triethylsilane (122 mL) was added to the solution thus obtained. The reaction mixture was cooled to below-30 ℃ and 94.2mL of boron trifluoride etherate was added slowly at a temperature below-30 ℃. After the addition was complete, the mixture was stirred for one hour below-30 ℃ and gradually warmed to-5 ℃ to 0 ℃ until the reaction was complete. After the reaction was complete, saturated NaHCO was slowly added ₃ Solution (468 mL). The reaction mixture was distilled to remove the organic solvent, and then ethyl acetate was added to the residue. The organic phase was collected and washed again with saturated NaHCO ₃ And water washing. The organic phase thus obtained is distilled at elevated temperature until an 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-triyltriacetate.

The oily residue from example 5 was dissolved in dichloromethane (602 mL) at ambient temperature, then DMAP (6.22 g) was added. The reaction mixture was cooled to 0 ℃ to 10 ℃ and 144.3mL of acetic anhydride was added at a temperature below 10 ℃. The reaction mixture was gradually warmed to ambient temperature and stirred until the reaction was complete. With water and saturated NaHCO ₃ The reaction mass was washed. The organic phase was collected and concentrated to an oily residue to which ethanol (1.68L) was added and about 300ml ethanol was removed by distillation. The clear solution was gradually cooled to 60 ℃ to 65 ℃ and seeded. The reaction mass was gradually cooled to 20 ℃ to 25 ℃ and the product was isolated. The product was dried at 50 ℃ in vacuo until the LOD (loss on drying) was below 1.0%. 123g of product are obtained, the yield being 71%. HPLC purity: 99.97 percent.

Example 7: preparation of dapagliflozin

(2R, 3R,4R,5S, 6S) -2- (acetoxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triyltriacetate (740 g), prepared as described in examples 1 to 6, was added to a solution of methanol (2.27L), water (0.74L) and NaOH (231 g) at 35 to 45 ℃ and stirred at 35 to 45 ℃ until the reaction was complete. After the reaction was complete, 1M HCl (1.63L) was added slowly. The reaction mass was distilled to remove the organic solvent and the product was extracted by tert-butyl methyl ether. The combined organic phases were washed with water and concentrated at elevated temperature until an oily residue was obtained. The content of IMP A impurity is lower than 0.02 percent.

Example 7a: amorphous dapagliflozin is prepared.

The oily residue containing about 262g dapagliflozin, as prepared according to example 7, was dissolved in toluene (2.5L) at a temperature of 60 ℃ to 70 ℃. At a temperature of 10 ℃ to 15 ℃ and having a W/m of 4 ³ A solution of dapagliflozin in toluene was slowly added to heptane (5.3L) at a stirring rate of P/V. In the process of addingAfter completion, the suspension was cooled to 0 ℃ and stirred at constant stirring rate. The suspension was separated and washed with pre-cooled heptane. The filtration rate is 14.10 ^-4 m/sec. The isolated product was dried in a vacuum desiccator at a temperature of 25 ℃ to 50 ℃. The impurity IMP a content was below 0.02% and the residual heptane and toluene was 1673ppm and below 89ppm.

Example 8: amorphous dapagliflozin is prepared by acid/base extraction.

4 different qualities of (2R, 3R,4R,5S, 6S) -2- (acetoxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (30 g) obtained by methods known in the art were added to a solution of methanol (90 ml), water (30 ml) and NaOH (9.36 g) and stirred at 35 ℃ to 45 ℃ until the reaction was complete and sampled for HPLC analysis (3R, 3R,4R,5S, 6S) -2- (acetoxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) and (30 g) was added to a solution of methanol (90 ml), water and NaOH (9.36 g) and (2 g) was added to a sampleSample No. 1)。

After the reaction was complete, 1M HCl (66 mL) was added slowly. The reaction mass was distilled to remove the organic solvent and the product was extracted by tert-butyl methyl ether. To the combined organic phases 68ml1m NaOH was added and the pH was set to 12.5 to 13.5. The phases were separated and the organic phase was washed again with 68ml of water without pH correction. The organic phase thus obtained was sampled for HPLC analysis: (Sample 2) And concentrated at elevated temperature until an oily residue is obtained.

The oily residue, containing about 21g dapagliflozin, was dissolved in toluene (210 mL) at a temperature of 60 ℃ to 70 ℃. A solution of dapagliflozin in toluene was slowly added to heptane (420 mL) at a temperature of 10 ℃ to 15 ℃ and with a stirring rate of P/V as defined in table 1. After the addition was complete, the suspension was cooled to 0 ℃ and stirred at a constant stirring rate. The suspension was separated and washed with pre-cooled heptane. The filtration rate is as defined in table 1. The isolated product was dried in a vacuum desiccator at a temperature of 25 ℃ to 50 ℃. For each case, a content of IMP A with the impurity indicated in Table 1 was obtainedAnd residual heptane and toluene as shown in Table 1Amorphous dapagliflozin。

Table 1: process parameters for the preparation of four different starting materials (cases).

As is evident from table 2, the final amorphous dapagliflozin prepared by the extraction process according to the invention comprises less than 0.02% of the impurity IMP a, regardless of the level of the 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

The oily residue comprising about 2g dapagliflozin, as obtained by the procedure described in example 8, case 1, was dissolved in 1.5ml of isopropyl acetate and 6ml of tert-butyl methyl ether at a temperature of 50 ℃ to 55 ℃. The solution thus prepared was added to 25mL heptane at 0 ℃. After the addition was complete, the suspension was stirred at-10 ℃ to 0 ℃. The suspension is separated and washed with pre-cooled heptane at a temperature of 25 ℃ to 50 ℃. 1.5g of dapagliflozin is obtained, wherein the content of impurity IMP A is lower than 0.02%.

Example 10

The oily residue comprising about 2g dapagliflozin, as obtained by the procedure described in example 8, case 1, was dissolved in 1.5ml of isopropyl acetate and 6ml of tert-butyl methyl ether at a temperature of 50 ℃ to 55 ℃. The solution thus prepared was added to 40mL of heptane at 0 ℃. After the addition was complete, the suspension was stirred at-10 ℃ to 0 ℃. The suspension is separated and washed with pre-cooled heptane at a temperature of 25 ℃ to 50 ℃. 1.5g of dapagliflozin is obtained, wherein the content of impurity IMP A is lower than 0.02%.

Example 11

Dapagliflozin (30 g) was dissolved in toluene (285 mL) at a temperature of 60 ℃ to 70 ℃. At 5 ℃ and having a W/m of 16 ³ A solution of dapagliflozin in toluene was slowly added to heptane (600 mL) at a stirring rate of P/V. After the addition was complete, the suspension was cooled to-10 ℃ and stirred at a constant stirring rate. The suspension was separated and washed with pre-cooled heptane. The isolated product was dried in a vacuum desiccator at a temperature of 25 ℃ to 50 ℃. The residual heptane and toluene levels were 1480ppm and 732ppm.

Example 12

Dapagliflozin (30 g) was dissolved in toluene (285 mL) at a temperature of 60 ℃ to 70 ℃. At 20 ℃ and having a W/m of 16 ³ A solution of dapagliflozin in toluene was slowly added to heptane (600 mL) at a stirring rate of P/V. After the addition was complete, the suspension was cooled to 5 ℃ and stirred at a constant stirring rate. The suspension was separated and washed with pre-cooled heptane. The isolated product was dried in a vacuum dryer at a temperature of 25 ℃ to 50 ℃. The residual heptane and toluene levels were 2873ppm and 639ppm.

Comparative example 1

Dapagliflozin (30 g) was dissolved in toluene (285 mL) at a temperature of 60 ℃ to 70 ℃. At-5 ℃ and having a W/m of 16 ³ A solution of dapagliflozin in toluene was slowly added to heptane (600 mL) at a stirring rate of P/V. After the addition was complete, the suspension was cooled to-15 ℃ and stirred at a constant stirring rate. The suspension was separated and washed with pre-cooled heptane. The isolated product was dried in a vacuum dryer at a temperature of 25 ℃ to 50 ℃. The residual heptane and toluene levels were 1940ppm and 1557ppm.

Comparative example 2

Dapagliflozin (30 g) was dissolved in toluene (285 mL) at a temperature of 60 ℃ to 70 ℃. At 25 ℃ and having a W/m of 16 ³ A solution of dapagliflozin in toluene was slowly added to heptane (600 mL) at a stirring rate of P/V. After the addition was complete, the suspension was cooled to 20 ℃ and stirred at a constant stirring rate. The suspension was separated and washed with pre-cooled heptane. Will separate the productThe material is dried in a vacuum drier at a temperature of 25 ℃ to 50 ℃. The residual heptane and toluene contents were 3663ppm and 2047ppm.

Comparative example 3

Dapagliflozin (30 g) was dissolved in toluene (285 mL) at a temperature of 60 ℃ to 70 ℃. At 30 ℃ and having a W/m of 16 ³ A solution of dapagliflozin in toluene was slowly added to heptane (600 mL) at a stirring rate of P/V. After the addition was complete, the suspension was cooled to 15 ℃ and stirred at a constant stirring rate. The suspension was separated and washed with pre-cooled heptane. The isolated product was dried in a vacuum dryer at a temperature of 25 ℃ to 50 ℃. The residual heptane and toluene levels were 2425ppm and 1812ppm.

Claims

1. A process for preparing 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 filtering the obtained solution,

ii) stirring at a temperature of 0 ℃ to 25 ℃, preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of power numbers P/V, combining the solution with an anti-solvent selected from non-aqueous and aprotic solvents and mixtures thereof,

iv) cooling under stirring until a temperature of-15 ℃ to 15 ℃ is achieved, preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of the power number P/V, and

v) the product is isolated, then washed and dried.

2. The process for preparing 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 selected from the group consisting of toluene, ethyl acetate, isopropyl acetate, t-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 anti-solvent used in step ii) is selected from alkanes and cyclohexane, and mixtures thereof; preferably selected from heptane and hexane and mixtures thereof; and more preferably, the anti-solvent used in step ii) is heptane.

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

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

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

7. The process for preparing amorphous dapagliflozin according to any one of the preceding claims, wherein the stirring rate of step ii), step iii) and step iv) is at 2W/m ³ To 250W/m ³ Preferably 2W/m ³ To 120W/m ³ And more preferably 2W/m ³ To 60W/m ³ Within the range of P/V.

8. A process for preparing amorphous dapagliflozin, comprising the steps of:

ii) dissolving dapagliflozin in a solvent selected from the group consisting of non-aqueous and aprotic solvents or polar aprotic and polar protic solvents and mixtures thereof, and filtering the obtained solution,

iii) At a temperature of 0 ℃ to 25 ℃ with stirring, preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of power numbers P/V, combining the solution with an anti-solvent selected from non-aqueous and aprotic solvents and mixtures thereof,

iv) at a crystallization temperature of from 0 ℃ to 25 ℃, preferably at 2W/m ³ To 250W/m ³ Stirring the suspension at a stirring rate in the range of P/V,

v) cooling with stirring until a temperature of-15 ℃ to 15 ℃ is achieved, preferably at 2W/m ³ To 250W/m ³ At a stirring rate in the range of the power number P/V, and

vi) the product is isolated, then washed and dried.

9. The process for the preparation of amorphous dapagliflozin according to claim 8, wherein the acid-base extraction of step i) is carried out by adding an aqueous alkaline solution having a pH value of from 8 to 14, preferably from 10 to 14, and more preferably from 12.5 to 13.5, preferably the aqueous alkaline solution comprises an alkaline substance selected from NaOH, KOH or any other alkaline substance.

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 selected from the group consisting of toluene, ethyl acetate, isopropyl acetate, t-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 selected 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 the temperature used in step iii) is from 0 ℃ to 25 ℃, preferably from 5 ℃ to 20 ℃, and more preferably from 10 ℃ to 15 ℃.

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

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

15. The process for the preparation of amorphous dapagliflozin according to any one of the preceding claims 8 to 14, wherein the stirring rate of step iii), step iv) and step v) is at 2W/m ³ To 250W/m ³ Preferably 2W/m ³ To 120W/m ³ And more preferably 2W/m ³ To 60W/m ³ Within the range of P/V.

16. A process for preparing dapagliflozin, optionally for preparing amorphous dapagliflozin, the process comprising the steps of:

reacting the compound obtained with ethoxybenzeneIn AlCl ₃ Optionally purifying the obtained compound by crystallization with seed crystals to provide (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methanone,

reacting the compound obtained with AlCl ₃ And NaBH ₄ Reacting in THF, optionally purifying the obtained compound with seed crystals using ethanol to provide 4-bromo-1-chloro-2- (4-ethoxybenzyl) benzene,

-reacting the obtained compound with a compound of (3R, 4S,5R, 6R) -3,4,5-tris ((trimethylsilyl) oxo) -6- (((trimethylsilyl) oxo) methyl) tetrahydro-2H-pyran-2-one in the presence of n-butyllithium in THF and toluene, followed by treatment with methanesulfonic acid in methanol, optionally purifying the obtained compound using heptane extraction to provide 3R,4S,5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol,

-reacting the obtained compound in situ with acetic anhydride in the presence of dimethylaminopyridine in dichloromethane, optionally purifying the obtained compound with seed crystals to provide (2r, 3r,4r,5s,6 s) -2- (acetoxymethyl) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-l

-2H-pyran-3,4,5-triyltriacetate,

-treating the obtained compound with sodium hydroxide in aqueous methanol to provide dapagliflozin,

-optionally subjecting the dapagliflozin to a process for preparing amorphous dapagliflozin according to any one of the preceding claims 1 to 15.