EP3013831A1

EP3013831A1 - Process for making anagrelide

Info

Publication number: EP3013831A1
Application number: EP13734706.8A
Authority: EP
Inventors: Petr MELSA; Jan FRANEK
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2013-06-28
Filing date: 2013-06-28
Publication date: 2016-05-04
Also published as: WO2014206484A1

Abstract

The invention relates to a process for the manufacture and purification of pharmaceutically active compound anagrelide of formula (1). The process is based on converting anagrelide or an acid addition salt thereof to a formate salt of anagrelide, in particular to anagrelide hemiformate.

Description

PROCESS FOR MAKING ANAGRELIDE

The invention relates to an improved process for the preparation and purification of pharmaceutically active compound anagrelide.

Anagrelide, chemically 6,7-dichloro- 1 ,2,3,5-tetrahydroimidazo[2, lb]quinazolin-2-one of formula (1)

is a compound useful for the treatment of (essential) thrombocythaemia.

The commercially marketed products Xagrid^® and Agrylin^® contain the hydrochloride monohydrate salt of the title compound (1). Anagrelide hydrochloride monohydrate is an off- white powder that is very slightly soluble in water.

Anagrelide free base was first disclosed in US 3932407 (Compound 47). In said document, it is prepared by chlorination of des-chloroanagrelide of formula (2).

(2)

Purification is effected by formation of anagrelide hydrochloride in acetonitrile.

US 4146718 teaches that anagrelide can be made by a reaction of the compound of formula (3), wherein R is an alkyl group, (e.g. by the compound of formula (3B)) with cyanogen bromide. (3B) The product is isolated as a hydrobromide salt and recrystallized from ethanolic HC1 as the hydrochloride. Furthermore, the document teaches that much higher yields are obtainable by reacting the alkyl aminobenzylglycinate compound of formula (3) with cyanogen halide in an aprotic solvent (e.g. in a hydrocarbon, halohydrocarbon, or ether), isolating the formed iminoquinazoline of formula (4), wherein R is an alkyl group and X is a chloro, bromo or iodo, e.g., the compound of formula (4B),

and reacting the compound of formula (4) in a solvent with a base, preferably an organic base, typically triethylamine. The produced free base of anagrelide can be purified by refluxing in 95% ethanol, followed by filtration of the not dissolved solid, which is the desired product. Essentially the same process is disclosed in WO 2009/087673, wherein the crude anagrelide free base is purified by refluxing in 90% aqueous ethanol and hot filtration of the not dissolved solid at 65-70°C. WO 2010/070318 teaches that due to the low solubility of anagrelide free base in most organic solvents, further purification in this stage is limited. Therefore, care is to be taken on the proper quality of intermediates in earlier steps of the synthesis. It also teaches that while the formation of anagrelide hydrochloride in refluxing methanol/hydrochloric acid exerts a powerful purification effect, acidic hydrolysis is fast at reflux conditions and the yield of the hydrochloride salt decreases rapidly over time.

It is apparent from the prior art documents that purification of anagrelide free base is not a straightforward process due to the limited solubility of anagrelide free base in most common solvents. Thus, there exists an objective need to search for further purification possibilities and to develop an alternative process for the purification of anagrelide. BRIEF DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a novel process and a novel intermediate for the manufacture and purification of anagrelide.

In a first aspect, the invention relates to a salt of anagrelide of formula (1)

with formic acid, preferably to anagrelide hemiformate, and yet more preferably to anagrelide hemiformate hemihydrate.

In a second aspect, the invention relates to a process for making anagrelide formate comprising dissolving anagrelide free base or an acid addition salt thereof, including any hydrated or solvated form thereof, in formic acid, and treating the obtained solution with water. In a particular embodiment, the product is isolated in solid state, advantageously as anagrelide hemiformate hemihydrate.

In an embodiment, the concentration of anagrelide in formic acid is 1 g in 1-10 ml of formic acid, preferably 1 g in 2-5 ml of formic acid and the temperature of dissolution is from 10 to 80°C.

The third aspect of the present invention relates to relates to a process for making anagrelide free base, comprising treating anagrelide formate with water or a mixture of water with an organic water-miscible solvent, e.g. with aqueous ethanol.

The fourth aspect of the present invention relates to a process of making anagrelide hydrochloride, incl. a hydrated or solvated form thereof, comprising treating anagrelide formate with hydrogen chloride or hydrochloric acid in a solvent.

In a fifth aspect, the invention relates to a process for the purification of anagrelide comprising: dissolving anagrelide free base of formula (1) or an acid addition salt thereof, including any hydrated or solvated form thereof, in formic acid; optionally filtering the solution, in some embodiments after treatment of the solution with a suitable surface active material; - precipitating anagrelide from the solution as a formate salt; converting anagrelide formate into anagrelide free base or an acid addition salt other than formate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 : DSC curve for anagrelide hemiformate hemihydrate

Fig. 2: XRPD pattern of crystalline anagrelide hemiformate hemihydrate Fig. 3 : XRPD pattern for anagrelide hydrochloride monohydrate, Form I Fig. 4: XRPD pattern for anagrelide hydrochloride monohydrate, Form II XRPD measurement conditions:

Apparatus XRPD: Bruker-AXS D8 Vario, Θ/2Θ geometry, reflection mode, Vantec PSD detector

Start angle (2 Θ): 2.0 °

End angle (2 Θ): 35.0 °

Scan step width: 0.02 °

Scan step time: 1.5 seconds

Radiation type: Cu

Radiation wavelengths: 1.54060 A (Koti), primary monochromator used

Exit slit: 6.0 mm

Focus slit: 0.2 mm

Divergence slit: Variable (V20)

Antiscatter slit: 11.8 mm

Receiving slit: 20.7 mm DETAILED DESCRIPTION OF THE INVENTION

The invention relates to an advantageous process for the manufacture and purification of anagrelide of formula (1). Throughout the disclosure and claims, "anagrelide" and

"anagrelide free base" are used interchangeably, as both denominations correspond to formula (1).

The process of the present invention is based on making, and optionally isolating, anagrelide formate ( a salt of anagrelide with formic acid), typically anagrelide hemiformate. The formate may be easily converted to anagrelide free base, basically without a need of an external base for neutralization of the formate ion. The anagrelide formate may be also used as an intermediate in making other salts of anagrelide, in particular for making

pharmaceutically useful anagrelide hydrochloride monohydrate, which is the active substance in the currently marketed pharmaceutical compositions comprising anagrelide,

advantageously without a need of making or isolating the free base.

It is well known in the art that anagrelide free base is, in particular at ambient temperature, insoluble in water and also in most common organic solvents including alcohols, esters, ketones, hydrocarbons, etc. According to the present knowledge, there does not exist a suitable "traditional" purification process based on dissolving anagrelide free base in a solvent, optionally filtering the solution with a surface active material, and precipitating the purified product from the solution thereof in a solvent, whereby impurities present would substantially remain in the solution. Instead, anagrelide free base is treated with a hot solvent, in which it remains undissolved, and is filtered hot from said solvent. Such arrangement is technologically complicated.

The present inventor found with surprise that anagrelide is well soluble in formic acid. Based on the discovery of this advantageous property, a simple and effective process both for the purification of anagrelide and for making pharmaceutically suitable acid addition salts of anagrelide was found. The process may be used, in particular, for the separation of anagrelide free base or anagrelide salts from insoluble, e.g., mechanical, impurities, as no such suitable process exists in the art.

Starting materials for the process of the present invention are anagrelide free base or an acid addition salt of anagrelide, particularly anagrelide hydrochloride. Any solvated or hydrated form thereof may be used. Anagrelide free base may be obtained by synthetic processes known in the art. It may also be obtained from an acid addition salt thereof, e.g. from anagrelide hydrochloride. It should be noted in this consequence that it is known in the art that anagrelide hydrochloride easily loses hydrogen chloride when suspended in water, particularly at enhanced temperature. As such hydrolysis often results in a material, which is filterable only with difficulties, a suitable alternative can be a neutralization of anagrelide hydrochloride with a base in a suitable solvent. The suitable solvent may be water, however filtration problems may occur also at this alternative. Therefore, the preferred solvent is acetonitrile, in which hydrochlorides of certain organic bases are soluble. E.g., conversion to anagrelide free base was successfully accomplished by suspending anagrelide hydrochloride or a hydrate thereof in acetonitrile containing Ν,Ν-diisopropylethylamine (DIPEA) at 60°C. Resulting DIPEA hydrochloride is freely soluble in acetonitrile and, in a considerable advantage over water, anagrelide free base is formed in a particulate form, which can be easily isolated by filtration in a quantitative yield.

In the first step of the process of the present invention, anagrelide free base or an acid addition salt thereof is dissolved in formic acid. In an advantageous embodiment, the concentration of anagrelide in formic acid (calculated as anagrelide free base) is 1 g in 1-10 ml of formic acid, preferably 1 g in 2-5 ml of formic acid. The dissolution temperature is advantageously ambient or higher than ambient temperature, generally between 10 and 80°C, preferably between 20 and 60°C. The solution of anagrelide in formic acid may then optionally be filtered, particularly in order to remove any insoluble material, e.g., mechanical impurities. It may also be treated with a surface active material, e.g. which activated charcoal. Such treatment exhibits a considerable purification effect, in particular in respect to impurities of formulas (5) and (6) below. The surface active material with adsorbed impurities is removed by conventional filtration process.

Thus, the solution of anagrelide in formic acid, advantageously in a concentration of 1 g anagrelide in 1-10 ml of formic acid, preferably 1 g in 2-5 ml of formic acid (calculated as anagrelide free base), is an advantageous composition, particularly for the purification of anagrelide.

In the second step of the process of the invention, the solution of anagrelide in formic acid is treated with a suitable antisolvent, which is preferably water. Advantageously, the antisolvent is added to the solution, typically under stirring, at ambient or higher than ambient temperature, typically at 20-75 °C. The amount of the antisolvent is not particularly limited and is advantageously 2-5 volume units per 1 volume unit of the solution. After mixing, the reaction mixture is advantageously cooled to ambient or lower than ambient temperature, typically to 5-20°C.

In the third step, the precipitated solid material is filtered by conventional filtration or centrifugation, optionally washed with the antisolvent and dried, advantageously at diminished pressure.

The isolated material contains formic acid, typically in an amount which corresponds to a half molar equivalent in respect to anagrelide. Thus, the isolated material is an anagrelide formate compound, typically anagrelide hemiformate. If water is used as the antisolvent, then the anagrelide formate compound is typically isolated as anagrelide hemiformate

hemihydrate.

The anagrelide formate in the isolated solid form, i.e. anagrelide hemiformate including anagrelide hemiformate hemihydrate, is a stable material, which may be stored at ambient conditions. It preferentially precipitates as a crystalline material with a characteristic X-ray powder diffraction (XRPD) pattern. It is, however, not excluded that it may be prepared in an amorphous state, e.g. by freeze drying of the solution in formic acid. The anagrelide formate may be obtained in a considerable degree of purity, including a purity of 99% and higher. In pharmaceutical perspective, it can thus be used as an intermediate in making

pharmaceutically useful acid addition salts of anagrelide, in particular anagrelide

hydrochloride. Details of a suitable process will be shown below.

In case of need or desire, formic acid may be removed from anagrelide formate by an intensive drying at a temperature of at least 100°C. Such drying yields anagrelide free base.

Alternatively, formic acid may be removed from anagrelide formate by triturating the formate with water, optionally with a mixture of water and a water-miscible organic solvent, for instance an aqueous aliphatic alcohol, most preferably aqueous ethanol. The temperature of such treatment may be from 20 to 60°C. As a result, anagrelide free base is obtained. As apparent, no external base is basically needed for the hydrolysis of the formate salt, although using such base is not explicitly excluded.

Thus, combining these two steps together, anagrelide free base or an acid addition salt thereof, including any hydrated or solvated form thereof, may be effectively purified by converting it into an anagrelide formate product, typically into anagrelide hemiformate hemihydrate, isolating the formate product and reconverting it into anagrelide base or an acid addition salt other than formate. In an alternative process, anagrelide free base or salt is dissolved in formic acid, the solution is purified by filtration, anagrelide formate is precipitated by addition of water and is hydrolysed to anagrelide free base without isolation from the reaction mixture by treatment of the mixture with the next portion of water, preferably at enhanced temperature.

As mentioned above, anagrelide formate of the present invention, typically anagrelide hemiformate hemihydrate, may be used for making pharmaceutically useful acid addition salts of anagrelide, e.g. anagrelide hydrochloride. In an important aspect, such salts may be made without prior conversion of the formate to anagrelide free base, e.g. by the process disclosed above, although such possibility is not excluded.

Thus, advantageously, anagrelide hydrochloride may be made by dissolving or suspending anagrelide formate of the present invention in a suitable solvent and treating the mixture with hydrogen chloride or aqueous hydrochloric acid. The suitable solvent may be, without limitation, an aliphatic alcohol, e.g. methanol, ethanol or isopropanol; an aliphatic ketone, e.g. acetone or methylethylketone; a combination thereof or a combination of the above with water. Dependent on the conditions of treatment, various polymorphic modifications of anagrelide hydrochloride may be made and isolated. For instance, anagrelide hydrochloride monohydrate may be made in two polymorphic forms, denoted herein as Form I and Form II, by suspending anagrelide hemiformate hemihydrate in ethanol and treating the mixture with aqueous hydrochloric acid. Form I is preferentially obtained by contacting the mixture with hydrochloric acid at a temperature of about 70-100°C, while Form II is preferentially obtained by contacting the mixture with hydrochloric acid at a temperature of about 35-40°C. Both forms exhibit characteristic and distinguishable X-ray powder diffraction (XRPD) patterns. The XRPD spectrum of anagrelide hydrochloride monohydrate Form I is shown in Fig. 3, while the XRPD spectrum of anagrelide hydrochloride

monohydrate Form II is shown in Fig. 4. The invention will be further illustrated by way of the following non-limiting examples.

EXAMPLES

Example 1

Preparation of anagrelide hemiformate hemihydrate from anagrelide free base

Anagrelide (4.5 g; 17.54 mmol) was suspended in formic acid (9 ml; 98%; p. a. grade) and the suspension was heated to 60°C with stirring. To the resulting clear solution water (22 ml) was added dropwise over 15 minutes to precipitate the product. The reaction mixture was stirred at 60°C for next 3 hours and then cooled down to 10°C. The suspension was filtered, washed with water (25 ml) and ethanol (25 ml) and dried for 1 hour at 60°C/100 mbar followed by 14 hours at 23°C/100 mbar to give 4.6 g (90% of the theoretical value) of a white to off-white solid (water content (K.F.) 3.2%).

Identity of the compound was confirmed by 'H-NMR and IR spectrum.

Crystallinity was confirmed by XRPD analysis (for XRPD pattern, see Fig. 2).

Presence and content of water and formic acid were confirmed by TGA and DSC analysis (for DSC curve, see Fig. 1).

Example 2

Preparation of anagrelide hemiformate hemihydrate from anagrelide

hydrochloride monohydrate

6.05 g of anagrelide hydrochloride monohydrate was weighed into a 250 ml round bottom flask, 48 g of formic acid was added and the mixture was heated under stirring to 40°C. Then the reaction mixture was filtered and washed by 3 x 6 ml of formic acid. At 30°C, 180 ml of water was added dropwise under stirring. The mixture was cooled to ambient temperature and the solid was isolated by filtration and washed with 20 g of methanol, 40 g of water and 20 g of methanol. Yield: 5.83 g after drying.

Example 3

Preparation of anagrelide free base from anagrelide hemiformate hemihydrate

Anagrelide hemiformate hemihydrate (1.0 g; 3.47 mmol) was suspended in a mixture of water (10 ml) and ethanol (1 ml; denaturated with toluene) and the suspension was stirred at 23°C for 3 hours. Then it was filtered, washed with ethanol (3 ml) and dried for 1 hour at 60°C/100 mbar to give 0.9 g (99% of the theoretical value) of off-white anagrelide free base (HPLC assay 99.4%).

Example 4

Preparation of anagrelide hydrochloride monohydrate Form I from anagrelide hemiformate hemihydrate

Anagrelide hemiformate hemihydrate (1.000 g; 3.47 mmol) was suspended in ethanol

(30 ml; denaturated with toluene) and the suspension was heated to reflux (100°C in oil bath) with stirring. Then concentrated aqueous hydrochloric acid (1.0 ml, 11.28 mmol) was added and the suspension was stirred for 5 minutes. The reaction mixture was cooled down to 25 °C over 30 minutes and stirring was continued for an additional 1 hour. Then the suspension was filtered, washed with ethanol (5 ml) and the product was dried at 40°C/100 mbar for 1 hour. Finally the product was hydrated in a chamber with 60-65% RH to afford 860 mg of a white solid (80% of the theoretical value) with water content (K.F.) 5.97%. The product was proved Form I by XRPD (see Fig.3). Example 5

Preparation of anagrelide hydrochloride monohydrate Form II from anagrelide hemiformate hemihydrate

Anagrelide hemiformate hemihydrate (2.5 g; 8.68 mmol) was suspended in ethanol (15 ml; denaturated with toluene) and the suspension was heated to 38°C with stirring. Then concentrated aqueous hydrochloric acid (0.95 ml, 10.72 mmol) was added dropwise over 1 minute. The reaction mixture was stirred for additional 20 minutes and then cooled down to 24°C over 35 minutes and stirring was continued for 1 hour. The suspension was filtered, washed with ethanol (10 ml) and dried for 1 hour at 40°C/100 mbar. The material was then allowed to rest on an open Petri dish for 48 hours at 23°C/~25% RH to give 2.6 g (97% of the theoretical value) of white to off-white anagrelide hydrochloride monohydrate (water content (K.F.) 5.74%). The product was proved Form II by XRPD (see Fig.4).

Claims

1. A salt of anagrelide of formula (1)

with formic acid.

2. The salt according to claim 1 , which is anagrelide hemiformate.

3. The salt according to claim 2, which is anagrelide hemiformate hemihydrate.

4. A process for making anagrelide formate comprising dissolving anagrelide or an acid addition salt thereof, including any hydrated or solvated form thereof, in formic acid, and treating the obtained solution with water.

5. The process according to claim 4, wherein the product is isolated from the reaction mixture in solid state.

6. The process according to claim 5, wherein the isolated product is anagrelide

hemiformate hemihydrate.

7. The process according to any one of claims 4 to 6, wherein the concentration of the solution of anagrelide in formic acid is 1 g in 1-10 ml of formic acid, preferably 1 g in 2-5 ml of formic acid.

8. The process according to any one of claims 4 to 7, wherein the temperature of

dissolution is from 10 to 80°C.

9. A process for making anagrelide free base, comprising treating anagrelide formate with water or a mixture of water with an organic water-miscible solvent, e.g. with aqueous ethanol.

10. A process for making anagrelide hydrochloride, including a hydrated or solvated form thereof, comprising treating anagrelide formate with hydrogen chloride or hydrochloric acid in a suitable solvent.

11. A process for the purification of anagrelide comprising:

- dissolving anagrelide of formula (1) or an acid addition salt thereof, including any hydrated or solvated form thereof, in formic acid;

- optionally filtering the solution;

- precipitating anagrelide from the solution as a formate salt; and

- converting the anagrelide formate into anagrelide free base or an acid addition salt other than formate.

12. A composition comprising a solution of anagrelide in formic acid, preferably in a

concentration of 1 g anagrelide in 1-10 ml of formic acid, most preferably 1 g in 2-5 ml of formic acid.

13. Use of a compound of any of claims 1 to 3 for the preparation of a pharmaceutical acceptable salt of anagrelide, preferably anagrelide hydrochloride or anagrelide hydrochloride monohydrate.