EP3013831A1 - Procédé de préparation d'anagrélide - Google Patents

Procédé de préparation d'anagrélide

Info

Publication number
EP3013831A1
EP3013831A1 EP13734706.8A EP13734706A EP3013831A1 EP 3013831 A1 EP3013831 A1 EP 3013831A1 EP 13734706 A EP13734706 A EP 13734706A EP 3013831 A1 EP3013831 A1 EP 3013831A1
Authority
EP
European Patent Office
Prior art keywords
anagrelide
formic acid
formate
salt
free base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13734706.8A
Other languages
German (de)
English (en)
Inventor
Petr MELSA
Jan FRANEK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Publication of EP3013831A1 publication Critical patent/EP3013831A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to an improved process for the preparation and purification of pharmaceutically active compound anagrelide.
  • Anagrelide hydrochloride monohydrate is an off- white powder that is very slightly soluble in water.
  • Purification is effected by formation of anagrelide hydrochloride in acetonitrile.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention relates to a novel process and a novel intermediate for the manufacture and purification of anagrelide.
  • the invention relates to a salt of anagrelide of formula (1)
  • formic acid preferably to anagrelide hemiformate, and yet more preferably to anagrelide hemiformate hemihydrate.
  • the invention in a second aspect, 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.
  • the product is isolated in solid state, advantageously as anagrelide hemiformate hemihydrate.
  • 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.
  • 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.
  • 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 II XRPD measurement conditions:
  • Apparatus XRPD Bruker-AXS D8 Vario, ⁇ /2 ⁇ geometry, reflection mode, Vantec PSD detector
  • Antiscatter slit 11.8 mm
  • the invention relates to an advantageous process for the manufacture and purification of anagrelide of formula (1).
  • 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
  • anagrelide hydrochloride monohydrate which is the active substance in the currently marketed pharmaceutical compositions comprising anagrelide
  • 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.
  • 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.
  • acetonitrile in which hydrochlorides of certain organic bases are soluble.
  • conversion to anagrelide free base was successfully accomplished by suspending anagrelide hydrochloride or a hydrate thereof in acetonitrile containing ⁇ , ⁇ -diisopropylethylamine (DIPEA) at 60°C.
  • 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.
  • anagrelide free base or an acid addition salt thereof is dissolved in formic acid.
  • 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.
  • the solution of anagrelide in formic acid is an advantageous composition, particularly for the purification of anagrelide.
  • the solution of anagrelide in formic acid is treated with a suitable antisolvent, which is preferably water.
  • a suitable antisolvent which is preferably water.
  • 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.
  • the reaction mixture is advantageously cooled to ambient or lower than ambient temperature, typically to 5-20°C.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • anagrelide free base is obtained.
  • no external base is basically needed for the hydrolysis of the formate salt, although using such base is not explicitly excluded.
  • anagrelide free base or an acid addition salt 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.
  • 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.
  • anagrelide formate of the present invention may be used for making pharmaceutically useful acid addition salts of anagrelide, e.g. anagrelide hydrochloride.
  • anagrelide hydrochloride e.g. anagrelide hydrochloride.
  • 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.
  • 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.
  • an aliphatic alcohol e.g. methanol, ethanol or isopropanol
  • an aliphatic ketone e.g. acetone or methylethylketone
  • a combination thereof a combination of the above with water.
  • 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
  • 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.
  • XRPD X-ray powder diffraction
  • 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%).
  • 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%).
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de fabrication et de purification du composé pharmaceutiquement actif anagrélide de formule (1). Le procédé repose sur la conversion d'anagrélide ou d'un sel d'addition d'acide de ce composé en un sel formiate d'anagrélide, en particulier l'hémiformiate d'anagrélide.
EP13734706.8A 2013-06-28 2013-06-28 Procédé de préparation d'anagrélide Withdrawn EP3013831A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2013/063615 WO2014206484A1 (fr) 2013-06-28 2013-06-28 Procédé de préparation d'anagrélide

Publications (1)

Publication Number Publication Date
EP3013831A1 true EP3013831A1 (fr) 2016-05-04

Family

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EP13734706.8A Withdrawn EP3013831A1 (fr) 2013-06-28 2013-06-28 Procédé de préparation d'anagrélide

Country Status (2)

Country Link
EP (1) EP3013831A1 (fr)
WO (1) WO2014206484A1 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3932407A (en) 1973-11-19 1976-01-13 Bristol-Myers Company Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones
US4146718A (en) 1978-04-10 1979-03-27 Bristol-Myers Company Alkyl 5,6-dichloro-3,4-dihydro-2(1h)-iminoquinazoline-3-acetate hydrohalides
CN101463035A (zh) 2007-12-19 2009-06-24 华生制药私人有限公司 生产盐酸阿那格雷一水合物的改进方法
GB0822970D0 (en) 2008-12-17 2009-01-21 Shire Llc Process for the preparation of anagrelide and analogues

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014206484A1 *

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