AN IMPROVED PROCESS
FOR THE PREPARATION OF DEFERASIROX
Field of Invention
The present invention provides an improved process for the preparation of Deferasirox, with a high degree of purity, specifically with less number of impurities. Furthermore, the present invention relates to a novel crystalline form of monosodium salt of deferasirox and its use in the preparation of deferasirox, substantially free of impurities specifically genotoxic impurity viz. 4-hydrazinobenzoic acid of formula (III).

Background of the Invention
Deferasirox of the formula (I), is a tridentate ligand that selectively binds Fe3+ ions. Deferasirox is primarily used for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis). The excess of iron (metal) deposited in body tissues can cause severe damage to organs such as liver, the heart and the endocrine organs and can lead to death. Iron chelators are able to excrete the iron deposited in the organs and thus, lower the iron related morbidity and mortality.

(I)

Deferasirox is one of such iron chelating agent, designated chemically as 4-(3, 5-bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid. Deferasirox is marketed under the trade name Exjade® by Novartis Pharmaceuticals Corp. for oral administration.
Methods of preparing deferasirox of formula I have been described in US 6,465,504 (US’504). US’504 is a product patent of deferasirox and is assigned to Novartis AG. The patent describes several methods for preparing deferasirox, wherein according to one synthetic process deferasirox is prepared by reacting salicyloyl chloride with salicylamide at 170oC to obtain 2-(2- hydroxyphenyl) benz [e] [1, 3] oxazin-4-one (Formula II), and further crystallization in ethanol provides slight yellow color crystals of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one (Formula II). 2-(2-Hydroxyphenyl) benz [e] [1, 3] oxazin-4-one is further reacted with 4-hydrazinobenzoic acid of formula III in presence of ethanol to give deferasirox. The process is schematically represented below in Scheme 1.

Scheme 1

According to another synthetic process disclosed in US’504, deferasirox is prepared by reaction of 1,2,4-dithiazolidine of formula (IV) with 4-hydrazinobenzoic acid of formula (III) without a solvent or in a polar solvent or their mixtures under cooling conditions, at room temperature or at increased temperature.

According to yet another synthetic process disclosed in US’504, compound of formula (V) is reacted with a hydrazinobenzoic acid of formula (III) in the presence of polar, protic solvents under weak acid catalysis, preferably in aqueous acetic acid at elevated temperature.

Moreover, US’504 patent also mentions deferasirox and its derivatives can form salts with a suitable basic agent or a suitable ion-exchange reagent and their use. However, the experimental details are not provided for preparation of their salts.

One of the major drawbacks of the synthetic route disclosed in Scheme 1 is that the condensation reaction between salicyloyl chloride and salicylamide is carried out at high temperature in the absence of a solvent to obtain 2-(2- hydroxyphenyl) benz [e] [1, 3] oxazin-4-one of formula (II), which is dark in color and resulting in formation of large amount of impurities. Another drawback of the reaction between salicyloyl chloride and salicylamide suffers sublimation of reactants and hence difficult to handle during large scale production.

WO 2009/094956 discloses a method of preparing 4-[3,5-bis(2- hydroxyphenyl)[l,2,4]triazol-l-yl]benzoic acid of formula (I) by reaction of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one of formula (II) with 4-hydrazinobenzoic acid of formula (III) in an organic acid or in a mixture of an organic acid and an organic solvent. The said process is also not effective in removing the impurities, specifically hydrazinobenzoic acid of formula (II).

WO 2009/130604 discloses solid state forms of deferasirox salts (specifically, triethylamine, dimethylamine, tert-butylamine, sodium (Na+), potassium (K+), magnesium (Mg2+), calcium (Ca2+) and zinc (Zn2+) salts), process for their preparation and use of these salts for the preparation of pure deferasirox.

The process of preparing deferasirox via the sodium salt as described in WO 2009/130604 is not efficient in removing impurities particularly the genotoxic impurity 4-hydrazinobenzoic acid of formula (III). WO 2009/130604 has exemplified the use of NaOH for the preparation of sodium salt of deferasirox as well as for the preparation of other alkali or alkaline earth metal salts of deferasirox. Hoerver, this patent does not provide the experimental details for the preparation of deferasirox base from its salt.

Moreover, the reactant 4-hydrazinobenzoic acid and the impurities thereof imparts dark color to the final pure deferasirox. Therefore, it is desirable to develop an improved process for the preparation of deferasirox, which improves color, yield and quality with minimal impurities.

Brief Description of the Drawing
Fig. 1: X-ray powder diffraction (“XRPD”) pattern of crystalline monosodium salt of deferasirox.
Fig. 2: Infrared absorption spectrum of crystalline monosodium salt of deferasirox.
Fig. 3: Thermo gravimetric analysis (TGA) of monosodium salt of deferasirox.
Fig. 4: X-ray powder diffraction (“XRPD”) pattern of crystalline deferasirox.

Description of the Invention
The above-mentioned methods of preparation of deferasirox suffer from the drawback of generating more impurities that decrease the yield of the reaction and impair the quality of the prepared deferasirox. It has also been found that deferasirox prepared according to the procedure described in the aforementioned patents contains impurities; in particular it contains 4-hydrazinobenzoic acid of formula (III) (hereinafter referred as the "genotoxic impurity") that is genotoxic and hence control is required in the drug compound manufacturing process to ensure that the impurity is present at the lowest possible levels.
The above-mentioned disadvantages can be overcome by the method of the invention, which involves method of purifying deferasirox comprising converting crude deferasirox to deferasirox monosodium salt using carbonate or bicarbonate salt of alkali or alkaline earth metals and converting the deferasirox monosodium salt to deferasirox base. “Crude deferasirox” as referred herein is either isolated or carried out as such without isolation. The conversion to the deferasirox monosodium salt is useful to reduce the level of impurity specifically 4-hydrazinobenzoic acid and colored impurities. The advantage of using carbonate or bicarbonate of alkali or alkaline earth metals as salt forming agent is that they form salt with deferasirox and with genotoxic impurity 4-hydrazinobenzoic acid. Deferasirox monosodium salt is water insoluble and therefore, it can easily be separated from deferasirox and other impurities. Conversion of deferasirox sodium salt to deferasirox base at acidic pH in presence of solvent like ethyl acetate or methyl acetate produces stable polymorphic form-I of deferasirox.

In an aspect, the invention provides monosodium salt of deferasirox of formula (VI) and isolation of deferasirox of formula (I) having polymorphic form-I.

In further aspect, the invention provides a process for the preparation of crystalline monosodium salt of deferasirox comprising:
(i) providing the reaction mixture obtained by reaction of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one of formula (II) with 4-hydrazinobenzoic acid of formula (III);
(ii) adding aqueous carbonate or bicarbonate of alkali or alkaline earth metals to the reaction mixture obtained in step (i) and;
(iii) isolating the crystalline monosodium salt of deferasirox directly from reaction mass.

In another aspect, the invention provides a process for the preparation of deferasirox comprising:
(i) providing a solution or suspension of deferasirox;
(ii) adding carbonate or bicarbonate of alkali or alkaline earth metals to the solution suspension obtained in step (i);
(iii) isolating the crystalline monosodium salt of deferasirox.
(iv) obtaining pure deferasirox from monosodium salt of step (iii) in presence of ethyl acetate at pH 1-2.

In yet another aspect, the invention provides a process for the preparation of deferasirox as mentioned in Scheme 2. The reaction shown in scheme 2 can be carried out with or without isolation of any of the intermediates.

Scheme 2

The novel crystalline monosodium salt of deferasirox is characterized by its X-ray powder diffraction (“XRPD”) pattern and infrared (“IR”) absorption spectrum. The crystalline form of monosodium salt of deferasirox is designated hereinafter as “crystalline Form J”. It is characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 1. Crystalline Form J of deferasirox sodium salt is also characterized by an XRPD pattern having significant peaks at about 5.279, 10.604, 13.963, 20.578, 22.990 ± 0.2 degrees 2?. The pattern also characterized by additional XRPD peaks at about 9,577, 12.114, 15.750, 18.246, 21.116, 21.936, 23.633, 24.361, 25.470, 27.188, 27.479 ± 0.2 degrees 2?.

Crystalline Form J of deferasirox sodium salt is characterized by an infrared absorption spectrum comprising peaks at about 3239, 1708, 1596, 1504, 1466, 1367, 1297, 1243, 1161, 875, 793, 750 ± 5 cm-1. Crystalline Form J of deferasirox sodium salt is also characterized by its infrared absorption spectrum substantially in accordance with the spectrum of Fig. 2.

According to the present invention, salicylamide and salicylic acid are mixed in an aprotic solvent in presence of thionyl chloride and a base to obtain 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one of formula (II). The base can be selected from pyridine, triethylamine, N,N-diisopropylamine and the like. The compound of formula (II), thus obtained can be either directly used or can be purified by crystallization.

Further the compound of formula (II) is dissolved or suspended in a solvent or mixture of solvents and 4- hydrazinobenzoic acid of formula (III) is added to the said mixture. The reaction mixture is further heated to complete the reaction to give crude deferasirox.

Crude deferasirox, either in-situ or after isolation, is reacted with carbonate or bicarbonate salt of alkali or alkaline earth metals to provide monosodium salt of deferasirox. Alkali or alkaline earth metals are selected from the group comprising of lithium, sodium, potassium, calcium, magnesium, cerium and the like. Formation of novel monosodium salt of deferasirox improves the color and purity of deferasirox. Furthermore, it helps in efficiently removing the genotoxic impurity i.e. compound of formula (III).

Subsequently, the novel monosodium salt of deferasirox is protonated by acid in presence of solvents selected from the group comprising of esters, ethers, ketones, hydrocarbons (alkyl or aryl), chlorinated hydrocarbons (alkyl or aryl) and the like. The solvent used is preferably ester and is selected from methyl acetate, ethyl acetate, butyl acetate and the like to obtain semi-pure deferasirox having polymorphic form-I. The acid can be selected from the group comprising of inorganic and organic acids. Inorganic acid can be selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like. The organic acid can be selected from the group comprising of formic acid, acetic acid and the like.

The said semi-pure deferasirox can be of desired purity or it can be optionally purified to achieve the desired purity level by crystallizing in the solvent or a mixture of solvents selected from the group comprising of alcohol, ester, ether, hydrocarbon (aliphatic or aromatic), halogenated hydrocarbon (aliphatic or aromatic), ketones, nitriles, sulfoxides, amides and the like. The purification can be preferably carried out in alcohol. The alcohol can be selected from the group comprising of methanol, ethanol, n-propanol, iso-propanol, n-butanol, cyclohexanol and the like.

By "pure deferasirox" it is meant that deferasirox free base or any of the pharmaceutically acceptable salts of deferasirox prepared in accordance with the present invention contains less than about 10 ppm, preferably less than 3 ppm or more preferably less than 1 ppm. of the genotoxic impurity.

The details of the process of the invention are provided in the Examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Examples

Example 1
Preparation of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one of formula (II)
100 gm of salicylamide, 118 gm of salicylic acid and 14 ml of triethylamine are heated in 300 ml of xylene. To the resulting solution added 118 gm of thionyl chloride and heated to reflux for 3 hrs. Xylene is distilled out under vacuum to concentrate the resulting solution. Titled compound is obtained by trituration with methanol.

Example 2
Preparation of crude deferasirox
A suspension of 100 g of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one thus obtained, 70.0 g of 4-hydrazinobenzoic acid in methanol and ethyl acetate is heated to the boiling temperature of the reaction mixture for 2-3 hours to obtain crude deferasirox.

Example 3
Preparation of crude deferasirox
A suspension of 100 g of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one thus obtained, 70.0 g of 4-hydrazinobenzoic acid in methanol or ethanol is heated to the boiling temperature of the reaction mixture for 2-3 hours to obtain crude deferasirox.

Example 4
Preparation of monosodium salt of deferasirox (VI)
To the crude deferasirox thus obtained, ethyl acetate, water and sodium bicarbonate (40 g) is added to the suspension and the suspension is stirred for 2 hours. The resulting product is filtered, washed with ethyl acetate and water and suck dried to obtain monosodium salt of deferasirox (genotoxic impurity not detected). Melting point : 382.5-384.4oC

Example 5
Preparation of deferasirox (semi-pure)
Sodium salt of deferasirox thus obtained is dissolved in a sodium hydroxide solution (30% aq. solution) to obtain a clear solution. After cooling to 5-10 oC Ethyl acetate (600 ml) is added and pH of the resulting solution is adjusted to 1-2 by adding aqueous hydrochloric acid. The resulting suspension is stirred at the temperature of 5-10oC for about 2 hours. The precipitated product washed and dried to obtain deferasirox (semi-pure). XRD of deferasirox exhibits form-I.

Example 6
Preparation of deferasirox (pure) (I)
Deferasirox (semi-pure), thus obtained (100.0g) is heated to reflux in methanol (5000 ml) to obtain clear solution. To the resulting solution charcoal is added, stirred, filtered and methanol was distilled out up to minimum volume. The material was cooled and filtered to obtain pure crystalline deferasirox Form I. (Yield: 85%; Purity: >99.9%)

Example 7
Preparation of deferasirox (pure) (I)
Deferasirox (semi-pure) (100.0g) is heated to reflux in methylene dichloride (MDC) (2300 ml) and methanol (1200 ml) to obtain clear solution. To the resulting solution charcoal is added, stirred, filtered and MDC & methanol was distilled up to minimum volume. The material was cooled and filtered to obtain pure crystalline deferasirox. (Yield: 85%; Purity: >99.9%) XRD of deferasirox exhibits form-I.

Example 8
Preparation of deferasirox (pure) (I)
Deferasirox (semi-pure) (100.0g) is heated to reflux in ethyl acetate (1500 ml) and methanol (500 ml) to obtain clear solution. To the resulting solution charcoal is added, stirred, filtered and ethyl acetate & methanol mixture was distilled out up to minimum volume. The material was cooled and filtered to obtain pure crystalline deferasirox. (Yield: 85%; Purity: >99.9%) XRD of deferasirox exhibits form-I.
While this provisional patent application contains the description of the principal inventive concepts. The complete patent application pursuant here to, will fully and particularly describe the preferred embodiments of the present invention.