WO2012131017A1 - Procédé de production du déférasirox - Google Patents

Procédé de production du déférasirox Download PDF

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Publication number
WO2012131017A1
WO2012131017A1 PCT/EP2012/055753 EP2012055753W WO2012131017A1 WO 2012131017 A1 WO2012131017 A1 WO 2012131017A1 EP 2012055753 W EP2012055753 W EP 2012055753W WO 2012131017 A1 WO2012131017 A1 WO 2012131017A1
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Prior art keywords
ethanol
mixture
reaction
comprised
toluene
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PCT/EP2012/055753
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English (en)
Inventor
Massimo Ferrari
Matteo Galli
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Erregierre SpA
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Erregierre SpA
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Publication of WO2012131017A1 publication Critical patent/WO2012131017A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to a process for the industrial production of deferasirox.
  • Deferasirox is the compound having the lUPAC name 4-[(3Z,5£)-3,5-bis(6-oxo- 1 -cyclohexa-2,4-dienylidene)-1 ,2,4-triazolidin-1 -yl]benzoic acid, and the following structural formula:
  • Deferasirox is used for the treatment of chronic iron overload, a pathological condition which can have metabolic causes, but is more often due to continual transfusions that are necessary in the treatment of various forms of anaemia, such as thalassaemia.
  • Chronic ion overload can impact negatively on the functioning of organs such as the heart and liver, in the most severe cases leading to the death of the patient.
  • This synthetic pathway results in a raw substance containing residual quantities of 4-hydrazinobenzoic acid within the range from 50 to 100 ppm. Because this impurity is potentially genotoxic and carcinogenic, a purification phase is necessary following the production of the compound.
  • the aim of the present invention is to provide an improved process for synthesisingdeferasirox, that produces the desired compound with the minimum possible amounts of impurities, with particular regard to 4-hydrazinobenzoic acid.
  • step a) the reaction of step a) is carried out by using methylene chloride as the starting solvent and distilling the mixture up to the end of the reaction until an oily residue is obtained, to which toluene is added;
  • step b) the reaction of step b) is carried out initially in toluene, working in such as way as to completely eliminate the water that forms, then by adding methanol and distilling to a dense residue, and finally by adding ethanol, heating under reflux, and centrifuging the reaction mixture to separate compound (II);
  • step c) the reaction of step c) is carried out in ethanol under reflux, then adding N,N- dimethyl formamide and solubilising under reflux, filtering the solution and adding thereto phosphoric acid and distilled water, and reacting under reflux.
  • the product obtained in the process described above is already of suitable purity for use in the pharmaceutical field, but it may be further purified by crystallization treatment from a mixture of water and ethanol, as detailed below.
  • the first step of the process of the invention comprises the reaction between salicylic acid and thionyl chloride, with formation of salicyloyl chloride.
  • an equimolar ratio between salicylic acid and thionyl chloride may be used, or preferably, a slight excess of the latter.
  • the reaction is conducted in the presence of pyridine, having the function of accelerating the reaction, and present in molar amounts varying between approximately 1 /50 and 1/70 relative to salicylic acid; and in methylene chloride as the solvent, forming a starting solution of concentration within the range from approximately 1 to 5 moles/litre for salicylic acid.
  • the temperature of reaction is within the range from ambient temperature to approximately 50 °C, preferably approximately 40 °C.
  • the mixture is allowed to react for times within the range from approximately 30 minutes to 3 hours, after which it is distilled until an oily residue is obtained.
  • the residue is taken up by addition of toluene in amounts within the range conveniently from approximately 40 to 100 cc (preferably between 50 and 70) per starting mole of salicylic acid.
  • the solution of salicyloyi chloride obtained is poured slowly into a second receptacle, containing a solution of salicylamide in toluene having a concentration within the range from approximately 2 to 6 moles/litre; the receptacle is maintained at temperature within the range from approximately 100 to 120 °C.
  • the ratio between the moles of salicylamide present in the second receptacle and the starting moles of salicylic acid is within the range from approximately 1 :1 to 0.5:1 , and preferably between approximately 0.6:1 , and 0.9:1 .
  • the mixture is allowed to react under reflux (at approximately 1 15 °C) for at least 15 hours and preferably for 20 hours, continually separating off and eliminating the water of condensation.
  • the mixture obtained is then cooled to approximately 65-70 °C, a volume of methanol within the range from approximately 1 /5 to one half of the total volume of toluene is added, and distillation is carried out until a dense residue results.
  • ethanol preferably denatured (for example with cyclohexane-methanol)
  • ethanol preferably denatured (for example with cyclohexane-methanol)
  • the mixture thus obtained is heated under reflux for a time within the range from 10 minutes to one hour, after which it is centrifuged (preferably first allowing it to cool to ambient temperature) and washed with ethanol (preferably denatured with cyclohexane-methanol).
  • the compound (II) thus obtained proves to have an HPLC purity greater than 99.0% and does not need further purification (as described for example in WO 2010/023685 A2), or drying (as described for example in WO 97/49395 A1 ), and used moist directly in the next step of the process of the invention.
  • the third step of the process of the invention, c), comprises reacting the compound (II) with 4-hydrazinobenzoic acid to form deferasirox.
  • the moist compound (II) obtained in step b) is reacted with 4-hydrazinobenzoic acid in a molar ratio within the range from 0.8:1 and 1 :0.8, and preferably essentially an equimolar ratio, in a solvent comprising ethyl alcohol containing approximately 3 vol.% of toluene (in a quantity indicatively within the range from 1 to 3 litres of solvent per mole of compound (II)).
  • the mass is heated under reflux for at least 2 hours, after which ⁇ , ⁇ -dimethylformamide (DMF) is added in a molar amount equal to approximately 5 times the moles in the compound (II), and the mixture is left for a further period of time under reflux with stirring, until complete solubilisation of the mass is achieved.
  • decolourising carbon of pharmaceutical quality
  • the solution is maintained with heating under reflux for a time within the range from 30 minutes to 2 hours, after which it is filtered.
  • distilled water and phosphoric acid are added, respectively in quantities within the range from approximately 0.5 to 1 litre (water) and from approximately 0.15 to 0.30 moles (phosphoric acid) per mole of starting compound (II).
  • the mixture is allowed to react under reflux (at around 80 °C) for a time preferably within the range from 30 minutes to 2 hours, then it is cooled to a temperature of approximately 30-35 °C, the system remains at this temperature for at least 30 minutes, and is centrifuged.
  • the solid substance obtained by centrifugation is then washed, for example with a mixture of water/ethanol in a ratio of 3:1 in volume (wherein "ethanol” means the above-mentioned 3 vol.% toluene/ethanol mixture).
  • the product obtained, when dried, is deferasirox, having the same crystalline form as the product obtained by the procedure described in WO 97/49395 A1 ; furthermore, this product has an HPLC purity greater than 99.8%.
  • the total yield of the process of the invention, calculated on the basis of the starting salicylic acid, is at least 35%.
  • the substance directly obtained by the process of synthesis ("raw" deferasirox) is of a quality that is already ideal for pharmaceutical applications, having a content of the impurity 4-hydrazinobenzoic acid that is below 0.5 ppm, in contrast with the substance obtained according to WO 97/49395 A1 , which contains this impurity in quantities not less than 50 ppm.
  • the process of the invention therefore enables a direct reduction (that is, without a need for further purification) of the relevant impurity that is 100 times greater than in the first document to have described synthesis of the compound.
  • the "raw" deferasirox obtained as described above can be further purified using a procedure suited to the particular composition of this raw substance.
  • this procedure comprises a suspension of said product with an ammonia solution in a water/ ethanol/toluene mixture (produced by adding to water a 3 vol.% toluene/ethanol mixture) of concentration within the range from approximately 0.2 to 1 M, preferably of approximately 0.4 M; heating the mass thus obtained under reflux (at approximately 78 °C); adding decolourising carbon, maintaining the system with heating under reflux for at least a further 30 minutes; cooling to 60-65 °C and filtering; heating the filtered solution under reflux and addition of acetic acid (for example, in the form of 80 wt.% solution), in a molar ratio of acetic acid/deferasirox within the range from 1 :1 to 4:1 , and preferably approximately 2:1 ; leaving to be heated under reflux for at least 30 minutes, then cooling to ambient temperature, centrifuging and washing the solid with a mixture comprising approximately 3 steps by volume of water to one step of an ethanol/toluene mixture as defined above; and finally drying (
  • step c) of the process of the invention for synthesizingdeferasirox just as in the further optional process of purification, it is also possible to use pure ethanol instead of the ⁇ 3 vol.% toluene/ethanol mixture; the use of this mixture is however preferred according to the present invention, because the inventors have verified that excellent results are obtained with its use, and its commercialisation is not subject to all the restrictions and controls imposed by fiscal regulations (UTIF) that apply to pure ethanol.
  • UTIF fiscal regulations
  • a reactor is charged with 10 kg of salicylic acid, 100 g of pyridine and 30 kg of methylene chloride, and the mixture is heated to 40 °C. 9 kg of thionyl chloride is then added, and the reaction mass is maintained at 40 °C for one hour. The resultant mass is then distilled to obtain an oily residue, to which 4 kg of toluene is added.
  • a solution of salicyloyl chloride is obtained by monitoring the end of the reaction by TLC (conversion to salicyloyl chloride greater than 98%).
  • the solution obtained in example 1 is poured into a second reactor, maintained at a temperature of 1 10 °C and containing 7 kg of salicylamide and 1 1 kg of toluene.
  • the resultant mass is allowed to react under reflux at approximately 1 15 °C, for 20 hours, continually removing the water liberated by the reaction.
  • the solution is then cooled to 65 °C, and 5 kg of methanol is added. Distillation is performed until a dense residue is obtained, to which 25 kg of denatured ethanol (denatured using cyclohexane-methanol) is then added; the whole is heated under reflux for 30 minutes, then cooled to ambient temperature and centrifuged, finally, it is washed with 7 kg of denatured ethanol.
  • the moist product obtained at the end of example 2 is placed in a reactor, together with 4.88 kg of 4-hydrazinobenzoic acid and 48 kg of a 3 wt.% toluene/ethanol mixture.
  • the mass is heated under reflux (approximately 77 °C) for 2 hours.
  • 12 kg of DMF is then added, and heating under reflux is continued (at a temperature of approximately 80 °C) until complete dissolution of the components present in the mixture is observed.
  • 400 g of pharmaceutical quality decolourising carbon is then added.
  • the suspension is heated under reflux (approximately 80 °C) with stirring for 30 minutes, then it is cooled to 60 °C and filtered.
  • the filtered solution is placed in a reactor, heated under reflux, and 800 g of 85 wt.% of phosphoric acid, and 24 kg of distilled water are added. A precipitate is formed, which is heated under reflux (approximately 80 °C) with continuous stirring for 30 minutes, after which the mixture is cooled to 30 °C, centrifuged, and the solid is washed with a mixture consisting of 24 kg of distilled water and 8 kg of 3% toluene/ethanol.
  • the raw product obtained in example 3 is further purified by placing in a reactor, together with 38.4 kg of 3 wt.% toluene/ethanol mixture, 1 3 kg of distilled water, and 1 .44 kg of a 30 wt.% solution of ammonia in water.
  • the mixture is heated under reflux (approximately 78 °C), so as to achieve complete dissolution of the solid.
  • 380 g of decolourising carbon Picapure SP Pharma suspended in water is added, and the suspension is maintained with stirring under reflux for 30 minutes; the suspension is then cooled to 60 °C and filtered.
  • the filtered solution is then put into a reactor, heated under reflux, and 3.94 kg of 80 wt. % acetic acid is added.
  • Precipitation of a solid occurs.
  • the precipitated mass is stirred under reflux (at approximately 80 °C) for 30 minutes, then it is cooled to ambient temperature, centrifuged separating the solid, and finally washed with the mixture formed from 19.2 kg of distilled water and 4.8 kg of ethanol/toluene as described previously.
  • the solid obtained is dried overnight at 90 °C, resulting in 8 kg of a crystalline product, which analyses confirm as being crystalline deferasirox of HPLC purity greater than 99,98%.
  • the yield from purification is equal to approximately 83% relative to raw deferasirox.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveau procédé de préparation du déférasirox, ou acide 4-[(3Z,5E)-3,5-bis- (6-oxo-1-cyclohexa-2,4-diénylidène)-1,2,4-triazolidin-1-yl]benzoïque, ayant la formule structurale (I) suivante.
PCT/EP2012/055753 2011-04-01 2012-03-30 Procédé de production du déférasirox Ceased WO2012131017A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2011A000543 2011-04-01
IT000543A ITMI20110543A1 (it) 2011-04-01 2011-04-01 Processo per la produzione di deferasirox

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WO2012131017A1 true WO2012131017A1 (fr) 2012-10-04

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103396373A (zh) * 2013-07-22 2013-11-20 江苏奥赛康药业股份有限公司 地拉罗司的制备方法及其中间体化合物
CN103554040A (zh) * 2013-11-08 2014-02-05 南京靖龙药物研发有限公司 一种地拉罗司衍生物的制备方法
CN104045561A (zh) * 2014-05-21 2014-09-17 江苏德峰药业有限公司 一种3,3,5-三甲基环己醇水杨酸酯的合成方法
CN104098519A (zh) * 2013-04-08 2014-10-15 江苏豪森药业股份有限公司 地拉罗司的精制方法
KR20150123934A (ko) * 2013-03-06 2015-11-04 바이오콘 리미티드 데페라시록스의 제조 방법
CN116199637A (zh) * 2023-01-15 2023-06-02 湖南欧亚药业有限公司 一种地拉罗司的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010023685A2 (fr) * 2008-08-29 2010-03-04 Matrix Laboratories Limited Forme cristalline de la 2-(2-hydroxyphényl)benz[e][1,3]oxazin-4-one, son procédé de production et son utilisation pour produire l'acide 4-(3,5-bis(2-hydroxyphényl)-1h-1,2,4-triazol-1-yl)benzoïque

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010023685A2 (fr) * 2008-08-29 2010-03-04 Matrix Laboratories Limited Forme cristalline de la 2-(2-hydroxyphényl)benz[e][1,3]oxazin-4-one, son procédé de production et son utilisation pour produire l'acide 4-(3,5-bis(2-hydroxyphényl)-1h-1,2,4-triazol-1-yl)benzoïque

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150123934A (ko) * 2013-03-06 2015-11-04 바이오콘 리미티드 데페라시록스의 제조 방법
KR102282372B1 (ko) * 2013-03-06 2021-07-27 바이오콘 리미티드 데페라시록스의 제조 방법
RU2659034C2 (ru) * 2013-03-06 2018-06-27 Биокон Лимитед Способ получения деферазирокса
EP2964659A4 (fr) * 2013-03-06 2016-11-02 Biocon Ltd Procédé pour la préparation de déférasirox
JP2016515103A (ja) * 2013-03-06 2016-05-26 バイオコン・リミテッドＢｉｏｃｏｎ Ｌｉｍｉｔｅｄ デフェラシロクスを調製するための方法
CN104098519A (zh) * 2013-04-08 2014-10-15 江苏豪森药业股份有限公司 地拉罗司的精制方法
CN104098519B (zh) * 2013-04-08 2018-08-21 江苏豪森药业集团有限公司 地拉罗司的精制方法
CN103396373B (zh) * 2013-07-22 2015-02-04 江苏奥赛康药业股份有限公司 地拉罗司的制备方法及其中间体化合物
CN103396373A (zh) * 2013-07-22 2013-11-20 江苏奥赛康药业股份有限公司 地拉罗司的制备方法及其中间体化合物
CN103554040B (zh) * 2013-11-08 2015-12-02 南京靖龙药物研发有限公司 一种地拉罗司衍生物的制备方法
CN103554040A (zh) * 2013-11-08 2014-02-05 南京靖龙药物研发有限公司 一种地拉罗司衍生物的制备方法
CN104045561A (zh) * 2014-05-21 2014-09-17 江苏德峰药业有限公司 一种3,3,5-三甲基环己醇水杨酸酯的合成方法
CN116199637A (zh) * 2023-01-15 2023-06-02 湖南欧亚药业有限公司 一种地拉罗司的制备方法

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