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Processes for the preparation of deferasirox, and deferasirox polymorphs

一种地拉罗司、结晶的技术，应用在植物学设备和方法、药物组合、动物驱避剂等方向，能够解决繁多步骤、复杂等问题

Inactive Publication Date: 2012-08-15
MAPI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] Although this method provided the desired material in high yield, it was more complex (numerous steps, no commercially available starting materials, and intermediates requiring further isolation and purification)

Method used

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  • Processes for the preparation of deferasirox, and deferasirox polymorphs
  • Processes for the preparation of deferasirox, and deferasirox polymorphs
  • Processes for the preparation of deferasirox, and deferasirox polymorphs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0313] Example 1 - Method A

[0314] o-Trimethylsiloxybenzonitrile (IV, X=SiMe 3 ) as described in British Patent GB 1330265 or Tetrahedron Letters, 1986, 27(3):347-348.

[0315] 2-(Methoxymethyl)oxybenzonitrile (IV, X=MOM) was prepared according to Tetrahedron, 2003, 59:5831-5836.

[0316] 2-Acetoxybenzonitrile (IV, X=Ac) was prepared as described in Bulletin de la Siete Chimique de France, 1958, 185-187.

[0317] General preparation of compounds of formula II:

[0318]Under an inert atmosphere, 16.0 g (0.2 mol) of sulfur trioxide was added dropwise at 0-3 ° C to treat dichloride in 75 ml of dichloroethane. 17.6g (0.2mol) of alkane, accompanied by cooling and stirring, thus generating di Alkane-sulfur trioxide complex slurry. Nitrile IV (0.4 mol) in 100 ml of dichloroethane was then added to the reaction mixture and the temperature was allowed to rise slowly to room temperature. Reaction monitoring was performed by TLC. After the reaction was complete, the solid wa...

Embodiment 2

[0321] Example 2 - Method B :

[0322] Preparation of salicyloyl chloride

[0323] Salicylic acid (5.0g, 36.2mmol) was suspended in dry hexane (40ml) and thionyl chloride (4.52g, 38mmol) was added under nitrogen atmosphere followed by a drop of pyridine. The mixture was refluxed for 2 hours with stirring. The clear yellow solution was cooled and concentrated in vacuo to give a thick oil which was used in the next step.

[0324] Preparation of 2-hydroxy-N-(2-hydroxybenzyl)benzamide [bis(salicyl)imide] (4)

[0325] 6 salicyloyl chloride+5(Me 3 Si) 2 NH→3 bis(salicyl)imide+4Me 3 SiCl+2NH 4 Cl

[0326] Salicyloyl chloride prepared above was dissolved in dry toluene (10ml) and added dropwise to a solution of hexamethyldisilazane (4.954g, 30.8mmol) in dry toluene (20ml). The mixture was stirred at 0-10 °C under nitrogen atmosphere for 1 hour. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and...

Embodiment 3

[0335] Example 3 - General preparation of polymorphs of deferasirox

[0336] 1. Reagents

[0337] Acetonitrile, HPLC grade, Sigma, Lot No.07278PH

[0338] Ethanol, HPLC grade, Sigma, Lot No. 11085CH

[0339] DMSO, HPLC grade, Sigma, Lot No.05737BH

[0340] Dichloromethane, Alfa Aesar, HPLC grade, Lot No. C27S008

[0341] Methanol, AR, SCRC, Lot No.T20090912

[0342] Ethanol acetate, AR, Yixing Secondary Chemical Company, Lot No.090607

[0343] MIBK, AR, SCRC, Lot No. T20080411

[0344] Isopropanol, AR, Sinopharm Chemical Reagent Co.Ltd, Lot No.T20090813

[0345] Acetone, AR, Sinopharm Chemical Reagent Co.Ltd, Lot No.090104

[0346] Toluene, AR, SCRC, Lot No.T20090603

[0347] tert-butyl methyl ether, HPLC grade, Fluka, Lot No. 1359496

[0348] THF, AR, Yixing Secondary Chemical, Lot No.090901

[0349] 1-Butanol, AR, SCRC, Lot No.T20080818

[0350] MEK, AR, SCRC, Lot No. T20090724

[0351] iPrOAc, AR, Shanghai Experimental Reagent Company, Lot No.20080410

[0352...

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PUM

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Abstract

The present invention relates to processes for the preparation of deferasirox, an oral iron chelator developed to treat iron overload due to e.g. multiple blood transfusions. The present invention further provides novel deferasirox pseudopolymorphs and a novel amorphous form of deferasirox, processes for their preparation, as well as pharmaceutical compositions comprising same, and use thereof in treating iron overload.

Description

field of invention [0001] The present invention relates to a process for the preparation of deferasirox, an oral iron chelator developed for the treatment of chronic iron overload e.g. caused by multiple blood transfusions. The present invention further provides new deferasirox pseudopolymorphs and new deferasirox amorphous forms, their preparation methods, pharmaceutical compositions containing them and their applications in the treatment of iron overload. Background of the invention [0002] People with chronic anemia such as thalassemia or sickle cell anemia often require regular red blood cell transfusions. Repeated infusions are toxic and ultimately lethal, and iron accumulates in multiple tissues of the body as insoluble ferritin. This chronic iron overload occurs because the body cannot effectively eliminate iron. Chronic iron overload is a serious symptom, and organ failure can occur due to the iron deposits produced. When the heart or liver is affected, the sympt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/60
CPCA61P3/12A61P7/08A61P39/04C07D249/08C07D291/06
Inventor M·米垂斯基E·马罗姆S·如博诺夫
Owner MAPI PHARMA
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