Crystalline forms of posaconazole intermediate and process for the preparation of amorphous posaconazole

Patent metadata

Field	Value
Publication number	US-10927102-B2
Application number	US-201916655632-A
Country	US
Kind code	B2
Filing date	Oct 17, 2019
Priority date	Sep 23, 2015
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

The present invention provides an industrial method production of amorphous posaconazole. The present invention also relates to a method for production of the posaconazole via and novel crystalline forms of posaconazole intermediate. More particularly the present invention relates to novel crystalline forms of posaconazole intermediate and methods for production of novel crystalline forms of posaconazole intermediate represented by the following structural formula III Which is key intermediate in the production of posaconazole. The present invention also provides for the one pot process for the preparation of amorphous posaconazole using novel crystalline forms of benzyl posaconazole.

First claim

The invention claimed is:

1. A one pot process for the preparation of the amorphous form of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one of the structural formula (IV), the process comprising:
a) treating 4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3 S)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one of the structural formula (III) with concentrated hydrochloric acid and stirring the reaction mixture at an elevated temperature;
b) cooling the reaction mixture and adding a halogenated hydrocarbon solvent;
c) separating the layers;
d) adding a halogenated hydrocarbon solvent to the aqueous layer and adjusting the pH to 8-12;
e) partially concentrating the organic layer and optionally adding an aliphatic ketone solvent to the reaction mixture;
f) mixing the reaction mixture of step e) and an aliphatic hydrocarbon solvent at a lower temperature; and
g) filtering and optionally washing with aliphatic hydrocarbon solvent to provide amorphous compound of the structural formula IV.

2. The process of claim 1 , wherein the 4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2 S, 3 S)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5 (4H)-one of the structural formula (III) used in step a) is in Crystalline Form B-1 or Crystalline Form B-2 or Crystalline Form B-3.

3. The process of claim 1 where, wherein step a) is carried out at a temperature of 55-70° C.

4. The process of claim 1 , wherein the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, chloroform, dichloroethane, and carbon tetrachloride.

5. A process for the preparation of the amorphous form of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl) tetrahydro-5(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one of the structural formula (IV), the process comprising:
a) treating 4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl) methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one of the structural formula (III) with concentrated hydrochloric acid and stirring the reaction mixture at a temperature of 55-70° C.,
b) cooling the reaction mixture and adding dichloromethane,
c) separating the layers,
d) adding dichloromethane to the aqueous layer and adjusting the pH to 8-12,
e) partially concentrating the organic layer and optionally adding acetone to the reaction mixture,
f) mixing the reaction mixture of step e) and cyclohexane at a temperature of 10-25° C., and
g) filtering and optionally washing with cyclohexane to provide amorphous compound of the structural formula IV.

Assignees

• Biocon Ltd

Inventors

• Charyulu Palle Venkata Raghavendra
• Gowda Dharshan Jakkali Chandre
• Rajmahendra Shanmughasamy
• Raman Manikandan

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• B01D2009/009

  Separation of organic compounds by selective or extractive crystallisation with the aid of auxiliary substances forming complex or molecular compounds, e.g. with ureum, thioureum or metal salts · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• B01D9/0045

  Washing of crystals, e.g. in wash columns · CPC title

• A61P35/00

  Antineoplastic agents · CPC title