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

Patent metadata

Field	Value
Publication number	US-10457668-B2
Application number	US-201615762523-A
Country	US
Kind code	B2
Filing date	Sep 22, 2016
Priority date	Sep 23, 2015
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

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 process for preparation of crystalline B-3 form of 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 (III) comprising of:
a) Treating a solution of 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (II) in a polar organic solvent under nitrogen atmosphere with an alkali solution at a lower temperature;
b) Adding ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (I) to step a) solution;
c) Adding an aliphatic ester solvent and water to the solution of step b);
d) Separating the layers;
e) Partially concentrating the organic layer and adding an aliphatic hydrocarbon solvent at a lower temperature;
f) Stirring the reaction mass of step e) at elevated temperature; and
g) Cooling the reaction mass of step f), filtering and optionally washing with aliphatic hydrocarbon solvent to provide compound III in crystalline Form B-3.

2. A process for preparation of crystalline B-3 form of 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 (III) as claimed in claim 1 comprising of:
a) Treating a solution of 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (II) in dimethyl sulfoxide under nitrogen atmosphere with sodium hydroxide solution at 10-20° C.;
b) Adding ((3 S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (I) to step a) solution;
c) Adding ethyl acetate and water to the solution of step b);
d) Separating the layers;
e) Partially concentrating the organic layer to 4-7 volumes and adding n-Heptane at 20 to 30° C.;
f) Stirring the reaction mass of step e) at 40 to 50° C.; and
g) Cooling the reaction mass of step f), filtering and optionally washing with n-Heptane to provide compound of the structural formula III in crystalline Form B-3.

3. A crystalline B-3 form of 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 (III) characterized by its powder X-ray diffractogram having peaks at about 7.07, 14.49, 15.68, 16.50, 18.05, 20.13, 20.87, 22.85 and 24.42±0.2 degrees of 2θ.

4. A crystalline B-3 form of 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 (III) as claimed in claim 3 characterized by a XRD pattern as depicted in FIG. 3 .

5. A process for preparation of crystalline B-1 form of 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 (III) comprising of:
a) Treating a solution of 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (II) in a polar organic solvent with an alkali solution at a lower temperature;
b) Adding ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (I) to step a) solution;
c) Adding an aliphatic ester solvent and water to the solution of step b);
d) Separating the layers;
e) Concentrating the organic layer and adding a halogenated hydrocarbon solvent and an aliphatic hydrocarbon solvent at a lower temperature; and
f) Cooling the reaction mass of step e), filtering and optionally washing with aliphatic hydrocarbon solvent to provide compound of the structural formula III in crystalline Form B-1.

6. A process for preparation of crystalline B-1 form of 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 (III) as claimed in claim 5 comprising of:
a) Treating a solution of 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (II) in dimethyl sulfoxide with sodium hydroxide solution at 5-15° C.;
b) Adding ((3 S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (I) to step a) solution;
c) Adding ethyl acetate and water to the solution of step b);
d) Separating the layers;
e) Concentrating the organic layer and adding dichloromethane and n-Heptane solvent at a lower temperature; and
f) Cooling the reaction mass of step e), filtering and optionally washing with n-Heptane to provide compound of the structural formula III in crystalline Form B-1.

7. A crystalline B-1 form of 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 (III) characterized by its powder X-ray diffractogram having peaks at about 4.14, 6.85, 9.92, 15.28, 15.69, 16.59, 17.29, 17.92, 18.27, 18.91, 20.63, 19.95, 23.58 and 25.12±0.2 degrees of 2θ.

8. A crystalline B-1 form of 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 (III) as claimed in claim 7 characterized by a XRD pattern as depicted in FIG. 1 .

9. A process for preparation of crystalline B-2 form of 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 (III) comprising of:
a) Treating a solution of 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (II) in a polar organic solvent with an alkali solution at a lower temperature;
b) Adding ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (I) to step a) solution;
c) Adding an aliphatic ester solvent and water to the solution of step b);
d) Separating the layers;
e) Partially concentrating the organic layer and adding an aliphatic hydrocarbon solvent at a lower temperature;
f) Stirring the reaction mass of step e) at elevated temperature; and
g) Cooling the reaction mass of step f), filtering and optionally washing with aliphatic hydrocarbon solvent to provide compound of the structural formula III in crystalline Form B-2.

10. A process for preparation of crystalline B-2 form of 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 (III) as claimed in claim 9 comprising of:
a) Treating a solution of 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (II) in dimethyl sulfoxide with sodium hydroxide solution at a lower temperature;
b) Adding ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (I) to step a) solution;
c) Adding ethyl acetate and water to the solution of step b);
d) Separating the layers;
e) Partially concentrating the organic la

Assignees

• Biocon Ltd

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/10

  Antimycotics · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• 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