Salts of antiviral phosphonate analogues and process for preparation thereof
AssigneeCipla Limited
InventorsManjinder Singh Phull, Ashwini Amol Sawant, Dharmaraj Ramachandra Rao, Geena Malhotra, Manish Gopaldas Gangrade
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Abstract
The present invention relates to certain acid salts of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)(phenoxy) phosphoryloxy)methyl pivalate of Formula (I), to processes for their preparation; to pharmaceutical compositions comprising such compounds, and methods of treating a disease which responds to inhibition of nucleotide reverse transcriptase activity.
Claims21
A process for preparing (((1-(6-amino-9H-burin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalic acid salt in crystalline form and having an XRD pattern comprising peaks at 4.16, 21.30 and 25.7° 20 #0.2° 20 or a solvate or hydrate thereof comprising the steps of:
- i) reacting (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate with oxalic acid in the presence of a solvent selected from isopropyl alcohol, acetone or methanol;
- and thereafter
- ii) isolating the acid addition salt so formed,
- wherein (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalic acid salt exhibits dissolution of at least 10% (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate at 60 minutes or at least 30% of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate at 120 minutes in 900 ml of 0.1M of hydrochloric acid having pH 7.4 at 37±0.5° C. with a paddle rotating at 75 revolutions per minute.
A process for preparing (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartaric acid salt in crystalline form and having an XRD pattern comprising peaks at 4.73 and 20.65° 2θ±0.2° 2θ or a solvate or hydrate thereof, comprising the steps of:
- i) reacting (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate with tartaric acid respectively in the presence of a solvent selected from isopropyl alcohol acetone or methanol;
- and thereafter
- ii) isolating the acid addition salt so formed,
- wherein (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartaric acid salt is-prepared-which-exhibits dissolution of at least 20% of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate at 60 minutes or at least 40% of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate at 120 minutes in 900 ml of 0.1M of hydrochloric acid having pH 7.4 at 37±0.5° C. with a paddle rotating at 75 revolutions per minute.
A process for preparing (((1-{6-amino-9H-purin-9-yl)propan-2-yloxy) methyl} (phenoxy) phosphoryloxy) methyl pivalate fumaric acid salt in crystalline form and having an XRD pattern comprising peaks at 5.03, 23.59 and 29.02° 2θ±0.2° 2θ or a solvate or hydrate thereof, comprising the steps of:
- i) reacting (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate with fumaric acid in the presence of a solvent selected from isopropyl alcohol, acetone or methanol;
- and thereafter
- ii) isolating the acid addition salt so formed,
- wherein (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate fumaric acid salt exhibits dissolution of at least 20% of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate at 60 minutes or at least 40% of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate at 120 minutes in 900 ml of 0.1M of hydrochloric acid having pH 7.4 at 37±0.5° C. with a paddle rotating at 75 revolutions per minute.
Dependencies are inferred from the claim text.