Phosphonate Ester Derivatives and Methods of Synthesis Thereof
AssigneeChimerix, Inc.
InventorsRoy W. Ware, Merrick R. Almond, Bernhard M. Lampert
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Abstract
The disclosure describes methods of synthesis of phosphonate ester derivatives. Preferred methods according to the disclosure allow for large-scale preparation of phosphonate ester compounds having high purity. In some embodiments, preferred methods according to the disclosure also allow for the preparation of phosphonate ester derivatives without the use of chromatographic purification methods and in better yield than previously used methods for preparing such compounds. Also disclosed are morphic forms of phosphonate ester derivatives.
Claims20
A morphic form of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester (Form A) characterized by an X-ray diffraction pattern including peaks at about 5.5, 19.3, 20.8, and 21.3 degrees 2θ.
A method for synthesizing phosphonic acid, P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-(hexadecyloxy)propyl]ester, sodium salt, comprising:
- (a) contacting (dichlorophosphoryl)methyl 4-methylbenzenesulfonate with 3-(hexadecyloxy)propan-1-ol in the presence of a base in a first suitable solvent to form a resultant mixture;
- (b) quenching the resultant mixture with a suitable quenching agent and water;
- (c) adjusting the pH of the quenched resultant mixture to 2.0 to form a crude product;
- and
- (d) dissolving the crude product in a second suitable solvent.
A method for synthesizing phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester, comprising:
- (a) contacting (S)—N1-[(2-hydroxy-3-(PG-O)-propyl]cytosine with phosphonic acid, P-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-(hexadecyloxy)propyl]ester, sodium salt in the presence of magnesium di-tert-butoxide and a suitable organic solvent A to form [3-(hexadecyloxy)propyl]hydrogen[[[(S)-1-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(PG-O)-propan-2-yl]oxy]methyl]phosphonate;
- and
- (b) contacting [3-(hexadecyloxy)propyl]hydrogen[[[(S)-1-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(PG-O)-propan-2-yl]oxy]methyl]phosphonate with a protecting-group removal agent in the presence of a suitable organic solvent B to form phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester;
- wherein PG is a hydroxyl protecting group.
Dependencies are inferred from the claim text.