Morphic forms of hexadecyloxypropyl-phosphonate esters and methods of synthesis thereof
The disclosure describes methods of synthesis of phosphonate ester compounds. The methods according to the disclosure allow for large-scale preparation of phosphonate ester compounds having high purity and stability. Also disclosed are morphic forms of phosphonate ester compounds.
1. A method of synthesizing Compound 2,
comprising:
(a) heating a mixture of (S)-trityl glycidyl ether, cytosine, a base, and a suitable organic solvent;
(b) cooling the reaction mixture and quenching with toluene to produce a slurry;
(c) cooling the slurry of step (b), filtering to give a solid and washing the solid with toluene;
(d) slurrying the solid of step (c) in toluene, filtering to give a solid, and washing the solid with an organic solvent;
(e) triturating the solid of step (d) in water/acetone; and
(f) filtering to give a solid filter cake.
2. The method of claim 1 , further comprising washing the solid filter cake of step (f) with acetone and suspending the solid filter cake in acetone.
3. The method of claim 2 , wherein the filter cake suspension in acetone is heated at about 35-45° C., and filtered.
4. The method of claim 3 , further comprising removing the acetone from the suspended filter cake and drying the filter cake in vacuo.
5. The method of claim 1 , comprising repeating steps d-e at least once.
6. The method of claim 5 , wherein steps d-e are repeated twice.
7. The method of claim 1 , wherein the purity of compound 2 is at least 91% (wt/wt).
8. The method of claim 1 , wherein the base in step (a) is a metal carbonate.
9. The method of claim 8 , wherein the base in step (a) is potassium carbonate.
10. The method of claim 1 , wherein the organic solvent of step (a) is N, N-dimethylformamide or tert-amyl alcohol.
11. The method of claim 1 , wherein the organic solvent of step (d) is acetone.
12. The method of claim 1 , wherein the mixture of step (a) is heated to about 60-120° C.
13. The method of claim 1 , wherein the mixture of step (a) is heated for about 4-14 hours.
14. The method of claim 1 , wherein the triturating in water and acetone in step (e) takes place at a temperature of about 17-22° C.
15. A method of synthesizing (S)—N 1 -[(2-hydroxy-3-triphenylmethoxy)propyl] cytosine, comprising:
(a) heating a mixture of (S)-trityl glycidyl ether, cytosine, potassium carbonate, and N, N-dimethylformamide (DMF) at about 85-95° C. for about 9 hours;
(b) cooling the reaction mixture of step (a) to about 66-70° C. and quenching with toluene;
(c) cooling the resulting slurry of step (b) to about −10 to 5° C., filtering and washing with toluene;
(d) slurrying the solids in toluene at about 15-25° C., filtering, and then washing with acetone;
(e) triturating the solids in water and acetone at a ratio of about 1:0.6 (wt/wt) at about 17-22° C., filtering to give a filter cake, and washing with acetone;
(f) suspending the filter cake of step (e) in acetone and heating at about 35-45° C. for about 3 hours, filtering to give a solid, and washing with acetone.
16. The method of claim 15 further comprising repeating steps (d) and (e).
17. The method of claim 15 wherein the solid of step (f) is dried in vacuo at a temperature equal to or less than about 40° C. for about 12 hours.
18. The method of claim 15 wherein the purity of the synthesized compound is equal to or greater than 99% as measured by HPLC.