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 preparing the morphic Form II of compound 1:
comprising:
(a) recrystallizing compound 1 three times from methanol;
(b) recrystallizing compound 1 once from n-heptane and methanol; and
(c) recrystallizing compound 1 again from methanol.
2. The method of claim 1 , wherein step (c) is carried out with seeding with an amount of morphic Form II of Compound 1.
3. The method of claim 2 , wherein the morphic Form II is seeded at an amount of about 0.5% wt/wt, about 3% wt/wt, or about 7% wt/wt.
4. The method of claim 1 , wherein the first three recrystallizations from methanol each comprise:
(a) dissolving Compound 1 in methanol at about 60-70° C. and stirring for about five minutes;
(b) cooling to 60° C. and stirring for about one hour;
(c) cooling to 50° C. over about six hours;
(d) cooling to 20° C. over about two hours and stirring for two hours; and
(e) filtering the resulting solid.
5. The method of claim 1 , wherein step (b) comprises:
(a) dissolving compound 1 in refluxing MeOH;
(b) adding n-heptane while maintaining the internal temp above about 50° C. over about 40 minutes;
(c) maintaining the solution at about 55° C. for about 30 minutes;
(d) cooling the solution to about 40° C. over about six hours;
(e) stirring the solution at about 40° C. for about two hours;
cooling the solution to about 20° C. over about at least six hours and stirring at about 20° C. for about at least two hours; and
(g) filtering the resulting solid.
6. The method of claim 5 , further comprising washing the solid with n-hexane and methanol.
7. The method of claim 2 , wherein step (c) comprises:
(a) stirring a solution of compound 1 at about 60° C. for about one hour;
(b) cooling the solution to about 50° C. over about eight hours;
(c) holding at about 50° C. for about two hours;
(d) cooling the solution to about 20° C. over about six hours;
(e) stirring the solution for about two hours at about 20° C.; and
(f) filtering the resulting solid.
8. The method of claim 7 , further comprising seeding the solution with a morphic Form II of Compound 1 after step (a).
9. The method of claim 1 , wherein the resulting morphic Form II of Compound 1 is anhydrous.
10. A pharmaceutical composition comprising the morphic Form II of Compound 1 prepared by the method of claim 1 and a pharmaceutically acceptable carrier.
11. A composition comprising morphic Form II of Compound 1
and Compounds A, B, C, and D:
12. The composition of claim 11 comprising greater than 90% wt/wt compound 1.
13. The composition of claim 11 comprising less than 10% wt/wt total Compounds A, B, C, and D.