Morphic forms of hexadecyloxypropyl-phosphonate esters and methods of synthesis thereof

• US 9,371,344 B2
• Filed: 01/23/2015
• Issued: 06/21/2016
• Est. Priority Date: 11/15/2013
• Status: Active Grant

• Current Assignee: Emergent BioDefense Operations Lansing, LLC (Emergent Biosolutions Inc.)
• Original Assignee: Chimerix Incorporated
• Inventors: Ware, Roy Wendell Jr., Downey, Aaron Leigh
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US14/604,334
• Publication Number:
  US 20150210724A1
• Time in Patent Office: 515 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07F 9/53 Organo-phosphine oxides; Organo-phosphine thioxides
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3

Abstract

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.

Claims

1. A method of preparing the morphic Form II of compound 1:

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

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.