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

• US 8,962,829 B1
• Filed: 10/10/2014
• Issued: 02/24/2015
• 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:
  US14/512,335
• Time in Patent Office: 137 Days
• Field of Search: 544/243, 514/86
• US Class Current: 544/243
• 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. Morphic Form II of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester (Compound 1).

2. The morphic Form II according to claim 1 characterized by an X-ray diffraction pattern including prominent peaks at about 2.81 and about 5.63 degrees 2⊖

.

3. The morphic Form II according to claim 1 characterized by an X-ray diffraction pattern with two or more peaks expressed in degrees 2⊖

(±

0.2) selected from 2.81, 5.63, 11.30, 12.05, 13.22, 13.45, 13.81, 14.32, 14.92, 15.64, 16.25, 16.41, 17.00, 17.67, 17.87, 18.15, 18.35, 18.50, 19.00, 19.57, 19.85, 20.22, 20.96, 21.06, 21.89, 22.76, 23.70, 23.95, 24.32, 24.70, 25.54, 26.12, 26.52, 26.81, 27.07, 27.48, 27.71, 29.11, 29.36, and 29.61.

4. The morphic Form II according to claim 1 characterized by an X-ray diffraction pattern substantially similar to that set forth in FIG. 1, FIG. 7, FIG. 13, FIG. 14, FIG. 20, or FIG. 21.

5. The morphic Form II according to claim 1 characterized by a DSC Thermogram substantially similar to that set forth in FIG. 4, FIG. 15, or FIG. 16.

6. The morphic Form II according to claim 1, characterized by a DSC Thermogram substantially similar to that set forth in FIG. 4.

7. The morphic Form II according to claim 1 produced by a purification process comprising recrystallizing a preparation of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester (Compound 1) from methanol.

8. A method of preparing the Form II of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester of claim 1, comprising the step of combining (S)—

N¹-[(2-hydroxy-3-triphenylmethoxy)propyl]cytosine (Compound

     2), P-[[[4-methylphenyl)sulfonyl]oxy]methyl]-, mono[3-(hexadecyloxy)propyl]ester, sodium salt (Compound

     4) with magnesium tert-butoxide, and a suitable organic solvent and crystallizing from methanol.

9. The method according to claim 8, wherein the Form II is more than or equal to about 91% wt/wt pure.

10. The method according to claim 8, wherein the morphic Form II is characterized by an X-ray diffraction pattern including peaks at about 2.81 and about 5.63 degrees 2⊖

.

11. The method according to claim 8, wherein the morphic Form II is characterized by an X-ray diffraction pattern with two or more peaks expressed in degrees 2⊖

(±

0.2) selected from 2.81, 5.63, 11.30, 12.05, 13.22, 13.45, 13.81, 14.32, 14.92, 15.64, 16.25, 16.41, 17.00, 17.67, 17.87, 18.15, 18.35, 18.50, 19.00, 19.57, 19.85, 20.22, 20.96, 21.06, 21.89, 22.76, 23.70, 23.95, 24.32, 24.70, 25.54, 26.12, 26.52, 26.81, 27.07, 27.48, 27.71, 29.11, 29.36, and 29.61.

12. The method according to claim 8, wherein the morphic Form II is characterized by an X-ray diffraction pattern substantially similar to that set forth in FIG. 1, FIG. 7, FIG. 13, FIG. 14, FIG. 20, FIG. 21, or FIG. 25.

13. The method according to claim 8, wherein the morphic Form II is characterized by an DSC Thermogram substantially similar to that set forth in FIG. 4, FIG. 15, or FIG. 16.

14. The method according to claim 8, further comprising seeding with about 0.5% wt/wt, about 3% wt/wt, or about 7% wt/wt of seed of the phosphonic acid.

15. The method of claim 14, wherein the seed is Form II or Form I of the phosphonic acid.

16. The morphic Form II of claim 1, characterized by a DSC thermogram showing an endotherm at about 41-43°

C.;

overlapping endotherms at about 90 and about 95°

C.; and

an endotherm at about 196°

C.

17. A composition comprising the morphic form II according to claim 1, characterized in that it contains less than about 1.5% wt/wt of Form H, Form I and/or amorphous forms.

19. A composition comprising the morphic form II according to claim 1, characterized in that it contains less than about 2% wt/wt total impurities.

18. A composition comprising morphic form II of Compound 1, characterized in that the composition contains less than about 2% wt/wt of any of the following compounds:

20. A composition of Compound 1 comprising Form II, Form I and Form H.

21. The composition of claim 20 comprising greater than 90% wt/wt Form II.

22. The composition of claim 20, comprising less than 10% wt/wt of Form I and Form H.