Phosphonate ester derivatives and methods of synthesis thereof

• US 8,569,321 B2
• Filed: 08/31/2011
• Issued: 10/29/2013
• Est. Priority Date: 08/31/2010
• Status: Active Grant

• Current Assignee: Emergent BioDefense Operations Lansing, LLC (Emergent Biosolutions Inc.)
• Original Assignee: Chimerix Incorporated
• Inventors: Ware, Roy W., Almond, Merrick R., Lampert, Bernhard M.
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Pagano, Alexander R
• Application Number:
  US13/223,249
• Publication Number:
  US 20120058976A1
• Time in Patent Office: 790 Days
• Field of Search: 544/243, 514/274
• US Class Current: 514/274
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/3808 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4021 Esters of aromatic acids (P-C aromatic linkage)
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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.

Claims

1. 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

.

2. The morphic form of claim 1 characterized by an X-ray diffraction pattern substantially similar to that set forth in FIG. 4.

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

4. A pharmaceutical composition comprising a morphic form of claim 1 and a pharmaceutically acceptable carrier.

5. A method for synthesizing the morphic form of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester of claim 1 (Form A), comprising:

(a) contacting cytosine with (S)-trityl glycidyl ether in the presence of a metal carbonate and a first suitable organic solvent to form (S)-N¹-[(2-hydroxy-3-triphenylmethoxy)propyl]cytosine;

(b) contacting (S)-N¹-[(2-hydroxy-3-triphenylmethoxy)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 second suitable organic solvent to form phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)-2-(triphenylmethoxy)ethyl]methyl]mono[3-(hexadecyloxy)propyl]ester;

(c) contacting phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)-2-(triphenylmethoxy)ethyl]methyl]mono[3-(hexadecyloxy)propyl]ester with a protecting-group removal agent in the presence of methanol to form crude phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester; and

(d) recrystallizing the crude phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester in a third suitable organic solvent.

6. The method of claim 5, wherein the first suitable organic solvent is N,N-dimethylformamide.

7. The method of claim 5, wherein the second suitable organic solvent is N,N-dimethylformamide.

8. The method of claim 5, wherein the third suitable organic solvent is methanol.

9. The method of claim 5, wherein the product obtained comprises less than 1.5% of N⁴-alkylated material.

10. The method of claim 5, wherein the magnesium di-tert-butoxide has a purity of greater than 98%.

11. The method of claim 5, wherein the phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl]ester produced has a purity of >

99%.