Methods and intermediates for preparing pharmaceutical agents

Patent metadata

Field	Value
Publication number	US-9428473-B2
Application number	US-201514799090-A
Country	US
Kind code	B2
Filing date	Jul 14, 2015
Priority date	Apr 3, 2009
Publication date	Aug 30, 2016
Grant date	Aug 30, 2016

Abstract

The invention provides methods and intermediates that are useful for preparing a compound of formula I:

and salts thereof.

First claim

What is claimed is:

1. A method for preparing a salt of a compound of formula XIV:

comprising treating a compound of Formula XIV with an acid in an organic solvent;
wherein the acid is an organic acid selected from the group consisting of oxalic acid, citric acid, and fumaric acid.

2. The method of claim 1 , wherein the acid is oxalic acid.

3. The method of claim 1 , wherein the organic solvent is selected from the group consisting of tert-butyl methyl ether, methylene chloride, tetrahydrofuran, acetone, acetonitrile, toluene, heptanes, isopropyl acetate, ethyl acetate, and an alcohol, and mixtures thereof.

4. The method of claim 1 , wherein the organic solvent is acetone.

5. The method of claim 1 , further comprising obtaining the compound of formula XIV by treating a compound of formula XIII:

or a salt thereof with morpholine to provide the compound of formula XIV.

6. The method of claim 5 , further comprising obtaining the compound of formula XIII by treating a compound of formula XII:

or a salt thereof with a suitable iodide source to provide the compound of formula XIII or a salt thereof.

7. The method of claim 1 , further comprising hydrolyzing the salt of the compound of formula XIV to provide a compound of formula Xa:

or a salt thereof.

8. The method of claim 7 , wherein the compound of formula Xa is a salt and is of formula X:

wherein M + is K + .

9. A method for preparing a salt of a compound of formula XIV:

comprising
a) treating a compound of formula XII:

or a salt thereof with a suitable iodide source to provide a compound of formula XIII:

 or a salt thereof;
b) treating the compound of formula XIII or a salt thereof with morpholine to provide a compound of formula XIV:

 and
(c) treating a compound of formula XIV with an acid in an organic solvent;
wherein the acid is an organic acid selected from the group consisting of oxalic acid, citric acid, and fumaric acid.

10. The method of claim 9 , wherein the compound of formula XIII is used in step b) without purification from step a).

11. The method of claim 9 , wherein the acid is oxalic acid.

12. The method of claim 9 , wherein the organic solvent is selected from the group consisting of tert-butyl methyl ether, methylene chloride, tetrahydrofuran, acetone, acetonitrile, toluene, heptanes, isopropyl acetate, ethyl acetate, and an alcohol, and mixtures thereof.

13. The method of claim 9 , wherein the organic solvent is acetone.

14. The method of claim 9 , further comprising hydrolyzing the salt of the compound of formula XIV to provide a compound of formula Xa:

or a salt thereof.

15. The method of claim 14 , wherein the compound of formula Xa: is a salt and is of the formula X:

wherein M + is K + .

16. An oxalate salt of a compound of formula XIV:

Assignees

• Gilead Sciences Inc

Inventors

• Polniaszek Richard
• Pfeiffer Steven
• Yu Richard
• Cullen Aaron
• Dowdy Eric
• Tran Duong
• Kent Kenneth
• Zhou Zhongxin
• Cordeau Douglas
• Easton-Scott Leah

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07C209/62

  by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds (C07C209/24 takes precedence) · CPC title

• C07D277/28 Primary

  Radicals substituted by nitrogen atoms · CPC title