Methods of synthesizing substituted purine compounds

Patent metadata

Field	Value
Publication number	US-9701707-B2
Application number	US-201514929736-A
Country	US
Kind code	B2
Filing date	Nov 2, 2015
Priority date	Mar 15, 2013
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

The present invention provides an efficient process for the synthesis of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol and hydrates thereof and methods for treating disorders in which DOT1-mediated protein methylation plays a part, such as cancer and neurological disorders, by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also provides novel crystalline forms of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol and hydrates thereof (Form A, Form B, and Form C), characterized by a unique X-ray diffraction pattern and Differential Scanning Calorimetry profile, as well as a unique crystalline structure.

First claim

What is claimed is:

1. A method for preparing high purity (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol by recrystallization, comprising:
dissolving a mixture of cis and trans isomers of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol in a first solution comprising acetonitrile and water to form a second solution;
seeding the second solution with a seed crystal of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol to generate a slurry of precipitate;
collecting the precipitate by filtration to yield the high purity (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol, wherein the high purity (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol contains less than 2% of the trans isomer.

2. The method of claim 1 , wherein the seed crystal has an area percentage purity by HPLC of greater than 99.5%.

3. The method of claim 1 , wherein the first solution has a ratio of acetonitrile to water of about 3:1.

4. The method of claim 1 , wherein the second solution is maintained at about 30° C. prior to seeding the second solution with the seed crystal.

5. The method of claim 1 , wherein the slurry is heated and cooled.

6. The method of claim 5 , wherein the slurry is heated to about 75° C.

7. The method of claim 6 , wherein the slurry is maintained at about 75° C. for about 1 to 2 hours.

8. The method of claim 5 , wherein the slurry is cooled to about 30° C.

9. The method of claim 8 , wherein the slurry is cooled slowly to about 30° C.

10. The method of claim 8 , wherein the cooled slurry is maintained at about 30° C. for about 12 to 16 hours.

11. The method of claim 1 , wherein the method comprises a first recrystallization and a second recrystallization.

12. The method of claim 1 , wherein the high purity (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol has a purity of greater than 99%.

13. The method of claim 1 , wherein the high purity (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol contains less than 1% of the trans isomer.

14. The method of claim 1 , wherein the precipitate is washed with a third solution comprising an organic solvent and water.

15. The method of claim 14 , wherein the organic solvent in the third solution is acetonitrile.

Assignees

• Epizyme Inc

Inventors

• Olhava Edward J

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

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

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title