US2013035306A1PendingUtilityA1

Process for preparing purine nucleosides

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Assignee: GENZYME CORPPriority: Aug 2, 2001Filed: Jul 6, 2012Published: Feb 7, 2013
Est. expiryAug 2, 2021(expired)· nominal 20-yr term from priority
Inventors:William E. BautaBrian D. BurkeBrian E. SchulmeierWilliam R. Cantrell, Jr.Dennis P. LovettJose Puente
A61P 35/00C07H 19/16A61P 31/12
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Claims

Abstract

The present invention provides for the preparation β-adenine nucleosides by coupling an adenine derivative containing an unprotected exocyclic amino group at the C-6 position and a blocked arabinofuranosyl derivative, in the presence of a base and solvent. The present invention also provides for the stereoselective preparation of 2-deoxy-β-D-adenine nucleosides wherein a blocked 2-deoxy-α-D-arabinofuranosyl halide is coupled with the salt of an adenine derivative. The forgoing aspects of the present invention are utilized in the preparation of a clofarabine composition wherein the ratio of β to α-anomer is at least 99:1.

Claims

exact text as granted — not AI-modified
1 . An anomeric composition comprising 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β D-arabinofuranosyl) adenine and 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl) adenine, wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl) adenine is greater than about 10:1. 
     
     
         2 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl) adenine is greater than about 15:1. 
     
     
         3 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl) adenine is greater than about 20:1. 
     
     
         4 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl) adenine is greater than about 40:1. 
     
     
         5 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl)adenine is greater than about 60:1. 
     
     
         6 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyDadenine is 10.7:1. 
     
     
         7 . The composition of  claim 1  substantially free of 2-chloroadenine. 
     
     
         8 . The composition of  claim 7  having a purity of at least 98.1% by HPLC (a.u.c.). 
     
     
         9 . The composition of  claim 7 , wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl)adenine is 11.9: 1. 
     
     
         10 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl)adenine is 19: 1. 
     
     
         11 . The composition of  claim 10  having a purity of at least 88% by HPLC (a.u.c.). 
     
     
         12 . The composition of  claim 1 , wherein the anomeric ratio of the 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro 0 -α-D-arabinofuranosyl) adenine is 19.4:1. 
     
     
         13 . The composition of  claim 11  having a purity of at least 90% by HPLC (a.u.c.). 
     
     
         14 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine to 2-chloro-9-(3,5-O-dibenzoyl-2-deoxy-2-fluoro-α-Darabinofuranosyl)adenine is between 6.73:1 and 22.1:1. 
     
     
         15 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)adenine to 2-chloro-9-(2′-deoxy-2′-fluoro-α-D-arabinofuranosyl)adenine as measured by high pressure liquid chromatography and spectrophotometric analysis is at least about 99:1. 
     
     
         16 . The composition of  claim 1 , wherein the composition consists essentially of 2-chloro-9-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) adenine having a purity of about 99.14% by HPLC (a.u.c.). 
     
     
         17 . The composition of  claim 16 , wherein the composition is substantially free of 2 chloro-9-(2′-deoxy-2′-fluoro-α-D-arabinofuranosyl)adenine. 
     
     
         18 . The composition of  claim 1 , wherein the anomeric ratio of 2-chloro-9-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl) adenine to 2-chloro-9-(2′-deoxy-2′-fluoro-α-D-arabinofuranosyl)adenine between about 126:1 and about 00:1.

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