Process for the synthesis of 2',3'-dideoxynucleosides

• US 5,220,003 A
• Filed: 03/29/1991
• Issued: 06/15/1993
• Est. Priority Date: 03/29/1991
• Status: Expired due to Term

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Gardiner, John M., Jung, Michael E.
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): CRANE, LAWRENCE E
• Application Number:
  US07/677,500
• Time in Patent Office: 809 Days
• Field of Search: 536/23, 536/24, 536/26
• US Class Current: 536/27.11
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

Methods are provided for preparing 3'"'"'-substituted-2'"'"',3'"'"'-dideoxynucleosides, and the like, from non-carbohydrate, non-nucleoside starting materials.

Claims

1. A process for making a 2'"'"',3'"'"'-dideoxynucleoside of the formula (I) ##STR29## wherein X is H and B is a purine or pyrimidine base, comprising the steps of

(a) converting a diol having the formula (II) ##STR30## wherein X is H, to a dideoxyribofuranoside having the formula (III) ##STR31## wherein X is H;

and (b) coupling a purine or pyrimidine base to the dideoxyribofuranoside of formula III to obtain the 2'"'"',3'"'"'-dideoxynucleoside of formula I defined above.

2. A process as recited in claim 1, wherein the diol of formula II is converted to the dideoxyribofuranoside of formula III by treating the diol with dilute acid.

3. A process as recited in claim 1, wherein the step of coupling the purine or pyrimidine base to the dideoxyribofuranoside comprises substeps of (i) forming a hydroxy-protected dideoxyribofuranoside having the formula (IV) ##STR32## wherein X is H and R is a hydroxy-protecting group, (ii) reacting the hydroxy-protected dideoxyribofuranoside of formula IV with a silylated purine or pyrimidine base in the presence of a trialkylsilyl triflate, and (iii) removing the hydroxy-protecting group to obtain the 2'"'"',3'"'"'-dideoxynucleoside of formula I defined above.

4. A process as recited in claim 1, further comprising the step of separating the 2'"'"',3'"'"'-dideoxynucleoside of formula I into α

and β

anomers having the formulas Ia and Ib, respectively, ##STR33## ##STR34## wherein X and B are as defined above.

5. A process as recited in claim 1, wherein X is H, and the diol of formula II is prepared by reacting an epoxy alcohol having the formula (V) ##STR35## with diisobutylaluminum hydride.

6. A process as recited in claim 1, wherein B is thymine.

7. A process as recited in claim 1, wherein B is cytosine.

8. A process for making a 2'"'"',3'"'"'-dideoxynucleoside of the formula (I) ##STR36## wherein B is a purine or pyrimidine base, comprising the steps of:

(a) reacting (1,3-butadien-1-yl)oxytrimethylsilane with trimethyl orthoformate to form 5,5-dimethoxypent-2-enal;

(b) reducing 5,5,-dimethoxypent-2-enal with diisobutylaluminum hydride to form 5,5-dimethoxypent-2-en-1-ol;

(c) forming (2R,3R) 3-(2,2-dimethoxyethyl)oxiranemethanol by Sharpless epoxidation of 5,5-dimethoxypent-2-en-1-ol;

(d) reacting (2R,3R) 3-(2,2-dimethoxyethyl)oxiranemethanol with diisobutylaluminum hydride to form 5,5-dimethoxypentane-1,2-diol;

(e) treating 5,5-dimethoxypentane-1,2-diol with dilute acid to form a 2,3-dideoxyribofuranoside having the formula II; and

##STR37## (f) coupling a purine or pyrimidine base to the dideoxyribofuranoside of formula II to obtain the 2'"'"',3'"'"'-dideoxynucleoside of formula I defined above.