Synthesis of protected 3′-amino nucleoside monomers

Patent metadata

Field	Value
Publication number	US-9365606-B2
Application number	US-201414276381-A
Country	US
Kind code	B2
Filing date	May 13, 2014
Priority date	Jul 2, 2004
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

Orthogonally protected 3′-amino nucleoside monomers and efficient methods for their synthesis are described. The methods employ selective protection of the 3′-amino group in the presence of the unprotected nucleoside base.

First claim

It is claimed:

1. A method of preparing an thymidine monomer having a free 5′-hydroxyl group and a protected 3′-amino group comprising:
(a) selectively reacting a 3′-amino group of a 3′-amino-3′-deoxy thymidine monomer in which the 5′-hydroxyl group and 3′-amino group are unprotected with a first protecting group, wherein the first protecting group is (i) a triarylmethy group or (ii) fluorenylmethoxycarbonyl (Fmoc) or a derivative thereof.

2. The method of claim 1 , wherein said triarylmethyl group is triphenylmethyl (trityl), monomethoxytrityl (MMT) or dimethoxytrityl (DMT).

3. The method of claim 1 , wherein the first protecting group is fluorenylmethoxycarbonyl (Fmoc) or a derivative thereof.

4. The method of claim 3 , wherein the first protecting group is removable with DBU or piperidine.

5. The method of claim 1 , wherein the method further comprises phosphitylation of the 5′-hydroxyl group.

6. The method of claim 2 , wherein said triarylmethyl group is triphenylmethyl (trityl) or monomethoxytrityl (MMT).

7. A method of preparing a thymidine monomer having a phosphitylated 5′-hydroxyl group and a protected 3′-amino group comprising:
(a) selectively reacting a 3′-amino group of a 3′-amino-3′-deoxy thymidine monomer in which the 5′-hydroxyl group and the 3′-amino group are unprotected with a triarylmethyl protecting group; and
(b) phosphitylating the 5′-hydroxyl group.

8. The method of claim 7 , wherein said triarylmethyl protecting group is triphenylmethyl (trityl), monomethoxytrityl (MMT) or dimethoxytrityl (DMT).

9. The method of claim 8 , wherein said triarylmethyl protecting group is triphenylmethyl (trityl) or monomethoxytrityl (MMT).

10. A method of preparing a thymidine monomer having a phosphitylated 5′-hydroxyl group and a protected 3′-amino group comprising:
(a) selectively reacting a 3′-amino group of a 3′-amino-3′-deoxy thymidine monomer in which the 5′-hydroxyl group and the 3′-amino group are unprotected with a fluorenylmethoxycarbonyl (Fmoc) protecting group; and
(b) phosphitylating the 5′-hydroxyl group.

Assignees

• Geron Corp

Inventors

• Gryaznov Sergei M
• Pongracz Krisztina
• Zielinska Daria

Classifications

• C07H19/12

  Triazine radicals · CPC title

• C07H19/16 Primary

  Purine radicals · CPC title

• C07H19/06

  Pyrimidine radicals · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title