Synthesis of 6-azido-6-deoxy-2-n-acetyl-hexosamine-nucleoside diphosphate

Patent metadata

Field	Value
Publication number	US-12281135-B2
Application number	US-202217582707-A
Country	US
Kind code	B2
Filing date	Jan 24, 2022
Priority date	Jul 25, 2019
Publication date	Apr 22, 2025
Grant date	Apr 22, 2025

Abstract

The current invention concerns methods for the synthesis of 6-azido-6-deoxy-2-N-acetyl-monosaccharide-nucleoside diphosphate, in particular 6-azido-6-deoxy-2-N-acetyl-D-galactosamine-nucleoside diphosphate or 6-azido-6-deoxy-2-N-acetyl-D-glucosamine-nucleoside diphosphate. The synthesis method according to the invention is characterized by being highly efficient and high yielding. Also part of the present invention are key intermediates of this process.

First claim

The invention claimed is:

1. A method for preparing a 6-azido-6-deoxy-1-monophosphate monosaccharide compound having structure (Va) or (Vb) according to the scheme:

comprising:
(x1) deprotecting the anomeric position of a compound having structure (VI) to form 1-hydroxy-monosaccharide compound having structure (XI);
(x2) converting the 1-hydroxy-monosaccharide compound having structure (XI) into a 6-azido-6-deoxy-1-monophosphite diester having structure (XII);
(x3) oxidizing the monophosphite diester having structure (XII) in the presence of an oxidizing agent, to form a 1-monophosphate diester compound having structure (XIII);
(x4) deprotecting the phosphate diester having structure (XIII) to form the 1-monophosphate monosaccharide compound having structure (Va), or
concomitantly deprotecting the phosphate diester and monosaccharide having structure (XIII) to form a 1-monophosphate monosaccharide compound having structure (Vb),

wherein R 1 and R 2 are independently selected from optionally substituted C(O)-alkyl, optionally substituted C(O)-aryl and optionally substituted C(O)-arylalkyl, and R 3 is selected from C 1-6 alkyl, allyl, 2-cyanoethyl, 2-alkylsulfonylethyl, 2-arylsulfonylethyl, 2,2,2-trichloroethyl, CH 2 OC(O) alkyl, fluorenylmethyl, 2-pyridylethyl, and phenyl-C 1-2 -alkyl, wherein the phenyl group of phenyl-C1-2-alkyl or the phenyl group of 2-arylsulfonylethyl, when 2-arylsulfonylethyl is 2-phenylsulfonylethyl, is optionally substituted with one or more halides or a nitro or methoxy group.

2. The method according to claim 1 , wherein the method is for preparing the monosaccharide compound having structure (Vb) and step (x4) involves concomitantly deprotecting the phosphate diester and monosaccharide having structure (XIII) to form the 1-monophosphate monosaccharide compound having structure (Vb).

3. The method according to claim 1 , wherein the method is for preparing the monosaccharide compound having structure (Va) and step (x4) involves deprotecting the phosphate diester having structure (XIII) to form the 1-monophosphate monosaccharide compound having structure (Va).

4. The method according to claim 1 , wherein the 6-azido-6-deoxy monosaccharide having structure (VI) is prepared from a 6-azido-6-deoxy monosaccharide compound having structure (I):

wherein R 1 is independently selected from optionally substituted C(O)-alkyl, optionally substituted C(O)-aryl and optionally substituted C(O)-arylalkyl.

5. The method according to claim 4 , wherein the 6-azido-6-deoxy monosaccharide having structure (VI) is prepared by:
(e) protecting the 6-azido-6-deoxy monosaccharide having structure (I) to form 6-azido-6-deoxy monosaccharide compound having structure (VI).

6. The method according to claim 4 , wherein the 6-azido-6-deoxy monosaccharide compound having structure (I) is prepared according to the scheme:

comprising:
(b) reacting a diol having structure (II) with a sulfitylating agent to form a cyclic sulfite having structure (IIIa);
(c) reacting the cyclic sulfite having structure (IIIa) with an oxidizing agent to form a cyclic sulfate having structure (IIIb);
(d) reacting the cyclic sulfate having structure (IIIb) with an inorganic azide to form the 6-azido-6-deoxy monosaccharide having structure (I),

wherein R 1 is independently selected from C(O)-alkyl, C(O)-aryl and C(O)-arylalkyl.

7. The method according to claim 1 , wherein the 6-azido-6-deoxy-1-monophosphate monosaccharide is 6-azido-6-deoxy-1-monophosphate N-acetyl-D-glucosamine.

8. The method according to claim 1 , wherein the 6-azido-6-deoxy-1-monophosphate monosaccharide is 6-azido-6-deoxy-1-monophosphate N-acetyl-D-galactosamine.

9. The method according to claim 1 , wherein the 6-azido-6-deoxy-1-monophosphate monosaccharide compound having structure (Va) or (Vb) is further converted into a nucleoside diphosphate having structure (IX), or a salt thereof:

wherein B is a nucleobase.

10. The method according to claim 9 , wherein 1-monophosphate monosaccharide compound having structure (Va) is converted into nucleoside diphosphate having structure (IX), or salt thereof, according to the scheme:

comprising:
(i) reacting the compound having structure (Va) with a nucleoside monophosphate to provide an acylated nucleoside diphosphate having structure (VIII); and
(j) deprotecting the acylated nucleoside diphosphate having structure (VIII) to obtain nucleoside diphosphate having structure (IX) or salt thereof,

wherein R 4 are both hydrogen or both occurrences of R 4 are joined together via a carbonyl moiety,
or according to the scheme:

comprising:
(j1) deprotecting the compound having structure (Va) to obtain a 1-monophosphate monosaccharide compound having structure (Vb),
(i1) reacting the compound having structure (Vb) with a nucleoside monophosphate to provide a nucleoside diphosphate having structure (IX).

11. The method according to claim 10 , wherein step (j1) is part of step (x4) that affords the compound having structure (Vb) in one step from the phosphate diester having structure (XIII).

12. The method according to claim 1 , wherein each occurrence of R 1 and R 2 is C(O) Me, C(O) tBu, C(O) Ph, or C(O) CH 2 Ph.

13. The method according to claim 1 , which is for preparing a nucleoside diphosphate having structure (IX) or salt thereof according to the scheme:

wherein:
R 1 is independently selected from optionally substituted C(O)-alkyl, optionally substituted C(O)-aryl and optionally substituted C(O)-arylalkyl;
R 2 is selected from optionally substituted C(O)-alkyl, optionally substituted C(O)-aryl and optionally substituted C(O)-arylalkyl;
R 3 is selected from C 1-6 alkyl, allyl, 2-cyanoethyl, 2-alkylsulfonylethyl, 2-arylsulfonylethyl, 2,2,2-trichloroethyl, CH 2 OC(O) alkyl, fluorenylmethyl, 2-pyridylethyl, and phenyl-C 1-2 -alkyl, wherein the phenyl group of phenyl-C 1-2 -alkyl or the phenyl group of 2-arylsulfonylethyl, when 2-arylsulfonylethyl is 2-phenylsulfonylethyl, is optionally substituted with one or more halides or a nitro or methoxy group;
R 4 are both hydrogen or both occurrences of R 4 are joined together via a carbonyl moiety;
B is a nucleobase,

wherein the process comprises:
(a) converting N-acetylglucosamine or N-acetylgalactosamine into a 1,3-di-acylated compound having structure (II);
(b) reacting the diol having structure (II) with a sulfitylating agent to form a cyclic sulfite having structure (IIIa);
(c) reacting the cyclic sulfite having structure (IIIa) with an oxidizing agent to form a cyclic sulfate having structure (IIIb);
(d) reacting the cyclic sulfate having structure (IIIb) with an inorganic azide to form a 6-azido-6-deoxy monosaccharide having structure (I);
(e) protecting the 6-azido-6-deoxy monosaccharide having structure (I) to form 6-azido-6-deoxy monosaccharide compound having structure (VI);
(x

Assignees

• Synaffix Bv

Inventors

• Hoogenboom Jorin
• Wijdeven Maria Antonia
• Verkade Jorge Merijn Mathieu
• Van Delft Floris Louis
• Van Berkel Sander Sebastiaan

Classifications

• C07H15/12

  attached to a nitrogen atom of the saccharide radical · CPC title

• C07H1/04 Primary

  Introducing polyphosphoric acid radicals · CPC title

• C07H1/02

  Phosphorylation · CPC title

• C07H19/10 Primary

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

• C07H13/04

  having the esterifying carboxyl radicals attached to acyclic carbon atoms · CPC title