METHODS FOR THE SYNTHESIS OF FUNCTIONALIZED NUCLEIC ACIDS

• US 20170029457A1
• Filed: 07/28/2016
• Published: 02/02/2017
• Est. Priority Date: 07/19/2011
• Status: Abandoned Application

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: WAVE Life Sciences Ltd.
• Inventors: Verdine, Gregory L., Meena, Iwamoto, Naoki, Butler, David Charles Donnell
• Application Number:
  US15/222,910
• Publication Number:
  US 20170029457A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: C07C 309/66 Methanesulfonates
• CPC Class Codes: C07D 295/108 to an acyclic saturated chain
• CPC Class Codes: C07H 13/04 having the esterifying carboxyl radicals attached to acyclic carbon atoms
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical

Abstract

Described herein are methods for the synthesis of derivatives of thiosulfonate reagents. Said reagents have utility for the synthesis of phosphorothiotriesters from H-phosphonates in a stereospecific fashion.

Claims

1. A process for the preparation of phosphorothiotriesters of structure IIIa comprising the steps of:

i) reacting an H-phosphonate of structure Ia with an silylating reagent to provide a silyloxyphosphonate; and

ii) reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIa to provide a phosphorothiotriester of structure IIIa;

wherein,

the H-phosphonate of structure Ia has the following structure;

3. The process of claim 1, wherein W is O.

4. The process of claim 1, wherein R¹ is selected from:

5. The process of claim 1, wherein the silylating reagent is selected from

1,1,3,3-tetramethyl-1,3-diphenyldisilazane;

1,3-dimethyl-1,1,3,3-tetraphenyldisilazane;

1-(trimethylsilyl)imidazole;

N-trimethylsilyl-N-methyl trifluoroacetamide;

bis(dimethylamino)dimethylsilane;

bromotrimethylsilane;

chlorodimethyl(pentafluorophenyl)silane;

chlorotriethyl silane;

chlorotriisopropylsilane;

chlorotrimethylsilane;

dichlorodimethylsilane;

hexamethyldisilazane;

N,N′

-bis(trimethylsilyl)urea;

N,N-bis(trimethylsilyl)methylamine;

N,N-dimethyltrimethylsilylamine;

N,O-bis(trimethylsilyl)acetamide;

N,O-bis(trimethylsilyl)carbamate;

N,O-bis(trimethylsilyl)trifluoroacetamide;

N-methyl-N-(trimethylsilyl)trifluoroacetamide;

N-methyl-N-trimethylsilylacetamide;

N-methyl-N-trimethylsilylheptafluorobutyramide;

N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide;

N-methyl-N-trimethylsilylheptafluorobutyramide;

trimethylsilyltriflate;

triethylsilyltriflate;

triisopropylsilyltriflate;

or

tert-butyldimethylsilyltriflate.

6. The process of claim 5, wherein the silylating reagent is selected from N,O-bis(trimethylsilyl)trifluoroacetamide, trimethylsilyltriflate, chlorotrimethylsilane, or 1-(trimethyl silyl)imidazole.

7. The process of claim 6, wherein the silylating reagent is selected from N,O-bis(trimethylsilyl)trifluoroacetamide.

8. The process of claim 1, wherein the H-phosphonate is covalently linked to a solid phase.

10. The process of claim 8, wherein the phosphorothiotriesters of structure IIIb comprise non-stereorandom phosphorous linkages and the H-phosphonate of structure Ic comprise non-stereorandom phosphorous linkages;

and W is independently selected from O, NH, or CH₂.

2. A process for the preparation of phosphorothiotriesters comprising non-stereorandom phosphorous linkages of structure IIIb comprising the steps of:

i) reacting a H-phosphonate comprising non-stereorandom phosphorous linkages of structure Ib with an silylating reagent to provide a silyloxyphosphonate; and

ii) reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIb to provide a phosphorothiotriester comprising non-stereorandom phosphorous linkages of structure IIIb;

wherein,

the H-phosphonate comprising non-stereorandom phosphorous linkages of structure Ib has the following structure;

9. A process for the preparation of phosphorothiotriesters of structure IIIc comprising the steps of:

i) reacting a H-phosphonate of structure Ic with an silylating reagent to provide a silyloxyphosphonate;

ii) reacting the silyloxyphosphonate with a bis(thiosulfonate) reagent of structure IVc to provide a phosphorothiotriester comprising a thiosulfonate group of structure Vc;

iii) reacting the phosphorothiotriester comprising a thiosulfonate group of structure Vc with a nucleophile of structure VIc to provide the phosphorothiotriesters of structure IIIc;

wherein,

the H-phosphonate of structure Ic has the following structure;

11. The process of claim 9, wherein W is O.

12. The process of claim 9, wherein R⁶ is methyl.

13. The process of claim 9, wherein bis(thiosulfonate) reagent of structure IVc is selected from:

14. The process of claim 9, wherein the nucleophile of structure VIc has the following structure:

15. The process of claim 9, wherein the silylating reagent is selected from

1,1,3,3-tetramethyl-1,3-diphenyldisilazane;

1,3-dimethyl-1,1,3,3-tetraphenyldisilazane;

1-(trimethylsilyl)imidazole;

N-trimethylsilyl-N-methyl trifluoroacetamide;

bis(dimethylamino)dimethylsilane;

bromotrimethylsilane;

chlorodimethyl(pentafluorophenyl)silane;

chlorotriethyl silane;

chlorotriisopropylsilane;

chlorotrimethylsilane;

dichlorodimethylsilane;

hexamethyldisilazane;

N,N′

-bis(trimethylsilyl)urea;

N,N-bis(trimethylsilyl)methylamine;

N,N-dimethyltrimethylsilylamine;

N,O-bis(trimethylsilyl)acetamide;

N,O-bis(trimethylsilyl)carbamate;

N,O-bis(trimethylsilyl)trifluoroacetamide;

N-methyl-N-(trimethylsilyl)trifluoroacetamide;

N-methyl-N-trimethylsilylacetamide;

N-methyl-N-trimethylsilylheptafluorobutyramide;

N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide;

N-methyl-N-trimethylsilylheptafluorobutyramide;

trimethylsilyltriflate;

triethylsilyltriflate;

triisopropylsilyltriflate;

or

tert-butyldimethylsilyltriflate.

16. The process of claim 15, wherein the silylating reagent is selected from N,O-bis(trimethylsilyl)trifluoroacetamide, trimethylsilyltriflate, chlorotrimethylsilane, or 1-(trimethyl silyl)imidazole.

17. The process of claim 16, wherein the silylating reagent is selected from N,O-bis(trimethylsilyl)trifluoroacetamide.

18. The process of claim 17, wherein the H-phosphonate is covalently linked to a solid phase.