Asymmetric auxiliary group

• US 9,598,458 B2
• Filed: 07/12/2013
• Issued: 03/21/2017
• Est. Priority Date: 07/13/2012
• Status: Active Grant

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: Wave Life Sciences Japan, Inc.
• Inventors: Shimizu, Mamoru, Wada, Takeshi
• Primary Examiner(s): BERRY, LAYLA D
• Application Number:
  US14/414,604
• Publication Number:
  US 20150197540A1
• Time in Patent Office: 1,348 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: C07B 53/00 Asymmetric syntheses
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07F 7/0812 comprising a heterocyclic ring
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/11 containing cyclic phosphate
• CPC Class Codes: C07H 19/207 the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
• CPC Class Codes: C07H 19/213 containing cyclic phosphate
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds

Abstract

To provide a chiral reagent or a salt thereof. The chiral reagent has following chemical formula (I). In the formula (I), G¹ and G² are independently a hydrogen atom, a nitro group (—NO₂), a halogen atom, a cyano group (—CN), a group of formula (II) or (III), or both G¹ and G² taken together to form a group of formula (IV).

Claims

1. A chiral reagent or a salt thereof, the chiral reagent having following chemical formula (I),

2. The chiral reagent or a salt thereof in accordance with claim 1, wherein the chiral reagent has following chemical formula (I′

);

3. The chiral reagent or a salt thereof in accordance with claim 2, wherein each of G¹ and G² is a group of formula (II).

4. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a group of formula (II), wherein each of G²¹ to G²³ is a hydrogen atom, and G² is a group of formula (II), wherein each of G²¹ and G²² is a hydrogen atom and G²³ is a nitro group or a cyano group.

5. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom, and G² is a group of formula (II), wherein G²¹ to G²³ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C_1-3 alkyl group, and at least one of G²¹, G²², and G²³ is a nitro group or a cyano group.

6. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom, and G² is a group of formula (II), wherein each of G²¹ and G²² is a hydrogen atom and G²³ is a nitro group.

7. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom, and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group, C_6-14 aryl group, C_7-14 aralkyl group, C_1-4 alkyl C_6-14 aryl group, C_1-4 alkoxy C_6-14 aryl group, or C_6-14 aryl C_1-4 alkyl group.

8. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom, and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group, C₆ aryl group, C_7-10 aralkyl group, C_1-4 alkyl C₆ aryl group, C_1-4 alkoxy C₆ aryl group, or C₆ aryl C_1-4 alkyl group.

9. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group, or C₆ aryl group.

10. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group.

11. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ and G³³ are C₆ aryl group and G³² is C_1-4 alkyl group.

12. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ and G² are taken together to form a group of formula (IV), wherein G⁴¹ to G⁴⁶ are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C_1-3 alkyl group.

13. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ and G² are taken together to form a group of formula (IV), wherein each of G⁴¹ to G⁴⁶ is a hydrogen atom.

14. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (V), wherein each of G⁵¹ to G⁵³ are independently a hydrogen atom, a nitro group, a methyl group, or a methoxy group.

15. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (V), wherein each of G⁵¹ and G⁵² is a hydrogen atom and G⁵³ is a 4-methyl group.

16. The chiral reagent or a salt thereof in accordance with claim 2, wherein the chiral reagent is represented by III-a, III-b, V-a, VII-a, VII-b, IX-a, IX-b, XI-a, XIII-a or XIII-b:

(S)-2-(Methyldiphenylsilyl)-1-((S)-pyrrolidin-2-yl)ethanol (III-a)

(R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (III-b)

(S)-2-(Trimethylsilyl)-1-((S)-1-pyrrolidin-2-yl)ethanol (V-a)

(R)-2-(4-Nitrophenyl)-1-((S)-pyrrolidin-2-yl)ethanol (IX-a)

(S)-2-(4-Nitrophenyl)-1-((R)-pyrrolidin-2-yl)ethanol (IX-b)

(S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a)

(R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b).

26. The chiral reagent or a salt thereof in accordance with claim 2, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ and G³³ are phenyl and G³² is methyl.

27. The chiral reagent or a salt thereof in accordance with claim 2, wherein the chiral reagent is:

17. A nucleoside 3′

-phosphoramidite derivative which is represented by formula (Va) or (Vb),

18. The nucleoside 3′

-phosphoramidite derivative in accordance with claim 17, wherein the nucleoside 3′

-phosphoramidite derivative is represented by formula (Va′

) or (Vb′

);

19. The nucleoside 3′

-phosphoramidite derivative in accordance with claim 17, wherein the nucleoside 3′

-phosphoramidite derivative is represented by formula 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, 16b, 17a, 17b, 18a, 18b, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, 23b, or 24a, wherein DMTr represents a 4,4′

-dimethoxytrityl group and TOM represents a triisopropylsiloxymethyl group;

24. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 23, wherein the nucleoside 3′

-phosphoramidite derivative is represented by formula (Va′

) or (Vb′

) in accordance with claim 18;

28. The nucleoside 3′

-phosphoramidite derivative of claim 18, wherein;

G¹ is hydrogen,

G² is a group of formula (III);

29. The nucleoside 3′

-phosphoramidite derivative of claim 28, wherein G⁵ is 4,4′

-dimethoxytrityl.

30. The nucleoside 3′

-phosphoramidite derivative of claim 29, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ and G³³ are C₆ aryl group and G³² is C_1-4 alkyl group.

31. The nucleoside 3′

-phosphoramidite derivative of claim 30, wherein G³¹ and G³³ are phenyl and G³² is methyl.

32. The nucleoside 3′

-phosphoramidite derivative of claim 29, wherein the nucleoside 3′

-phosphoramidite derivative is of structure Va′

.

33. The nucleoside 3′

-phosphoramidite derivative of claim 29, wherein the nucleoside 3′

-phosphoramidite derivative is of structure Vb′

.

20. A method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives comprising steps of:

reacting a molecule comprising an achiral H-phosphonate moiety, and a chiral reagent or a salt thereof, to form a monomer of a nucleoside 3′

-phosphoramidite derivative,

reacting the monomer and a nucleoside to form a condensed intermediate; and

converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety, wherein a chiral X-phosphonate moiety is a modified internucleoside phosphate linkage wherein one of the oxygen atoms of the phosphate is replaced so that the X-phosphonate moiety is chiral at the phosphorus atom,

wherein the chiral reagent has following chemical formula (I),

21. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 20, wherein the wherein the chiral reagent has following chemical formula (I′

);

22. The method for synthesis of a stereocontrolled phosphorus atom-modified oligonucleotide derivative in accordance with claim 20, wherein the chiral reagent is represented by III-a, V-a, VII-a, VII-b, IX-a, IX-b, XI-a, XIII-a or XIII-b:

(S)-2-(Methyldiphenylsilyl)-1-((S)-pyrrolidin-2-yl)ethanol (III-a)

(R)-2-(Methyldiphenylsilyl)-1-((R)-1-pyrrolidin-2-yl)ethanol (III-b)

(S)-2-(Trimethylsilyl)-1-((S)-1-pyrrolidin-2-yl)ethanol (V-a)

(R)-2,2-Diphenyl-1-((S)-pyrrolidin-2-yl)ethanol (VII-a)

(S)-2,2-Diphenyl-1-((R)-pyrrolidin-2-yl)ethanol (VII-b)

(R)-2-(4-Nitrophenyl)-1-((S)-pyrrolidin-2-yl)ethanol (IX-a)

(S)-2-(4-Nitrophenyl)-1-((R)-pyrrolidin-2-yl)ethanol (IX-b)

(R)-(9H-Fluororen-9-yl)((S)-pyrrolidin-2-yl)methanol (XI-a)

(S)-2-Tosyl-1-((S)-1-tritylpyrrolidin-2-yl)ethanol (XIII-a)

(R)-2-Tosyl-1-((R)-1-tritylpyrrolidin-2-yl)ethanol (XIII-b).

34. The method for synthesis of a stereocontrolled phosphorus atom-modified oligonucleotide derivative in accordance with claim 21, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ to G³³ are independently C_1-4 alkyl group, or C₆ aryl group.

35. The method for synthesis of a stereocontrolled phosphorus atom-modified oligonucleotide derivative in accordance with claim 21, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ and G³³ are C₆ aryl group and G³² is C_1-4 alkyl group.

36. The method for synthesis of a stereocontrolled phosphorus atom-modified oligonucleotide derivative in accordance with claim 20, wherein the chiral reagent is

23. A method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives comprising steps of:

reacting a nucleoside 3′

-phosphoramidite derivative which is represented by formula (Va) or (Vb) with an activating reagent and a nucleoside to form a condensed intermediate; and

converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety,

25. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 23, wherein the nucleoside 3′

-phosphoramidite derivative is represented by formula 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, 16b, 17a, 17b, 18a, 18b, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, 23b, or 24a;

37. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 23, wherein:

G¹ is hydrogen,

G² is a group of formula (III);

38. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 37, wherein G⁵ is 4,4′

-dimethoxytrityl.

39. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 38, wherein G¹ is a hydrogen atom and G² is a group of formula (III), wherein G³¹ and G³³ are C₆ aryl group and G³² is C_1-4 alkyl group.

40. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 39, wherein G³¹ and G³³ are phenyl and G³² is methyl.

41. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 38, wherein the nucleoside 3′

-phosphoramidite derivative is of structure Va′

.

42. The method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives in accordance with claim 38, wherein the nucleoside 3′

-phosphoramidite derivative is of structure Vb′

.