Methods of preparing carbanucleosides using amides

Patent metadata

Field	Value
Publication number	US-11697666-B2
Application number	US-202217720704-A
Country	US
Kind code	B2
Filing date	Apr 14, 2022
Priority date	Apr 16, 2021
Publication date	Jul 11, 2023
Grant date	Jul 11, 2023

Abstract

The present disclosure describes methods of preparing carbanucleosides.

First claim

What is claimed is:

1. A method of preparing a compound of Formula (II-a) or Formula (II-b):

comprising:
(a) preparing a first input mixture, wherein the first input mixture comprises an amine protecting agent, a first base, a metalating agent, and a compound of Formula (IV):

to provide a first output mixture; and
(b) preparing a second input mixture comprising the first output mixture and a compound of Formula (V) to provide a second output mixture comprising the compound of Formula (II-a) or Formula (II-b), wherein the compound of Formula (V) has the structure:

wherein
R a is

M a is Li or MgX a;
X a is Cl, Br, or I;
R b is hydrogen or —OH; and
X b is Cl, Br, or I.

2. The method of claim 1 , for preparing the compound of Formula (II-a) or Formula II b):

comprising:
(a) preparing the first input mixture in a first reactor, wherein the first input mixture comprises an amine protecting agent, the first base, the metalating agent, and the compound of Formula (IV):

wherein the first reactor provides the first output mixture; and
(b) adding the first output mixture and the compound of Formula (V) to form the second input mixture in a second reactor, wherein the compound of Formula (V) has the structure:

wherein
R a is

M a is Li or MgX a;
X a is Cl, Br, or I;
R b is hydrogen or —OH;
X b is Cl, Br, or I; and
the second reactor provides the second output mixture comprising the compound of Formula (II-a) or Formula (II-b).

3. The method of claim 2 , wherein the method comprises:
(al) forming a third reaction mixture comprising the compound of Formula (III) having the structure:

the amine having the formula

and iPrMgCl, thereby forming the compound of Formula (V) having the structure:

(a) adding the first input mixture to the first reactor, wherein the first input mixture comprises TMS-Cl, PhMgCl, iPrMgCl, and the compound of Formula (IV) having the structure:

wherein the first reactor provides the first output mixture; and
(b) adding the first output mixture and the compound of Formula (V) to the second reactor thereby forming the compound of Formula (II-a) or Formula (II-b) having the structure:

4. The method of claims 2 , wherein the first reactor and the second are different reactors.

5. The method of claim 2 , wherein the first reactor and the second reactor are the same type of reactor.

6. The method of claim 2 , wherein the first reactor and the second reactor are different types of reactors.

7. The method of claims 2 , wherein the first reactor and the second reactor are a single reactor.

8. The method of claim 7 , wherein the single reactor is a continuous flow reactor, a plug flow reactor, a continuous tubular reactor, or a mixed flow reactor.

9. The method of claim 7 , wherein the first reactor is a first reaction zone in the single reactor and the second reactor is a second reaction zone in the single reactor.

10. The method of claim 1 , wherein the amine protecting agent is trifluoroacetic anhydride, di(tert-butyl) dicarbonate, trimethylsilyl chloride (TMSCl), triethylsilyl chloride (TESCl), triisopropylsilyl chloride, tert-butyldimethylsilyl chloride (TBDMSCl), tert-butyldiphenylsilyl chloride (TBDPSCl), triphenylsilyl chloride, or 1,2-bis (chlorodimethylsilyl)ethane.

11. The method of claim 1 , wherein the first base is R 1 MgX 1 or R 1 Li;
R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and
X 1 is Cl, Br, or I.

12. The method of claim 1 , wherein the metalating agent is R 2 MgX 2 or R 2 Li;
R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and
X 2 is Cl, Br, or I.

13. The method of claim 1 , wherein the amine protecting agent is trimethylsilyl chloride (TMSCl);
the first base is PhMgCl;
the metalating agent is iPrMgCl; and
M a is MgCl.

14. The method of claim 1 , wherein the first input mixture further comprises a first solvent that is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof.

15. The method of claim 1 , wherein the second input mixture further comprises a second solvent that is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof.

16. The method of claim 1 , further comprising combining the second output mixture and an acid.

17. The method of claim 16 , wherein the acid comprises formic acid, acetic acid, citric acid, propanoic acid, butyric acid, or benzoic acid.

18. The method of claim 1 , further comprising preparing the compound of Formula (V), the method comprising:
(al) forming a third reaction mixture comprising a compound of Formula (III):

an amine of the formula H-R a ; and
a third base that is R 3 MgX 3 or R 3 Li; wherein
R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and
X 3 is Cl, Br, or I;
thereby providing the compound of Formula (V).

19. The method of claim 18 , wherein the amine has the formula

and the third base is iPrMgCl.

20. The method of claim 18 , wherein the third reaction mixture further comprises a third solvent that is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, n-heptane, 1,2-dichloroethane, chloroform, or chlorobenzene, or a combination thereof.

21. The method of claim 1 , wherein the yield of the compound of Formula (II-a) or Formula (II-b) is from about 60% to about 90%.

22. The method of claim 1 , wherein the purity of the compound of Formula (II

Assignees

• Gilead Sciences Inc

Inventors

• Johnson Trevor C
• Kraft Matthew
• Young Marshall D

Classifications

• C07H9/06 Primary

  the hetero ring containing nitrogen as ring hetero atoms · CPC title

• C07H7/06

  Heterocyclic radicals · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title