Process for the synthesis of pyrazolopyrimidines
AssigneeEpoch Biosciences, Inc.
InventorsRobert O. Dempcy, A. David Adams, Michael W. Reed
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Abstract
The present invention provides a nucleoside comprising a pyrazolopyrimidine base and a process for producing the same. In particular, the processes of the present invention comprises using a halogenated pyrazolopyrimidine base and removing the halogen after the base is coupled to a sugar moiety. The presence of the halogen on the nucleoside base allows facile and economical production of a large quantity of nucleosides.
Claims43
A PPG phosphoramidite comprising a photolabile hydroxy protecting group, wherein said phosphoramidite nucleoside is of the formula:
- 30
- wherein
- R1 is selected from the group consisting of hydrogen and alkyl;
- R2 is selected from the group consisting of hydrogen, alkyl, and an amine protecting group, or R1 and R2 together form an amine protecting group;
- each of Z1, Z2, Z4, and Z6 is independently selected from the group consisting of hydrogen, halide, alkyl, —OR11, wherein each R11 is independently selected from the group consisting of hydrogen, alkyl, and a hydroxy protecting group or two R11 groups form a diol protecting group, or Z2 and Z4 together with the carbon atoms to which they are attached and C-3 carbon atom of the carbohydrate ring form a five-to seven membered ring;
- and
- one of Z3 or Z5 is —OR12 and the other is —OR13, where R12 is a photolabile hydroxy protecting group and R13 is a phosphoramidite.
A process for producing a non-halogenated nucleoside base containing nucleoside comprising:
- (a) contacting a halogenated nucleoside base with an activated sugar under conditions sufficient to produce a halogenated nucleoside base containing nucleoside;
- and
- (b) reducing said halogenated nucleoside base containing nucleoside under conditions sufficient to produce said non-halogenated nucleoside base containing nucleoside.
A process for producing a nucleoside comprising a hydropyrazolopyrimidine nucleoside base, said process comprising hydrolyzing and reducing or reducing and hydrolyzing an iodopyrazolopyrimidine nucleoside of the formula:
- 32
- under conditions sufficient to produce a hydropyrazolopyrimidine nucleoside of the formula:
- 33
- wherein
- R1 is selected from the group consisting of hydrogen and alkyl;
- R2 is selected from the group consisting of hydrogen, alkyl, and an amine protecting group, or R1 and R2 together form an amine protecting group;
- R3 is selected from the group consisting of alkyl, and a hydroxy protecting group;
- and
- each of Y1, Y2, Y3, Y4, Y5, and Y6 is independently selected from the group consisting of hydrogen, halide, alkyl, —OR4, wherein each R4is independently selected from the group consisting of hydrogen, alkyl, and a hydroxy protecting group or two R4 groups form a diol protecting group, or Y2 and Y4 together with the carbon atoms to which they are attached to and C-3 carbon atom of the carbohydrate ring form a five-to seven membered ring.
A process for producing a nucleoside comprising:
- (a) contacting an iodopyrazolopyrimidine of the formula:
- 46
- with an activated sugar of the formula:
- 47
- under conditions sufficient to produce an deoxy iodopyrazolopyrimidine nucleoside of the formula:
- 48
- (b) producing an amino dihydro hydropyrazolopyrimidine nucleoside from said deoxy iodopyrazolopyrimidine nucleoside, wherein said amino dihydro hydropyrazolopyrimidine nucleoside is of the formula:
- 49
- wherein
- R3 is alkyl;
- R5 and R6 are hydroxy protecting groups;
- and
- X1 is a leaving group.
Dependencies are inferred from the claim text.