Method for producing bicyclic phosphoramidite

A method for producing a compound represented by formula (II):

• wherein Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group, and n represents an integer of 0 to 4, the method comprising:
• (i) a step of solvolyzing the acetal moiety of a compound represented by formula (III):
• wherein Z1, Z2, and n have the same meanings as above, and Y represents a methyl group substituted with 1 to 3 aryl groups, a methyl group substituted with 1 to 3 aryl groups in which each aryl ring is substituted with a lower alkyl, lower alkoxy, halogen, or cyano group, a lower alkoxymethyl group, a tetrahydropyranyl group, or a silyl group, in a lower alkyl alcohol solvent in the presence of an acid catalyst, to deprotect Y;
• (ii) a step of cyclizing the diol moiety of the compound represented by formula (IV) obtained in step (i):
• wherein Z1, Z2, and n have the same meanings as above, and A represents a lower alkyl group;
• and
• (iii) a step of hydrolyzing the anomer position of the compound represented by formula (V) obtained in step (ii):
• wherein Z1, Z2, A and n have the same meanings as above.

A method for producing a compound represented by formula (VI):

• wherein R1 represents a lower alkyl group or a hydrogen atom, R2 represents a hydroxyl group, an amino group, or an amino group protected by an aliphatic acyl group or an aromatic acyl group, P1 represents a trityl group optionally substituted with 1 to 3 lower alkoxy groups, and n represents an integer of 0 to 4, or a salt thereof, the method comprising:
• (i) a step of reacting a compound represented by formula (II):
• wherein Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group, and n represents an integer of 0 to 4, with an activator in a solvent, to convert a hydroxyl group at the 1-position into a group that forms a leaving group;
• and
• (ii) a step of reacting the compound represented by formula (VII) obtained in step (i):
• wherein Z1, Z2, and n have the same meanings as above, X1 represents a group that forms a leaving group, with a compound represented by formula (VIII):
• wherein R1 and R2 have the same meanings as above, or a salt thereof, in a solvent in the presence of a halogenating agent, to stereoselectively obtain a compound represented by formula (IX):
• wherein Z1, Z2, R1, R2, and n have the same meanings as above, or a salt thereof.

A method for producing a compound represented by formula (X):

• wherein R3 represents an aliphatic acyl group or an aromatic acyl group, P1 represents a trityl group optionally substituted with 1 to 3 lower alkoxy groups, and n represents an integer of 0 to 4, or a salt thereof, the method comprising:
• (i) a step of reacting a compound represented by formula (II):
• wherein Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group, and n has the same meaning as above, with an activator in a solvent, to convert a hydroxyl group at the 1-position into a group that forms a leaving group;
• (ii) a step of reacting the compound represented by formula (XI) obtained in step (i):
• wherein Z1, Z2, and n have the same meanings as above, X2 represents a group that forms a leaving group, with a compound represented by formula (XII):
• wherein R3 has the same meaning as above, or a salt thereof, in a solvent in the presence of an acid reagent;
• and
• (iii) a step of performing isomerization, to stereoselectively obtain a compound represented by formula (XIII):
• wherein Z1, Z2, R3, and n have the same meanings as above, or a salt thereof.

A method for producing a compound represented by formula (X):

• wherein P1 represents a trityl group optionally substituted with 1 to 3 lower alkoxy groups, R3 represents an aliphatic acyl group or an aromatic acyl group, and n represents an integer of 1 to 4, or a salt thereof, the method comprising:
• (i) a step of reacting a compound represented by formula (XIV):
• wherein Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group, and n represents an integer of 0 to 4, or a salt thereof, with an aminating agent, to replace the chlorine atom at the 6-position of the purine ring with an amino group;
• and
• (ii) a step of reacting the compound represented by formula (XV) obtained in step (i):
• wherein Z1, Z2, and n have the same meanings as above, or a salt thereof, with a reducing agent in a solvent in the presence of a metal catalyst to replace the chlorine atom at the 2-position of the purine ring with a hydrogen atom and deprotect Z1 and Z2, to obtain a compound represented by formula (XVI):
• wherein n has the same meaning as above, or a salt thereof.

A method for producing a compound represented by formula (XVIII):

• wherein P1 represents a trityl group optionally substituted with 1 to 3 lower alkoxy groups, R4 represents an aliphatic acyl group or an aromatic acyl group, and n represents an integer of 1 to 4, or a salt thereof, the method comprising:
• (i) a step of reacting a compound represented by formula (XIV):
• wherein Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group, and n represents an integer of 0 to 4, or a salt thereof, with benzyl alcohol optionally substituted with a lower alkyl, lower alkoxy, halogen, or cyano group in a solvent in the presence of a base, to replace the chlorine atom at the 6-position of the purine ring with a benzyloxy group optionally substituted with a lower alkyl, lower alkoxy, halogen, or cyano group;
• and
• (ii) a step of cross-coupling the compound represented by formula (XIX) obtained in step (i):
• wherein Z1, Z2, and n have the same meanings as above, and R5 represents a benzyl group optionally substituted with a lower alkyl, lower alkoxy, halogen, or cyano group, or a salt thereof, with an amidating agent in a solvent in the presence of a palladium catalyst and a phosphine ligand, to obtain a compound represented by formula (XX):
• wherein Z1, Z2, R4, R5, and n have the same meanings as above, or a salt thereof.

A method for producing a compound represented by formula (XXII):

• wherein R1 represents a lower alkyl group or a hydrogen atom, R6 represents an aliphatic acyl group or an aromatic acyl group, P1 represents a trityl group optionally substituted with 1 to 3 lower alkoxy groups, and n represents an integer of 0 to 4, or a salt thereof, the method comprising:
• (i) a step of reacting a compound represented by formula (XXIII):
• wherein P1, R1, and n have the same meanings as above, or a salt thereof, with a protection reagent for a hydroxyl group in a solvent, to protect the hydroxyl group at the 3′-position;
• (ii) a step of reacting the compound represented by formula (XXIV) obtained in step (i):
• wherein P1, R1, and n have the same meanings as above, Z3 represents an aliphatic acyl group or an aromatic acyl group, or a salt thereof, with an activator in a solvent in the presence of a base and a catalyst;
• and
• (iii) a step of then performing reaction with an aminating agent, to obtain a compound represented by formula (XXV):
• wherein P1, R1, Z3, and n have the same meanings as above, or a salt thereof.

A production method comprising the steps of:

• reacting a compound represented by formula (XXVII):
• or a salt thereof, with an amidite-forming reagent in a solvent in the presence of an activator and a drying agent,
• wherein P1 represents a trityl group optionally substituted with 1 to 3 lower alkoxy groups, B represents a 2-oxo-pyrimidin-1-yl group optionally having one or more substituents selected from the group α below or a purin-9-yl group, and n represents an integer of 0 to 4, to produce a compound represented by formula (XXVIII):
• or a salt thereof, wherein P1, B, and n have the same meanings as above.
• (group α):
• a hydroxyl group, a protected hydroxyl group, a lower alkoxy group, a mercapto group, a protected mercapto group, a lower alkylthio group, an amino group, a protected amino group, a lower alkylamino group, a lower alkyl group, and a halogen atom;