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US 2007/0179290 A1Published application
Production method of fluorinated purine nucleoside derivative, intermediate therefor and production method thereof
AssigneeAjinomoto Co., Inc.
InventorsTakayoshi Torii, Tomoyuki Onishi, Kunisuke Izawa
Life of this patent
Estimating the term…
Abstract
Purine nucleosides which are fluorinated at the 3′-position (preferably the α-position), may be economically and efficiently produced by fluorinating a novel purine nucleoside derivative (1) in which the hydroxyl group at the 5′-position is protected to obtain a novel purine nucleoside derivative (2) in a high yield. The derivative (2) is subjected to desulfurization, deprotection of R1 and, as necessary protection, deprotection, or modification of nucleic acid base moiety, to obtain the desired purine nucleoside (3). wherein each symbol is as defined in the specification.
Claims34
A method of producing a fluorinated purine nucleoside represented by formula (2):
- wherein R1 is a hydroxyl-protecting group;
- X1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group, which comprises reacting a purine nucleoside represented by formula (1):
- wherein R1, X1, and Y1 are as defined above, with a fluorinating agent.
1 more element
A method of producing a fluorinated purine nucleoside represented by formula (3):
- wherein X2 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y2 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group, which comprises subjecting a fluorinated purine nucleoside represented by formula (2):
- wherein R1 is a hydroxyl-protecting group;
- X1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group, to, in any order:
- (A) desulfurizing to remove sulfur atom,
- (B) deprotecting to eliminate R1, and
- (C) when X1 and X2 are different groups, and/or Y1 and Y2 are different groups, converting X1 to X2 and/or Y1 to Y2.
5 more elements
A method of producing a fluorinated purine nucleoside represented by formula (3):
- wherein X2 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y2 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group, which comprises reacting a purine nucleoside represented by formula (1):
- wherein R1 is a hydroxyl-protecting group;
- X1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group, with a fluorinating agent to obtain a fluorinated purine nucleoside represented by formula (2):
- wherein R1, X1, and Y1 are as defined above, and then subjecting the fluorinated purine nucleoside to, in any order:
- (A) desulfurizing to remove sulfur atom,
- (B) deprotecting to eliminate R1, and
- (C) when X1 and X2 are different groups, and/or Y1 and Y2 are different groups, converting X1 to X2 and/or Y1 to Y2.
6 more elements
A method of producing a purine nucleoside represented by formula (1):
- wherein R1 is a hydroxyl-protecting group;
- X1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group, which comprises subjecting a purine nucleoside represented by formula (A):
- wherein X3 is a hydrogen atom, an amino group, or a hydroxyl group;
- and Y3 is a hydrogen atom, an amino group, or a hydroxyl group, to, in any order:
- (D) introducing R1 into the 5′-position hydroxyl group to protect the hydroxyl group, and
- (E) when X3 and X1 are different groups, and/or when Y3 and Y1 are different groups, converting X3 to X1 and/or Y3 to Y1.
4 more elements
A method of producing a fluorinated purine nucleoside represented by formula (3):
- wherein X2 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y2 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group, which comprises subjecting a purine nucleoside represented by formula (A):
- wherein X3 is a hydrogen atom, an amino group, or a hydroxyl group;
- and Y3 is a hydrogen atom, an amino group, or a hydroxyl group, to, in any order:
- (D) introducing R1 into the 5′-position hydroxyl group to protect the hydroxyl group, and
- (E) when X3 and X1 are different groups, and/or when Y3 and Y1 are different groups, converting X3 to X1 and/or Y3 to Y1, to obtain a purine nucleoside represented by formula (1):
- wherein R1 is a hydroxyl-protecting group;
- X1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group, reacting the purine nucleoside with a fluorinating agent to obtain a fluorinated purine nucleoside represented by formula (2):
- wherein R1, X1, and Y1 are as defined above, and then subjecting the fluorinated purine nucleoside to, in any order:
- (A) desulfurizing to remove sulfur atom,
- (B) deprotecting to eliminate R1, and
- (C) when X1 and X2 are different groups, and/or Y1 and Y2 are different groups, converting X1 to X2 and/or Y1 to Y2.
10 more elements
A method of producing a fluorinated purine nucleoside represented by formula (5):
- wherein R1 is a hydroxyl-protecting group;
- and R2 and R2′ are each independently a hydrogen atom or an amino-protecting group, or R2 and R2′ in combination optionally form an amino-protecting group, which comprises reacting a purine nucleoside represented by formula (4):
- wherein R1, R2, and R2′ are as defined above, with a fluorinating agent.
A method of producing a fluorinated purine nucleoside represented by formula (6):
- which comprises subjecting a fluorinated purine nucleoside represented by formula (5):
- wherein R1 is a hydroxyl-protecting group;
- and R2 and R2′ are each independently a hydrogen atom or an amino-protecting group, or R2 and R2 in combination optionally form an amino-protecting group, to, in any order:
- (A) desulfurizing to remove sulfur atom,
- (B) deprotecting to eliminate R1, and
- (C′) when R2 and/or R2′ are/is amino-protecting group(s), deprotecting to eliminate the protecting group.
3 more elements
A method of producing a fluorinated purine nucleoside represented by formula (6):
- which comprises reacting a purine nucleoside represented by formula (4):
- wherein R1 is a hydroxyl-protecting group;
- and R2 and R2′ are each independently a hydrogen atom or an amino-protecting group, or R2 and R2′ in combination optionally form an amino-protecting group, with a fluorinating agent to obtain a fluorinated purine nucleoside represented by formula (5):
- wherein R1, R2, and R2′ are as defined above, and subjecting the fluorinated purine nucleoside to, in any order:
- (A) desulfurizing to remove sulfur atom,
- (B) deprotecting to eliminate R1, and
- (C′) when R2 and/or R2′ are/is amino-protecting group(s), deprotecting to eliminate the protecting group.
4 more elements
A method of producing a purine nucleoside represented by formula (4):
- wherein R1 is a hydroxyl-protecting group;
- and R2 and R2′ are each independently a hydrogen atom or an amino-protecting group, or R2 and R2′ in combination optionally form an amino-protecting group, which comprises subjecting a purine nucleoside represented by formula (B):
- to, in any order:
- (D) introducing R1 into the 5′-position hydroxyl group to protect the hydroxyl group, and
- (E′) when R2 and/or R2′ are/is amino-protecting group(s), introducing the protecting group.
2 more elements
A method of producing a fluorinated purine nucleoside represented by formula (6):
- which comprises subjecting a purine nucleoside represented by formula (B):
- to, in any order:
- (D) introducing R1 into the 5′-position hydroxyl group to protect the hydroxyl group, and
- (E′) when R2 and/or R2′ are/is amino-protecting group(s), introducing the protecting group, to obtain a purine nucleoside represented by formula (4):
- wherein R1 is a hydroxyl-protecting group;
- and R2 and R2′ are each independently a hydrogen atom or an amino-protecting group, or R2 and R2′ in combination optionally form an amino-protecting group, reacting the purine nucleoside with a fluorinating agent to obtain a fluorinated purine nucleoside represented by formula (5):
- wherein R1, R2, and R2′ are as defined above, and then subjecting the fluorinated purine nucleoside to, in any order:
- (A) desulfurizing to remove sulfur atom,
- (B) deprotecting to eliminate R1, and
- (C′) when R2 and/or R2′ are/is amino-protecting group(s), deprotecting to eliminate the protecting group.
7 more elements
A 8,2′-anhydro-8-mercapto-9-arabinofuranosyl purine represented by formula (1):
- wherein R1 is a hydroxyl-protecting group;
- X1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group.
A 8,2′-anhydro-8-mercapto-9-arabinofuranosyl guanine represented by formula (4):
- wherein R1 is a hydroxyl-protecting group;
- and R2 and R2′ are each independently a hydrogen atom or an amino-protecting group, or R2 and R2′ in combination optionally form an amino-protecting group.
A 8,2′-anhydro-3′-deoxy-3′-fluoro-8-mercapto-9-arabinofuranosyl purine represented by formula (2):
- wherein R1 is a hydroxyl-protecting group;
- X1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group;
- and Y1 is a hydrogen atom, a halogen atom, an optionally substituted amino group, or an optionally substituted hydroxyl group.
A 8,2′-anhydro-3′-deoxy-3′-fluoro-8-mercapto-9-arabinofuranosyl guanine represented by formula (5):
- wherein R1 is a hydroxyl-protecting group;
- and R2 and R2′ are each independently a hydrogen atom or an amino-protecting group, or R2 and R2′ in combination optionally form an amino-protecting group.
Dependencies are inferred from the claim text.