L-nucleic acid derivatives and process for the synthesis thereof
AssigneeMitsui Chemicals, Inc.
InventorsHajime Iizuka, Kazuhiko Togashi, Tsuneji Suzuki
Life of this patent
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Abstract
A novel method has been found to produce 2,2′-anhydro-1-(β-L-arabinofuranosyl)thymine as a novel useful intermediate compound. A novel method has been further found to produce thymidine from 2,2′-anhydro-1-(β-L-arabinofuranosyl)thymine. A novel method has been further found to L-2′-deoxyribose derivatives as a useful synthetic intermediate through L-2,2′-anhydro-5,6-dihydrocyclouridine derivative. According to these methods, synthesis of various L-nucleic acid derivatives, synthesis of which has been difficult till now.
Claims17
A process for producing L-thymidine comprising:
- (a) a step of reacting L-arabinoaminooxazoline represented by the following formula (1)
- with an acrylic acid derivative represented by the following formula (2)
- (wherein R1 is a lower alkyl group, and X is chlorine, a p-toluenesulfonyloxy group or a methanesulfonyloxy group) to synthesize a L-arabinoaminooxazoline derivative represented by the following formula (3)
- (wherein X and R1 have the same definitions as given above),
- (b) a step of reacting a base with the L-arabinoaminooxazoline derivative represented by the formula (3) to synthesize a L-2,2 anhydronucleic acid derivative represented by the following formula (4)
- (c) a step of isomerizing the L-2,2 anhydronucleic acid derivative represented by the formula (4) to synthesize 2,2 anhydro-1-((-L-arabinofuranosyl)thymine represented by the following formula (5)
- (d) a step of subjecting the 2,2 anhydro-1-((-L-arabinofuranosyl)thymine represented by the formula (5) to halogenation and subsequent protection, or protection and subsequent halogenation, or protection and simultaneous halogenation to synthesize a 2 position-halogenated L-thymidine derivative represented by the following formula (6)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group, and Y is a halogen atom),
- (e) a step of dehalogenation of the compound represented by the formula (6) to synthesize a L-thymidine derivative represented by the following formula (7)
- (wherein R2 and R3 have the same definitions as given above), and
- (f) a step of deblocking the compound represented by the formula (7) to synthesize L-thymidine.
A process for producing 2,2 anhydro-1-((-L-arabinofuranosyl)thymine comprising:
- (a) a step of reacting L-arabinoaminooxazoline represented by the following formula (1)
- with an acrylic acid derivative represented by the following formula (2)
- (wherein R1 is a lower alkyl group and X is chlorine, a p-toluenesulfonyloxy group or a methanesulfonyloxy group) to synthesize a L-arabinoaminooxazoline derivative represented by the following formula (3)
- (wherein X and R1 have the same definitions as given above),
- (b) a step of allowing a base to act on the L-arabinoaminooxazoline derivative represented by the formula (3) to synthesize a L-2,2 anhydronucleic acid derivative represented by the following formula (4)
- and
- (c) a step of isomerizing the a L-2,2 anhydronucleic acid derivative represented by the formula (4) to synthesize 2,2 anhydro-1-((-L-arabinofuranosyl)thymine represented by the following formula (5).
A process for producing a L-arabinoaminooxazoline derivative comprising:
- a step of reacting L-arabinoaminooxazoline represented by the following formula (1)
- with an acrylic acid derivative represented by the following formula (2)
- (wherein R1 is a lower alkyl group, and X is chlorine, a p-toluenesulfonyloxy group or a methanesulfonyloxy group) to synthesize a L-arabinoaminooxazoline derivative represented by the following formula (3)
- (wherein X and R1 have the same definitions as given above).
A L-arabinoaminooxazoline derivative represented by the following formula (3)
- (wherein R1 is a lower alkyl group, and X is chlorine, a p-toluenesulfonyloxy group or a methanesulfonyloxy group).
A process for producing a L-2,2 anhydronucleic acid derivative comprising allowing a base to act on a L-arabinoaminooxazoline derivative represented by the following formula (3)
- (wherein R1 is a lower alkyl group and X is chlorine, a p-toluenesulfonyloxy group or a methanesulfonyloxy group) to synthesize a L-2,2 anhydronucleic acid derivative represented by the following formula (4)
A L-2,2 anhydronucleic acid derivative represented by the following formula (4)
A process for producing 2,2 anhydro-1-((-L-arabinofuranosyl)thymine comprising isomerizing a L-2,2 anhydronucleic acid derivative represented by the following formula (4)
- to synthesize 2,2 anhydro-1-((-L-arabinofuranosyl)thymine represented by the following formula (5)
2,2 Anhydro-1-((-L-arabinofuranosyl)thymine represented by the following formula (5)
A process for producing a 2 position-halogenated L-thymidine derivative comprising subjecting 2,2 anhydro-1-((-L-arabinofuranosyl)thymine represented by the following formula (5)
- to halogenation and subsequent protection, or protection and subsequent halogenation, or protection and simultaneous halogenation to synthesize a 2 position-halogenated L-thymidine derivative represented by the following formula (6)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group, and Y is a halogen atom).
A 2 position-halogenated L-thymidine derivative represented by the following formula (6)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group, and Y is a halogen atom).
A process for producing a L-thymidine derivative comprising subjecting a compound represented by the following formula (6)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group, and Y is a halogen atom) to dehalogenation to synthesize a L-thymidine derivative represented by the following formula (7)
- (wherein R2 and R3 have the same definitions as given above).
A process for producing a L-2-deoxyribose derivative, comprising:
- I. a step of reacting L-arabinoaminooxazoline represented by the following formula (1)
- with a lower alkyl acrylic acid ester to synthesize L-2,2 anhydro-1-((-arabinofuranosyl) -5,6-dihydrouridine represented by the following formula (8)
- II. a step of protection of the L-2,2 anhydro-1-((-arabinofuranosyl)-5,6-dihydrouridine represented by the formula (8) to synthesize a L-2,2 anhydro-5,6-dihydrouridine derivative represented by the following formula (9)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group),
- III. a step of halogenation of the L-2,2 anhydro-5,6-dihydrouridine derivative represented by the formula (9) to synthesize a 2 position-halogenated L-5,6-dihydrouridine derivative represented by the following formula (10)
- (wherein R2, R3 and Y have the same definitions as given above),
- IV. a step of subjecting the compound represented by the formula (10) to dehalogenation, or dehalogenation and subsequent deblocking, or deblocking and subsequent dehalogenation, or deblocking and simultaneous dehalogenation to synthesize a L-2 deoxy-5,6-dihydoruridine derivative represented by the following formula (11)
- (wherein R4 and R5 are each independently a hydrogen atom or a protecting group for hydroxyl group), and
- V. a step of a decomposition reaction of the compound represented by the formula (11) to obtain a L-2-deoxyribose derivative represented by the following formula (12)
- wherein R4 and R5 have the same definitions as given above, and R6 is hydrogen, a methyl group or an ethyl group).
A process for producing a L-2,2 anhydro-5,6-dihydrouridine derivative comprising:
- I. a step of reacting L-arabinoaminooxazoline represented by the following formula (1)
- with a lower alkyl acrylic acid ester to synthesize L-2,2 anhydro-1-((-arabinofuranosyl)-5,6-dihydrouridine represented by the following formula (8)
- and
- II. a step of subjecting the compound represented by the formula (8) to protection to synthesize a L-2,2 anhydro-5,6-dihydrouridine derivative represented by the following formula (9)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group).
A L-2,2 anhydro-5,6-dihydrouridine derivative represented by the following formula (9)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group).
A process for producing a 2 position-halogenated L-5,6-dihydrouridine derivative comprising halogenating a compound represented by the following formula (9)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group) to synthesize a 2 position-halogenated L-5,6-dihydrouridine derivative represented by the following formula (10)
- (wherein R2, R3 have the same definition as given above and Y is a halogen atom).
A process for producing a L-2 deoxy-5,6-dihydrouridine derivative comprising subjecting a compound represented by the following formula (10)
- (wherein R2 and R3 are each independently a protecting group for hydroxyl group and Y is a halogen atom) to dehalogenation, or dehalogenation and subsequent deblocking, or deblocking and subsequent dehalogenation, or deblocking and simultaneous dehalogenation to synthesize a L-2 deoxy-5,6-dihydrouridine derivative represented by the following formula (11)
- (wherein R4 and R5 are each independently a hydrogen atom or a protecting group for hydroxyl group).
A process for producing a L-2-deoxyribose derivative comprising decomposing a L-2 deoxy-5,6-dihydrouridine derivative represented by the following formula (11)
- (wherein R4 and R5 are each independently a hydrogen atom or a protecting group for hydroxyl group) to obtain a L-2-deoxyribose derivative represented by the following formula (12)
- (wherein R4 and R5 have the same definitions as given above, and R6 is hydrogen, a methyl group or an ethyl group).
Dependencies are inferred from the claim text.