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US 2002/0120129 A1Published application
Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives
AssigneeSirna Therapeutics, Inc.
InventorsLeonid Beigelman, Alexander Karpeisky, Vladmir Serebryany, Peter Haeberli, David Sweedler
Life of this patent
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Abstract
The present invention provides methods for the chemical synthesis of nucleosides and derivatives thereof, including 2′-amino, 2′-N-phthaloyl, 2′-O-methyl, 2′-O-silyl, 2′OH nucleosides, C-nucleosides, nucleoside phosphoramidites, C-nucleoside phosphoramidites, and non-nucleoside derivatives.
Claims75
A method for synthesizing a compound of Formula I:
- 24
- wherein R1 and R2 are independently hydrogen, NR10R11, (NR10R11)alkyl, alkyl, fluoro or chloro, wherein R10 and R11 are independently hydrogen, alkyl, alkanoyl, acyl, alkoxy, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl;
- and R3 is independently alkyl, alkoxyalkyl, alkyl-thio-alkyl, cyanoalkyl, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl;
- comprising:
- a) introducing a 5′,3′-bridging silyl protecting group to a compound of Formula II,
- 25
- wherein R1 and R2 are as defined in Formula I, to yield a compound of Formula III;
- 26
- wherein R1 and R2 are as defined in Formula I and each R4 is independently alkyl, aryl or isoalkyl;
- b) alkylating the product of step (a) to yield a compound of Formula IV;
- 27
- wherein R1, R2 and R3 are as defined in Formula I and R4 is as defined in Formula III;
- and
- c) deprotecting the product of step (b) to yield a compound of Formula I.
11 more elements
A method for synthesizing a compound having Formula V:
- 28
- wherein R1 and R2 are independently hydrogen, NR10R11, (NR10R11)alkyl, alkyl, fluoro or chloro, wherein R10 and R11 are independently hydrogen, alkyl, alkanoyl, acyl, alkoxy, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl;
- R3 is independently alkyl, alkoxyalkyl, alkyl-thio-alkyl, cyanoalkyl, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl;
- R5 is an acid labile protecting moiety;
- and R6 is a phosphorous containing moiety;
- comprising:
- a) introducing a 5′,3′-bridging silyl protecting group to a compound of Formula II to yield a compound of Formula III;
- b) alkylating the product of step (a) to yield a compound of Formula IV;
- c) introducing at least one exocyclic amine protecting moiety to the product of step (b) provided that at least one of R1 or R2 in step (b) is amino;
- d) deprotecting the product of step (c) to yield a compound of Formula I;
- and
- e) introducing an acid labile protecting moiety followed by a phosphorous containing moiety to the product of step (d) to yield a compound of Formula V.
9 more elements
A method for synthesizing a compound having Formula VI:
- 29
- wherein R3 is independently alkyl, alkoxyalkyl, alkyl-thio-alkyl, cyanoalkyl, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl;
- and R7 is H, acyl, or arylalkanoyl, comprising:
- a) introducing a 5′,3′-bridging silyl protecting group to inosine to yield a compound of Formula VII;
- 30
- wherein each R4 is independently alkyl, aryl or isoalkyl;
- b) introducing an imidazole moiety to the product of step (a) to yield a compound of Formula VIII;
- 31
- wherein each R4 is independently alkyl, aryl or isoalkyl;
- c) alkylating the product of step (b) to yield a compound of Formula IX;
- 32
- wherein each R4 is independently alkyl, aryl or isoalkyl and R3 is as defined in Formula VI;
- d) aminating the product of step (c) to yield a compound of Formula X;
- 33
- wherein R3 and R7 are as defined in Formula VI;
- and
- e) desilylating the product of step (d) to yield a compound of Formula VI.
14 more elements
A method for synthesizing a compound having Formula VI, comprising:
- a) introducing a 5′,3′-bridging silyl protecting group to inosine to yield a compound of Formula XI;
- 34
- wherein each R4 is independently alkyl aryl or isoalkyl;
- b) introducing an imidazole moiety to the product of step (a) to yield a compound of Formula XII;
- 35
- wherein each R4 is independently alkyl, aryl or isoalkyl;
- c) alkylating the product of step (b) to yield a compound of Formula XIII;
- 36
- wherein R3 is as defined in Formula VI and each R4 is independently alkyl, aryl or isoalkyl;
- d) aminating the product of step (c) to yield a compound of Formula XIV;
- 37
- wherein R3 and R7 are as defined in Formula VI;
- and
- e) desilylating the product of step (d) to yield a compound of Formula VI.
11 more elements
A method for synthesizing a compound having Formula XVI:
- 39
- wherein R8 is a succinate moiety, aklyisilyl moiety, or H;
- and R9 is an acid labile protecting moiety or H, comprising:
- a) depyrimidination of a compound of formula XVII;
- 40
- wherein R8 is an silylalkyl moiety to yield a compound of Formula XVI, wherein R8 is an silylalkyl moiety;
- and R9 is H;
- b) introducing an acid labile protecting moiety to the product of step (a) to yield a compound of Formula XVI, wherein R8 is an silylalkyl moiety and R9 is an acid labile protecting moiety;
- c) deprotecting the product of step (b) to yield a compound for Formula XVI, wherein R8 is H and R9 is an acid labile protecting moiety;
- and
- d) introducing a succinate moiety to the product of step (c) to yield a compound of Formula XVI, wherein R8 is a succinate moiety and R9 is an acid labile protecting moiety.
8 more elements
A method for synthesizing a compound having Formula XVI:
- 41
- wherein R8 is a phosphorous containing moiety, aklylsilyl moiety, or H;
- and R9 is an acid labile protecting moiety or H, comprising:
- a) depyrimidination of a compound of formula XVII;
- 42
- wherein R8 is an aklylsilyl moiety to yield a compound of Formula XVI, wherein R8 is an silylalkyl moiety and R9 is H;
- b) introducing an acid labile protecting moiety to the product of step (a) to yield a compound of Formula XVI, wherein R8 is an silylalkyl moiety and R9 is an acid labile protecting moiety;
- c) deprotecting the product of step (b) to yield a compound for Formula XVI, wherein R8 is H and R9 is an acid labile protecting moiety;
- and
- d) introducing a phosphorous containing moiety to the product of step (c) under conditions suitable to yield a compound of Formula XVI, wherein R8 is a phosphorous containing moiety and R9 is an acid labile protecting moiety.
7 more elements
A compound of Formula VIII;
- 43
- wherein each R4 is independently alkyl, aryl or isoalkyl.
A compound of Formula IX;
- 44
- wherein R3 is independently alkyl, alkoxyalkyl, alkyl-thio-alkyl, cyanoalkyl, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl and each R4 is independently alkyl, aryl or isoalkyl.
A compound of Formula XII;
- 45
- wherein each R4 is independently alkyl, aryl or isoalkyl.
A compound of Formula XIII;
- 46
- wherein R3 is independently alkyl, alkoxyalkyl, alkyl-thio-alkyl, cyanoalkyl, or arylalkyl optionally substituted with up to three groups that are independently halogen, alkoxy, nitro, or alkyl and each R4 is independently alkyl, aryl or isoalkyl.
Dependencies are inferred from the claim text.