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US 12,760,056 B2Granted
Method for producing bicyclic phosphoramidite
AssigneeDaiichi Sankyo Company, Limited
InventorsMakoto Michida, Kazutoshi Ukai, Yuzo Abe, Moe Matsumoto, Makoto Yamaoka, Kei Kurahashi
Life of this patent
Estimating the term…
Abstract
The present invention provides a crystalline 2,4-bridged common intermediate useful for producing a plurality of ENA monomers, a method for stereoselectively producing the intermediate, and a method for efficiently producing ENA monomers using the intermediate.
Claims18
A compound represented by formula (I′):
A method for producing a compound represented by formula (VI):
- or a salt or a tautomer thereof;
- 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;
- n represents an integer of 0 to 4;
- Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group;
- and
- X1 represents a group that forms a leaving group.
6 more elements
A method for producing a compound represented by formula (X):
- or a salt or a tautomer thereof, the method comprising:
- (i) a step of reacting a compound represented by formula (II):
- 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):
- with a compound represented by formula (XII):
- or a salt or a tautomer thereof, in a solvent in the presence of an acid reagent;
- (iii) a step of performing isomerization, to stereoselectively obtain a compound represented by formula (XIII):
- or a salt or a tautomer thereof;
- (iv) a step of reacting the compound represented by formula (XIII) obtained in step (iii):
- or a salt or a tautomer thereof, with a deprotection reagent for a hydroxyl group in a solvent, to deprotect Z1 and Z2;
- and
- (v) a step of reacting the diol compound obtained in step (iv) or a salt or a tautomer thereof, with a protection reagent for a primary hydroxyl group and selectively protecting the primary hydroxyl group, to obtain a compound represented by formula (X):
- or a salt or a tautomer thereof;
- 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;
- n represents an integer of 0 to 4;
- Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group;
- and
- X2 represents a group that forms a leaving group.
17 more elements
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.
A compound represented by formula (XIV′):
A method for producing a compound represented by formula (XVIII):
- or a salt or a tautomer thereof, the method comprising:
- (i) a step of reacting a compound represented by formula (XIV):
- 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;
- (ii) a step of cross-coupling the compound represented by formula (XIX) obtained in step (i):
- 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):
- or a salt or a tautomer thereof;
- (iii) a step of reacting the compound represented by formula (XX) obtained in step (ii):
- or a salt or a tautomer thereof, with a deprotection reagent for a hydroxyl group in a solvent, to deprotect Z1, Z2 and R5;
- and
- (iv) a step of reacting the compound represented by formula (XXI) obtained in step (iii):
- or a salt or a tautomer thereof, with a protection reagent for a primary hydroxyl group and selectively protecting the primary hydroxyl group, to obtain a compound represented by formula (XVIII):
- or a salt or a tautomer thereof;
- 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;
- n represents an integer of 0 to 4;
- wherein Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group;
- and
- R5 represents a benzyl group optionally substituted with a lower alkyl, lower alkoxy, halogen, or cyano group.
16 more elements
A method for producing a compound represented by formula (XXII):
- or a salt or a tautomer thereof, the method comprising:
- (i) a step of reacting a compound represented by formula (XXIII):
- or a salt or a tautomer 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):
- or a salt or a tautomer thereof, with an activator in a solvent in the presence of a base and a catalyst;
- (iii) a step of then performing a reaction with an aminating agent, to obtain a compound represented by formula (XXV):
- or a salt or a tautomer thereof;
- (iv) a step of reacting the compound represented by formula (XXV) obtained in step (iii):
- or a salt or a tautomer thereof, with an acylating agent in a solvent, and
- (v) a step of reacting the compound represented by formula (XXVI) obtained in step (iv):
- or a salt or a tautomer thereof, with a deprotection reagent for a hydroxyl group and deprotecting only Z3, to obtain a compound represented by formula (XXII):
- a salt or a tautomer thereof,
- 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;
- n represents an integer of 0 to 4;
- and
- Z3 represents an aliphatic acyl group or an aromatic acyl group.
16 more elements
A production method comprising the steps of:
- reacting a compound represented by formula (XXVII):
- or a salt or a tautomer thereof, with an amidite-forming reagent in a solvent in the presence of an activator and a drying agent,
- to produce a compound represented by formula (XXVIII):
- or a salt or a tautomer thereof
- 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;
- n represents an integer of 0 to 4;
- and
- group α represents 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, or a halogen atom.
7 more elements
A method for producing a compound represented by formula (II):
- the method comprising:
- (i) a step of solvolyzing the acetal moiety of a compound represented by formula (III):
- 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):
- and
- (iii) a step of hydrolyzing the anomer position of the compound represented by formula (V) obtained in step (ii):
- wherein the acid catalyst is sulfuric acid, p-toluenesulfonic acid, or methanesulfonic acid,
- wherein step (ii) is performed using a trivalent phosphorus reagent and an azodicarboxylate ester,
- wherein the trivalent phosphorus reagent is triphenylphosphine or tri(n-butyl)phosphine,
- wherein the azodicarboxylate ester is diethyl azodicarboxylate, diisopropyl azodicarboxylate, or di t-butyl azodicarboxylate,
- wherein step (iii) is performed using an acid, and
- wherein the acid is hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid;
- wherein:
- Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group;
- n represents an integer of 0 to 4;
- 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;
- and
- A represents a lower alkyl group.
19 more elements
A method for producing a compound represented by formula (VI):
- or a salt or a tautomer thereof, the method comprising:
- (i) a step of reacting a compound represented by formula (II):
- 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 (VII) obtained in step (i):
- with a compound represented by formula (VIII):
- or a salt or a tautomer thereof, in a solvent in the presence of a halogenating agent, to stereoselectively obtain a compound represented by formula (IX):
- or a salt or a tautomer thereof;
- (iii) a step of reacting the compound represented by formula (IX) obtained in step (ii):
- or a salt or a tautomer thereof, with a deprotection reagent for a hydroxyl group in a solvent, to deprotect Z1 and Z2;
- and
- (iv) a step of reacting the diol compound obtained in step (iii) or a salt or a tautomer thereof, with a protection reagent for a primary hydroxyl group, to obtain a compound represented by formula (VI):
- wherein the activator is acetic anhydride, benzoic anhydride, trichloroacetonitrile, carbonyldiimidazole, or diphenyl chlorophosphate, and
- wherein the halogenating agent is chlorotrimethylsilane, bromotrimethylsilane, or iodotrimethylsilane;
- 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;
- n represents an integer of 0 to 4;
- Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group;
- and
- X1 represents a group that forms a leaving group.
18 more elements
A method for producing a compound represented by formula (VI):
- or a salt thereof or a tautomer, the method comprising:
- (i) a step of reacting a compound represented by formula (II):
- 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 (VII) obtained in step (i):
- with a compound represented by formula (VIII):
- or a salt or a tautomer thereof, in a solvent in the presence of a halogenating agent, to stereoselectively obtain a compound represented by formula (IX):
- or a salt or a tautomer thereof;
- (iii) a step of reacting the compound represented by formula (IX) obtained in step (ii):
- or a salt or a tautomer thereof, with a deprotection reagent for a hydroxyl group in a solvent, to deprotect Z1 and Z2;
- and
- (iv) a step of reacting the diol compound obtained in step (iii) or a salt or a tautomer thereof, with a protection reagent for a primary hydroxyl group, to obtain a compound represented by formula (VI):
- wherein the activator is acetic anhydride, benzoic anhydride, trichloroacetonitrile, carbonyldiimidazole, or diphenyl chlorophosphate, and
- wherein the halogenating agent is chlorotrimethylsilane, bromotrimethylsilane, or iodotrimethylsilane;
- 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;
- n represents an integer of 0 to 4;
- Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group;
- and
- X1 represents a group that forms a leaving group.
18 more elements
A method for producing a compound represented by formula (X):
- or a salt or a tautomer thereof, the method comprising:
- (i) a step of reacting a compound represented by formula (II):
- 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):
- with a compound represented by formula (XII):
- or a salt or a tautomer thereof, in a solvent in the presence of an acid reagent;
- (iii) a step of performing isomerization, to stereoselectively obtain a compound represented by formula (XIII):
- or a salt or a tautomer thereof;
- (iv) a step of reacting the compound represented by formula (XIII) obtained in step (iii):
- or a salt or a tautomer thereof, with a deprotection reagent for a hydroxyl group in a solvent, to deprotect Z1 and Z2;
- and
- (v) a step of reacting the diol compound obtained in step (iv) or a salt or a tautomer thereof, with a protection reagent for a primary hydroxyl group and selectively protecting the primary hydroxyl group, to obtain a compound represented by formula (X):
- wherein the activator is acetic anhydride, benzoic anhydride, trichloroacetonitrile, carbonyldiimidazole, or diphenyl chlorophosphite, and
- wherein the acid reagent is trimethylsilyl trifluoromethanesulfonate and trifluoroacetic acid;
- 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;
- n represents an integer of 0 to 4;
- Z1 and Z2 are identical or different and each represent a protective group for a hydroxy group;
- and
- X2 represents a group that forms a leaving group.
18 more elements
A method for producing a compound represented by formula (XXII):
- or a salt or a tautomer thereof, the method comprising:
- (i) a step of reacting a compound represented by formula (XXIII):
- a salt or a tautomer 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):
- or a salt or a tautomer thereof, with an activator in a solvent in the presence of a base and a catalyst;
- (iii) a step of then performing a reaction with an aminating agent, to obtain a compound represented by formula (XXV):
- or a salt or a tautomer thereof;
- (iv) a step of reacting the compound represented by formula (XXV) obtained in step (iii):
- or a salt or a tautomer thereof, with an acylating agent in a solvent,
- (v) a step of reacting the compound represented by formula (XXVI) obtained in step (iv):
- or a salt or a tautomer thereof, with a deprotection reagent for a hydroxyl group and deprotecting only Z3, to obtain a compound represented by formula (XXII):
- wherein the activator is p-toluenesulfonyl chloride or 2,4,6-triisopropylbenzenesulfonyl chloride;
- 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;
- n represents an integer of 0 to 4;
- and
- Z3 represents an aliphatic acyl group or an aromatic acyl group.
16 more elements
A production method comprising the steps of:
- reacting a compound represented by formula (XXVII):
- or a salt or a tautomer thereof, with an amidite-forming reagent in a solvent in the presence of an activator and a drying agent,
- to produce a compound represented by formula (XXVIII):
- or a salt or a tautomer thereof
- wherein the activator is 4,5-dicyanoimidazole,
- wherein the amidite-forming reagent is 2-cyanoethyl N,N,N′,N′-tetraisopropyl phosphorodiamidite, and
- wherein the drying agent is molecular sieve 3A, molecular sieve 4A, or molecular sieve 5A;
- 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;
- n represents an integer of 0 to 4;
- and
- group α represents 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, or a halogen atom.
10 more elements
A production method comprising the steps of:
- reacting a compound represented by formula (XXVII):
- or a salt or a tautomer thereof, with an amidite-forming reagent in a solvent in the presence of an activator and a drying agent,
- to produce a compound represented by formula (XXVIII):
- or a salt or a tautomer thereof
- wherein the activator is 4,5-dicyanoimidazole,
- wherein the amidite-forming reagent is 2-cyanoethyl N,N,N′,N′-tetraisopropyl phosphorodiamidite, and
- wherein the drying agent is molecular sieve 3A, molecular sieve 4A, or molecular sieve 5A;
- 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;
- n represents an integer of 0 to 4;
- and
- group α a represents 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, or a halogen atom.
10 more elements
Dependencies are inferred from the claim text.