Method for producing oligonucleic acid compound

A method for producing a compound [C] of the following formula

• comprising:
• subjecting a compound [A] having a hydroxyl group or a primary or secondary amino group to a condensation reaction with a compound [B] having a substituent group containing a phosphorous atom of formula [1]:
• wherein
• ** represents a binding position,
• D represents a halogen, 5- to 6-membered saturated cyclic amino, or di(C1-6 alkyl)amino,
• W0 represents a lone pair of electrons, an oxygen atom, or a sulfur atom, and
• X represents a hydroxyl group substituted with a removable group under a neutral condition, 1,1,3,3-tetra(C1-6 alkyl)guanidyl, C1-6 alkoxy, di(C1-6 alkyl)amino, mono(amino-C1-6 alkyl substituted with a removable group under a basic condition)amino, di(amino-C1-6 alkyl substituted with a removable group under a basic condition)amino, or a substituent represented by formula [2]:
• wherein
• * represents a binding position with a phosphorus atom,
• a represents an integer from 0 to 2,
• E represents CH2, CH-A1, or N-A2,
• A1 represents C1-6 alkyl, mono(C1-6 alkyl)amino-C1-6 alkyl substituted with a removable group under a basic condition, di(C1-6 alkyl)amino-C1-6 alkyl, tri(C1-6 alkyl)ammonio-C1-6 alkyl, amino substituted with a removable group under a basic condition, mono(C1-6 alkyl)amino substituted with a removable group under a basic condition, di(C1-6 alkyl)amino, tri(C1-6 alkyl)ammonio, amino substituted with amidino substituted with a removable group under a basic condition, or a substituent represented by the following formula [3]:
• wherein
• * represents a binding position with E,
• b represents an integer from 0 to 2,
• c represents 0 or 1,
• R11 represents C1-6 alkyl, and
• M represents CH2, an oxygen atom, a sulfur atom, or N-(a removable group under a basic condition), and
• A2 represents C1-6 alkyl, mono(C1-6 alkyl)amino-C1-6 alkyl substituted with a removable group under a basic condition, di(C1-6 alkyl)amino-C1-6 alkyl, tri(C1-6 alkyl)ammonio-C1-6 alkyl, a removable group under a basic condition, aryl, or heteroaryl,
• in the presence of at least one reaction accelerator selected from the group consisting of a tetra C1-18 alkyl ammonium chloride, choline chloride, a 1-C1-18 alkyl-3-C1-18 alkylimidazolium chloride, 1-C1-18 alkyl-1-C1-18 alkylpyrrolidinium chloride, 1-ethylpyridinium bromide, 1-ethylpyridinium chloride and 1-butylpyridinium chloride to obtain the compound of the formula [C]:
• wherein
• W0 and X are as defined above,
• A represents a group obtained by removing one hydrogen atom of the hydroxyl group or the primary or secondary amino group of the compound [A] from the compound [A], and
• B represents a group obtained by removing the substituent of the formula [1] from the compound [B],
• wherein the compound [A] and the compound [B] contain one or more nucleoside units, provided that adjacent nucleoside units in the compounds are binding to each other via a phosphate bond if the compound [A] and the compound [B] contain multiple nucleoside units in its molecule,
• wherein
• the one or more nucleoside units of the compound [A] is represented by formula [4d],
• wherein
• * represents
• (1) a binding position with a phosphate bond to an oxygen atom at the 5′-position of an adjacent nucleoside unit,
• (2) a binding position with a hydrogen atom, or
• (3) a binding position with a substituent [6];
• ** represents
• (1) a binding position with a phosphate bond to an oxygen atom at the 3′-position of an adjacent nucleoside unit,
• (2) a binding position with a hydrogen atom, or
• (3) a binding position with a substituent [6] of the following formula [6];
• G-T* [6]
• wherein
• * represents a binding position with ** O or *N in the formula [4d],
• G represents
• (1) a silyl substituent,
• (2) long-chain C10-300alkyl-carbonyl,
• (3) benzoyl substituted with 1 to 5 long-chain C10-300alkyloxy and/or long-chain C10-300alkenyloxy, or
• (4) a substituent represented by the following formula [7]:
• Z-L* [7]
• wherein
• * represents a binding position with T,
• Z represents
• (1) (soluble polymer soluble in an organic solvent)-oxy,
• (2) (soluble polymer soluble in an organic solvent)-amino,
• (3) long-chain C10-300alkyloxy,
• ′(4) a solid phase carrier, or
• ′(5) a substituent represented by one of the following formula [8A], formula [8B], formula [8C], formula [8D], formula [8E], formula [8F], formula [8G], formula [8H], formula, formula, formula [8K], formula [8L], formula [8M], and formula [8N]:
• wherein
• * represents a binding position with L,
• j represents an integer from 0 to 4,
• k represents an integer from 0 to 5,
• R8a represents a hydrogen atom or C1-6 alkyl,
• R8b is the same or different and each represent long-chain C10-300alkyl,
• R8c is the same or different and each represent a substituent represented by one of the following formula [9A], formula [9B], formula [9C], formula [9D] and formula [9E]:
• wherein
• * represents a binding position, and
• R9 represents long-chain C10-300alkyl and/or long-chain C10-300alkenyl,
• R8d is the same or different and each represent a hydrogen atom, a halogen, long-chain C10-300alkyl optionally substituted with 1 to 13 halogens, or long-chain C10-300alkyloxy optionally substituted with 1 to 13 halogens,
• R8e represents
• (1) long-chain C10-300alkyl,
• (2) long-chain C10-300alkyl-carbonyl, or
• (3) benzoyl substituted with 1 to 5 long-chain C10-300alkyloxy and/or long-chain C10-300alkenyloxy, and
• R8f represents
• (1) long-chain C10-300alkyl,
• (2) long-chain C10-300alkyl-carbonyl, or
• (3) long-chain C10-300alkenyl-carbonyl, and
• L represents a substituent represented by formula [10]:
• wherein
• * represents a binding position with Z,
• ** represents a binding position with T, and
• L1 represents an optionally substituted C2-10 alkylene or an optionally substituted C6-10 arylene, and
• T represents a single bond or a substituent represented by formula [11]:
• wherein
• X is as defined above,
• W is as defined above for W0,
• * represents a binding position with ** O or *N in the formula [4d],
• ** represents a binding position with G, and
• q represents an integer from 0 to 10,
• provided that T is a single bond when G is a silyl substituent,
• BP represents an optionally protected nucleic acid base, and the one or more nucleoside units of the compound [B] is represented by formula [4h],
• wherein
• BP is as defined above;
• *** represents
• (1) a binding position with a phosphorous atom of the phosphate bond to an oxygen atom at the 3′-position of or a nitrogen atom at the 3′-position of an adjacent nucleoside unit,
• (2) a binding position with the substituent of the formula [1], or
• (3) a binding position with a removable group under an acidic condition;
• and
• the substituent of the formula [1] is represented by the following formula [1A]:
• wherein
• ** represents a binding position,
• D represents a halogen, 5- to 6-membered saturated cyclic amino, or di(C1-6 alkyl)amino,
• W represents a lone pair of electrons, an oxygen atom, or a sulfur atom, and
• X represents a hydroxyl group substituted with a removable group under a neutral condition, 1,1,3,3-tetra(C1-6 alkyl)guanidyl, C1-6 alkoxy, di(C1-6 alkyl)amino, mono(amino-C1-6 alkyl substituted with a removable group under a basic condition)amino, di(amino-C1-6 alkyl substituted with a removable group under a basic condition)amino, or a substituent represented by the following formula [2];
• wherein
• * represents a binding position with a phosphorus atom,
• a represents an integer from 0 to 2,
• E represents CH2, CH-A1, or N-A2,
• A1 represents C1-6 alkyl, mono(C1-6 alkyl)amino-C1-6 alkyl substituted with a removable group under a basic condition, di(C1-6 alkyl)amino-C1-6 alkyl, tri(C1-6 alkyl)ammonio-C1-6 alkyl, amino substituted with a removable group under a basic condition, mono(C1-6 alkyl)amino substituted with a removable group under a basic condition, di(C1-6 alkyl)amino, tri(C1-6 alkyl)ammonio, amino substituted with amidino substituted with a removable group under a basic condition, or a substituent represented by the following formula [3]:
• wherein
• * represents a binding position with E,
• b represents an integer from 0 to 2,
• c represents 0 or 1,
• R11 represents C1-6 alkyl, and
• M represents CH2, an oxygen atom, a sulfur atom, or N-(a removable group under a basic condition), and
• A2 represents C1-6 alkyl, mono(C1-6 alkyl)amino-C1-6 alkyl substituted with a removable group under a basic condition, di(C1-6 alkyl)amino-C1-6 alkyl, tri(C1-6 alkyl)ammonio-C1-6 alkyl, a removable group under a basic condition, aryl, or heteroaryl.