Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-03-06
2004-11-23
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S028500
Reexamination Certificate
active
06822090
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for producing cytidine derivatives. The cytidine derivatives are useful not only as pharmaceuticals, such as antitumor agents and antiviral agents, and agricultural chemicals, but also as a raw material of antisense DNAs that are being developed now.
BACKGROUND ART
Examples of the known method for producing cytidine derivatives are as follows.
(1) The method in which 5′-O-(dimethoxytrityl)uridine derivatives are condensed with 1,2,4-triazole to give 1-[5′-O-(dimethoxytrityl)-&bgr;-D-ribofuranosyl]-4-(1,2,4-tri azol-1-yl)pyrimidin-2-(1H) -one derivatives, which are then reacted with an amine in dioxane solvent to yield 5′-O-(dimethoxytrityl)cytidine derivatives (Journal of Organic Chemistry, 47, 3623 (1982)).
(2) The method in which 2′-deoxy-2′-methyluridine derivatives are reacted with 4-(N,N-dimethylamino)pyridine (thereinafter referred to as DMAP) to give 4-[4-(N,N-dimethylamino)pyridinium] derivatives, which are then treated with 28% NH
4
OH to yield 2′-deoxy-2′-methylcytidine derivatives (Arch. Pharm., 329, 66 (1996)).
As for the above methods, the method (1) using 1,2,4-triazole is unsuitable for mass production, since the reaction for the synthesis of 4-(1,2,4-triazol-1-yl)pyrimidin-2-(1H)-one derivatives is extremely slow and time-consuming, and the extraction of the product is required, thereby taking a lot of time and effort; and the method (2) via 4-[4-(dimethylamino)pyridinium] derivatives is also unsuitable for mass production, since the reaction is extremely slow and time-consuming, and, if less than 2.0 equivalents of DMAP is used based on the reaction substrate, then the unchanged substrates remain and the manipulation to separate them from the product becomes necessary, resulting in an increase in the number of processes, as described in the comparative examples later.
DISCLOSURE OF INVENTION
Thus, any efficient methods for producing cytidine derivatives capable of supplying them in large quantities have been absent previously. The present invention provides a method for producing cytidine derivatives efficiently.
The inventors have intensively investigated in order to solve the above problems, and then found that uridine derivatives can be reacted with a tertiary amine and a dehydrating reactant in the presence of a deacidifying agent, followed by ammonia, or a primary or secondary amine to yield cytidine derivatives in a short period of time by means of an easy manipulation. That is, the reaction time, which was long in the conventional methods, was largely reduced. Furthermore, it was found that the tertiary amine to be used could be reduced to nearly the same mole based on the uridine derivative, and then the present invention was completed.
Accordingly, the method for producing cytidine derivatives of the present invention is the method, characterized in that a uridine derivative represented by formula (1):
wherein, X represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a halogen atom(s), or an alkenyl group having 2 to 4 carbon atoms, and R1 and R2 each independently represent either a hydrogen atom or a hydroxyl-protecting group, and R3 represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group having 1 to 4 carbon atoms, a hydroxyl group substituted with a hydroxyl-protecting group, is reacted with a tertiary amine and dehydrating reactant, followed by ammonia, or a primary or secondary amine represented by formula (2):
HNR4R5 (2)
wherein, R4 and R5 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 8 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a halogen atom(s), or an alkenyl group having 2 to 4 carbon atoms, or R4 and R5 may be linked together to form a ring,
for producing a cytidine derivative represented by formula (3):
wherein, X, R1, R2, R3, R4 and R5 are as defined above.
Preferably, in the above formulas, examples of the hydroxyl-protecting groups, i.e. R1 and R2, include an aliphatic acyl group having 1 to 4 carbon atoms, an aromatic acyl group, an aromatic acyl group substituted with an alkyl group(s) having 1 to 4 carbon atoms, an aromatic acyl group substituted with a halogen atom(s), an aromatic acyl group substituted with an alkoxy group(s) having 1 to 4 carbon atoms, or a trialkylsilyl group, R3 may be a hydrogen atom, an alkoxy group having 1 to 4 carbon atoms, an aliphatic alkyloxy group having 1 to 4 carbon atoms substituted with an alkoxy group(s) having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 4 carbon atoms, an aromatic acyloxy group, an aromatic acyloxy group substituted with an alkyl group(s) having 1 to 4 carbon atoms, an aromatic acyloxy group substituted with a halogen atom(s), or an aromatic acyloxy group substituted with an alkoxy group(s) having 1 to 4 carbon atoms.
The preferred combination of X and R3 in the above formulas (1) and (3) includes the combination in which X represents a hydrogen atom or a methyl group, and R3 is a hydrogen atom, a methoxy group, or a methoxyethyl group.
Examples of the above tertiary amine include an alicyclic amine represented by formula (4):
wherein, n and m each independently represent an integer of 1 to 4, Y represents hydrogen atom, carbon atom, nitrogen atom, oxygen atom, or sulfur atom, Z represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a halogen atom(s), an alkenyl group having 2 to 4 carbon atoms, or Z may be linked to A to form a ring, A represents an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a halogen atom(s), an alkenyl group having 2 to 4 carbon atoms, or A may be linked to Z to form a ring; and an aliphatic amine represented by formula (6):
wherein, R6, R7 and R8 each independently represent an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 8 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a halogen atom(s), or an alkenyl group having 2 to 4 carbon atoms.
The specific examples of the tertiary amine include N-methylpiperidine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane, N,N′-dimethylpiperazine, and trimethylamine.
On the other hand, the method for producing cytidine derivatives of the present invention can possess the reaction route capable of obtaining a cytidine derivative represented by formula (5):
wherein, X, R1, R2, R3, n, m, A, Y and Z are as defined above,
as a reaction intermediate, in reacting the uridine derivative with the tertiary amine and the dehydrating reactant.
Examples of the dehydrating reactants in the above reaction include acid halides or acid anhydrides, and in this case, the above reaction is preferably conducted in the presence of a deacidifying agent. The specific examples of the above dehydrating reactant include p-toluenesulfonyl chloride.
The molar ratio of the above tertiary amine to the uridine derivative represented by formula (1) may be, for example, 1.2 or less.
A cytidine derivative represented by formula (5):
wherein, X, R1, R2, R3, n, m, A, Y and Z are as defined above, or salt thereof is a novel compound, and included in the present invention. The compounds of the above formula (5) include one, where X represents a hydrogen atom or a methyl group, R1 and R2 are a hydrogen atom or a hydroxyl-protecting group, R3 is a hydrogen atom, a methoxy group, a methoxyethyloxy group, n and m are 2, A is a methyl group, and Y is a methylene group or an oxygen atom.
Another aspect of the method for producing cytidine derivatives according to the present invention is the method for producing a cytidine derivative represented by formula (3):
wherein, X, R1, R2, R3, R4 and R5 are as d
Fukazawa Nobuyuki
Komatsu Hironori
Kouno Toshiyuki
Morizane Kunihiko
Tanikawa Hiroharu
Krishnan Ganapathy
Mitsui Chemicals Inc.
Wilson James O.
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