JPS6038396A - Preparation of 5-fluorocytidine compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a carcinostatic agent and antiviral agent in high yield efficiently, by reacting a cytidine compound with fluorinating agent in a mixed solvent containing hydrogen fluoride and a carboxylic acid, etc. to give an intermediate, reacting it with ammonia, etc. CONSTITUTION:A cytidine compound shown by the formula I (R<1>-R<4> are H, or lower acyl) is reacted with a fluorinating agent (e.g., F2, CF3OF, etc., usually diluted in an inert gas such as N2 to 50mol% and used) in a mixed solvent of (A) hydrogen fluoride and (B) a carboxylic acid shown by the formula R<5>OH [R<5> is (halogenated)lower acyl, or halogenated lower alkyl] or a halogenated alcohol (preferably acetic acid, or trifluoroacetic acid) (preferably 5-80wt% component A, <=500ppm water content) to give a 5-fluorocytidine intermediate shown by the formula II. This compound is reacted with ammonia or an amine, to give the desired compound by the formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 5-fluorocytidine compounds.

5-Fluorocytidine compounds, such as 5-fluorontidine represented by the formula: are used as anticancer agents and antiviral agents.

Conventionally, the synthesis of 5-fluorocytidine compounds requires total synthesis consisting of several reaction steps, and the yield throughout the entire reaction has been low.

In order to improve this problem, attempts have been made to directly fluorinate cytidine compounds using various fluorinating agents to synthesize 5-fluorocytidine compounds in good yields.

For example, Japanese Patent Publication No. 55-45560 discloses that a 5-fluorocytidine compound can be produced by completely reacting a cytidine compound with fluorine treated with an inert gas. However, according to this manufacturing method, 1
6 to fluorinate ~10 mmol of cytidine compound.
It takes up to 10 hours, and furthermore, the reaction product must undergo troublesome purification using a silica gel column or the like.

Further, a method for directly fluorinating a cytidine compound using a fluorinating agent other than the above-mentioned fluorine also has the same problem as above.

The purpose of the present invention is to solve the above problems and provide a method for efficiently producing a 5-fluorocytidine compound.
a) A cytidine compound and a fluorinating agent are reacted in a mixed solvent containing (i) hydrogen fluoride and (i) a carboxylic acid or a halogenated alcohol to form a 5-fluorocytidine intermediate, (b) this 5 - A method for reacting a fluorocytidine intermediate with ammonia or an amine.

The compound is a cytidine compound (wherein R1 to R4 are the same or different and represent hydrogen or a lower acyl group) and is a starting material for step (a) of the present invention.

The fluorinating agent used in step (a) of the present invention includes:
F2. Examples include CF30F, which is usually used after being diluted with an inert gas such as N2 to a concentration of 5θ mol % or less.

The acid used as a solvent in step (a) of the present invention or the hydrogenated alcohol u, general formula: (wherein R5
represents a lower acyl group, a halogenated lower acyl group, or a halogenated lower alkyl group. ) Compounds represented by acetic acid, propionic acid, trifluoroacetic acid, X (CFx ) It CHxO
Examples include H (in the formula, X is hydrogen or fluorine, 1 = 1 to 8), and preferably acetic acid or trifluoroacetic acid.

The mixing ratio of (i) hydrogen fluoride and dicarboxylic acid or halogenated alcohol in the solvent used in the present invention is not particularly limited, but (i) hydrogen fluoride is 5 to 80% by weight based on the total amount of the solvent. % is preferable in terms of increasing the reaction rate of step (a) and in terms of handling;
) It is preferred that the carboxylic acid or halogenated furcol be present in the reaction system in an amount equal to or more than the same mole relative to the cytidine compound as the starting material in order to increase the yield of step (a).

In addition to the above-mentioned solvents, solvents commonly used in reactions using F! and the like as fluorinating agents, such as halogenated hydrocarbons and nitriles, can also be used as co-solvents in step (a).

In this step (a), the yield decreases if water is present in the solvent. The water content in the solvent is preferably 500° or less relative to the solvent.

The reaction temperature in step 6-(a) is usually below room temperature and above the freezing point of the solvent.

(a) In the reaction step, 5 represented by the general formula: (wherein Rl and Rs are the same as above)
- A fluorocytidine intermediate is formed.

Unlike its related compound, the uridine compound, the reaction rate of the cytidine compound when fluorinated with pg or the like was extremely low.

The present inventors have discovered that in step (a) of the present invention, when hydrogen fluoride is present in the solvent, the reaction rate of the fluorination reaction is increased.

The 5-fluorocytidine intermediate obtained in step (a) is separated from the solvent in step (a), for example, after removing the solvent under reduced pressure, and then in step (b), ammonia or amine ( By reacting with any of the primary to tertiary amines (any of which can be used), it can be converted to a 5-fluorocytidine compound represented by the general formula: (wherein Ryl is the same as above).

The above ammonia or amine is usually dissolved in a lower alcohol such as methanol in advance, and is added to the 5-fluorocytidine intermediate obtained in the (-) step to react.

The reaction temperature in this step (b) is usually room temperature, and the reaction time is within 5 hours.

Next, Examples and Comparative Examples will be shown to provide a detailed explanation of the present invention. (a) and (b) in Examples and Comparative Examples are based on the above-mentioned steps (a) and (b), respectively.

Example (a) 71.21 (5 mmol) of Cytidium was dissolved in solvent 25 consisting of 15 parts by weight of hydrogen fluoride and 85 parts by weight of acetic acid.
It dissolves in m/. This solution was maintained at 5° C., and a mixed gas containing fluorine diluted to 10 mol % with nitrogen was passed through the solution for 1 hour at a flow rate of 25 d/min while stirring vigorously. After the reaction was completed, the solvent was removed under reduced pressure.

(b) A saturated ammonia solution in methanol was added to the above residue, and the mixture was stirred for 1 hour.

Next, the methanol solution described in E was passed through an anion exchange resin column, and then methanol was removed under reduced pressure at room temperature.

Dissolve the residue in ethanol, add a small amount of ether and recrystallize to obtain 5-fluorocytidine (melting point: 193°C)
1.1 F (4.2 mmol, yield 84%) was obtained.

Comparative Example (a) A reaction was carried out in the same manner as in Example, except that 25 d of acetic acid was used as the solvent.

(b) In this step, the same reaction as in Example was carried out to obtain 1.18 g of white crystals.

When the above white crystals were analyzed by high performance liquid chromatography, the formation t of 5-fluorocytidine was Q, 13 /
/ (Q, 5 tn +11o1) and unreacted (1) C? 9- There was still 1g of gin left.

that's all Patent applicant: Daikin Industries, Ltd. 10-

Claims (1)

[Claims] t(a) General formula: (In the formula, R1 and R4 are the same or different and represent hydrogen or a lower acyl group.) A cytidine compound represented by the following formula and a fluorinating agent are combined into i) hydrogen fluoride. and io general formula: (wherein R6 represents a lower acyl group, a halogenated acyl group, or a halogenated lower alkyl group). and general formula 2 (wherein, R1-
R5 is the same as above. ) to obtain a 5-fluorocytidine intermediate represented by (b) the general formula consisting of reacting this 5-fluorocytidine intermediate with ammonia or an amine: (wherein R1 and R4 are the same as above). A method for producing the represented 5-fluorocytidine compound.