JPS58140098A - Uridine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formulaI(R1 is H or acyl and R2 is 5-18C alkyl, alkenyl, >=6C cycloalkyl, phenyl, or naphthyl, or R1 is 2-4C acyl and R2 is 5-18C alkyl, alkenyl, or R1 is >=5C acyl and R2 is R'2-, R'2O- (R'2 is alkyl, alkenyl, phenyl, naphthyl, etc.)]. EXAMPLE:5'-O-Acetyl-5-fluoro-6-methoxy-5,6-dihydrouridine. USE:An antitumor agent. PROCESS:A compound shown by the formula II is reacted with fluorine in an element state or hyprofluorite shown by the formula RfOF(Rf is perfluoroalkyl) in the presence of an organic acid shown by the formula, so that fluorine and an acyloxy R'2COOH group are introduced to the 5 position and 6 position respectively, and, if necessary, the acyloxy group at the 6 position is converted into an alkoxy group with an alcohol shown by the formula R'-OH.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing uridine derivatives and a novel urinone derivative, and more specifically, to a method for producing uridine derivatives, and more particularly to a compound having the general formula: [wherein R represents hydrogen or an ar//l group. 5 of the compound shown in ]
At the same time as position is fluorinated, an anluoqui7 group or an alkokino group is introduced into the 6th position to give the general formula: %Formula% [wherein, R1 has the same meaning as above. R2 is R2'- or R
2'Co - (where R and l are aliphatic or aromatic hydrocarbon groups). ] The present invention relates to a method for producing the uridine derivative shown in the following and a novel compound among the uridyl derivatives (1).

In Japanese Patent Publication No. 41-18945, R has 1 to 1 carbon atoms.
A compound in which the acyl group of 4 and R2 are hydrogen, an alkyl group having 1 to 4 carbon atoms, or an acyl group having 2 to 4 carbon atoms (It
) is described. This production method uses a 5-fluorouridine derivative as a starting material and consists of the following steps: However, this production method is not economically advantageous because the 5-fluorouridine derivative is expensive.

As a result of repeated research to develop a new method for producing uridine derivatives (II), the present inventors discovered that compound (1), which is much cheaper than 5-fluorouridine derivatives, was able to be produced by poly-fluorinated compound (1) in a specific solvent. The uridino derivative (I) is obtained by
Furthermore, the inventors have discovered that it is possible to synthesize new compounds that are difficult to synthesize using the method described in the above-mentioned patent publication, and have completed the present invention.

That is, one gist of the present invention is to prepare the compound (1) using the general formula: R2' C0OH [wherein R2/ has the same meaning as above. ] In the presence of an organic acid represented by the following, elemental fluorine or the general formula: RfOF [wherein J represents a perfluoroalkyl group having 1 or 2 carbon atoms. ] to introduce fluorine at the 5th position and an acyloxy group at the 6th position by reacting with a hypofluoride represented by Same meaning. ], or (2) in the presence of water, reacting with elemental fluorine or the above-mentioned no-ibofluoride to introduce a hydroxy group into the 5- and 6-position fluorine, Then, the hydroxy group at the 6-position is alkylated or acylated, or (3) the general formula: R,'OH [wherein R2' has the same meaning as above]. ] In the presence of an alcohol represented by the formula Eri compound (I
The present invention relates to a method for producing a uridine derivative, which is characterized by obtaining a uridine derivative.

In the above formula, the acyl group of R1 preferably has 2 to 10 carbon atoms.
is an acyl group, and specific examples will be described later.

The aliphatic hydrocarbon group of R2/ preferably has 1 to 2 carbon atoms.
0 saturated or unsaturated alkyl group or a 7-chloroalkyl group having 6 or less carbon atoms.

Specific examples of saturated alkyl groups include methyl, ethyl, furoyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, tecyl, dodecyl, hexanoyl, octadecyl, etc., which may be linear or branched. It's fine. Specific examples of the unsaturated alkyl group include corresponding unsaturated groups.

Examples of the cycloalkyl group include cycloalkyl, cyclopentyl, and cyclobutyl.

Preferred examples of the aromatic hydrocarbon group include phenyl, tolyl, naphthyl, etc., and these groups include alkyl,
May be substituted with alkoxy or the like.

Among the acyl groups represented by R2'CO- above, examples of aliphatic acyl groups include acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, lauroyl, myristoyl, valmitoyl, stearoyl, and oleyl. Aromatic reed/14. ! : Then benzoyl,
An example is toluile.

Examples of the acyl group for R1 include the above-mentioned acyl groups having 2 to 10 carbon atoms. □Compound (1) used as a starting material in the method of the present invention can be prepared by using uridine as a starting material according to a known method. - and 3'-position protection and 5'-position esterification, followed by z- and 8
It can be easily prepared in high yield by hydrolysis of the protecting group at the '-position (e.g., DoM, Brown,
et al., J.

(See Chem, Soc, 1956, 2888)
.

Examples of reagents that form protecting groups include isopropylidene, and when these protecting groups are easily removed under acidic conditions, the compound [I] having the protecting group can be used as a starting material without hydrolysis. is also possible.

The reaction (1) above is carried out in the presence of an organic acid in an amount sufficient to dissolve the starting material compound (1"), and in the presence of an equimolar or more amount of elemental fluorine or hypofluoride relative to the starting material. The reaction can be carried out at a temperature of -70 to 50 C using .The reaction proceeds relatively quickly.

The reaction (2) occurs selectively if water is present in the reaction system. As the reaction solvent, water or a mixed solvent such as water and an organic acid or water and hydrogen fluoride can be used.

The reaction temperature when the reaction is carried out in water is θ to 100C. In the case of other mixed solvents, the decomposition temperature of the produced adduct differs depending on the solvent composition, so a temperature at which such decomposition does not occur is selected. Elemental fluorine or ibofluoride is used in an amount of 1 to 2 moles per mole of the starting material.

Alkylation of hydroxy groups can be carried out by reaction with alcohol R2'OH in the presence of a catalyst such as hydrochloric acid or methanesulfonic acid, and acylation can be carried out using an acylating agent such as a suitable acid halide or acid anhydride. This can be carried out under mild conditions.

In the reaction (8), when elemental fluorine is used, the fluorine is mixed in equimol -2 at -50 to 50r in a mixed solvent of hydrogen fluoride, trifluoroacetic acid, etc. and alcohol.
The reaction is carried out using twice the molar amount. Further, when using hypofluoride, the reaction is carried out using equimolar to 5 times the mole of hypofluoride in a solvent such as trichlorofluoromethane at an OC or lower, preferably from -50C1 to -30C.

In the compound (1) produced in this way, R1 has the same meaning as above and R2 is an alkyl group or alkenyl group having 5 to 18 carbon atoms, a cycloalkyl group having 6 or less carbon atoms, a phenyl group or a naphthyl group. group, R
1 is an acyl group having 2 to 4 carbon atoms and R2 is an acyl group having 5 to 1 carbon atoms.
8 alkyl or alkenyl group, or R
, is an acyl group having 5 or more carbon atoms and R2 is R
,'- or R2'CO- is a novel compound and is an aspect of the present invention. These new compounds are
Among compound (1), it is particularly less toxic than 5-fluorouridine, and has remarkable survival prolonging and tumor growth inhibiting effects on various animal tumors.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 200 m capacity Daiflon (trademark, Daikin Industries, Ltd.) equipped with a stirrer, cooler, gas inlet and thermometer
5'-〇-acetyluridine in a resin flask8. O
II was dissolved in 100 m/m of glacial acetic acid, and a fluorine/nitrogen mixed gas (20% fluorine) was added thereto at a flow rate of 50 m/m at room temperature.
n, for 1 hour.

Thin layer chromatography (silica gel plate 60F 2
54 (Merck & Co., Ltd.) 5X10 vice; chloroform:methanol = 5:1) to confirm that the starting material was consumed, and from the disappearance of ultraviolet absorption, 5.6-saturated compound 5.
-Fluoro-6-acetoxy-5'-0-acetyluridine was observed to be produced.

Amorphous 5-
1.5 fi of fluoro-6-acetoxy-5'-0-7 cetyl uridine was obtained. -N MR (d, -MeOH
; TM8i external standard) δ-2,12ppm (OCO
CH,).

Add 50ml of methanol to the remaining 50ml of glacial acetic acid solution, let stand for 3 days, dry under reduced pressure at room temperature, and analyze by thin layer chromatography (chloroform:methanol-5:l)
R, (measured by heating the plate at 200C for 1 hour after development and irradiating it with ultraviolet light) is 0.57, 0.55 and 0.51, which is 5'-〇-acetyl-5 containing isomers.
-Fluoro6-medoxy5,6-cyhydrouridine 1.8I! I got it.

Example 2 A solution of 5'-〇-acetyl-5-fluoro-6-acetoxy-5,6-dihydrouridine in glacial acetic acid prepared in the same manner as in Example 1 in 50 ml of glacial acetic acid and 50 ml of n~hexanol.
After stirring at 40C for 3 days, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography. 1
In 9F-NMR analysis (d, -MeOH; trifluoroacetic acid external standard), δ = 115.2 ppm, 129
．． 1 ppm and 18 Q, 5′-〇-acetyl-5 containing eight isomers showing chemical shifts of 4 ppm.
-Fluoro-6-hexanoki7-5,6-cyhydrouridine 1.51 was obtained.

Example 3 In a flask similar to Example 1, 8.09 of 5'-〇-hexanoyl uridine was dissolved in 100 of glacial acetic acid, and fluorine/nitrogen mixed gas (20% fluorine) was added to it at a flow rate of 60 at room temperature.
ml/min for 1 hour.

Consumption of starting material and 5°6-
The formation of saturated compounds was confirmed. A 50% solution of glacial acetic acid was dried under reduced pressure at room temperature to give 1.61% of 5'-〇-hexanoyl-5-fluoro-6-acetoxy-5,6-cyhydrouridine.
I got it. 'H-NMR (d, -MeOH; TMS i
External 1 quasi) δ-2, 12ppm (OCOCHs)
.

Add 50-d of n-butanol to the remaining 50+d of glacial acetic acid,
After stirring for 3 days, the solvent was distilled off and column chromatography (silica gel (Merck & Co., Ltd.) 70-230 mesh; chloroform:methanol = 10:1) was performed.
70.0.65 and Q, 5' containing isomers that are 62
-〇-hexanoyl-5-fluoro-6-poxy-5
, 1.3 g of 6-sihydrouridine was obtained.

Patent Applicant Daikin Industries, Ltd. Agent Patent Attorney Aoyama Aoyama (and 2 others) Procedural Amendment (spontaneous) 1. Indication of the case Patent Application No. 12205 of 1981 3. Relationship with the person making the amendment case Patent applicant address New Hankyu Building, 1-12-39 Umeda, Kita-ku, Osaka, Osaka Name (285) Daikin Industries, Ltd. Representative Yama 1) Minoru 5. Date of amendment order: (Voluntary) 6. Subject of amendment : "Detailed description of the invention" in the specification
Column 7, Contents of Amendment The width of the detailed description of the invention in the specification, the following parts will be amended.

Claims (1)

[Claims] [In the formula, R1 represents hydrogen or an acyl group. ] (1) General formula: R2'cOOH [R2' represents an aliphatic or aromatic hydrocarbon group. ] In the presence of an organic acid represented by 'elemental fluorine or the general formula: RfOF [wherein J is perfluoroalkyl]. ] to introduce fluorine at the 5-position and an acyloxy group at the 6-position by reacting with a hypofluoride represented by the formula: R2'OH [where R2/ is the same as above]. significance. ] ↓ into an alcohol represented by ↓alkoxy group, or (2) in the presence of water, react with elemental fluorine or the above-mentioned ibofluoride to introduce fluorine at the 5th position and a hydroxyl group at the 6th position. , then alkylating or acylating the 6-position hydroxy group, or (3) General formula: R2'OH [wherein: R2' has the same meaning as above. ] By reacting with elemental fluorine or the above-mentioned hypofluoride in the presence of an alcohol represented by the general formula: 0H HOOH [wherein R1 is the above-mentioned Same meaning. R2 is R2'- or R
, 'Co- (R and / have the same meanings as above). ] A method for producing a uridine derivative, characterized by obtaining a compound represented by the following. 2. The method according to claim 1, wherein the aliphatic hydrocarbon group of R2 is a saturated or unsaturated alkyl group having 1 to 20 carbon atoms or a cycloalkyl group having 6 or less carbon atoms. 3. The method according to claim 1, wherein the aromatic hydrocarbon group of R2 is a substituted or unsubstituted aryl group. 4. The manufacturing method according to claim 1, wherein R8 is an acyl group having 2 to 10 carbon atoms. 5, R2 is an alkyl group or alkenyl group having 5 to 20 carbon atoms, and 6 carbon atoms! The method according to claim 1, which is a cycloalkyl group, a phenyl group, or a naphthyl group. 6. The method according to claim 1, wherein R3 is an acyl group having 2 to 4 carbon atoms and R2 is an alkyl group or alkenyl group having 5 to 18 carbon atoms. 7. The manufacturing method according to claim 1, wherein R3 is an acyl group having 5 to 10 carbon atoms. [In the formula, R1 is hydrogen or an acyl group, and R1 is an alkyl group or alkenyl group having 5 to 18 carbon atoms, and 6 carbon atoms.
or a cycloalkyl group, a phenyl group, or a naphthyl group less than that, or R8 represents an acyl group having 2 to 4 carbon atoms, and R2 represents an alkyl group or alkenyl group having 5 to 18 carbon atoms, or RI represents a 5 to 5 carbon atoms or more acyl groups and R2 are R2'- or R,' O-(
Here, R2' is an alkyl group, an alkenyl group, a cycloalkyl group, a phenyl group or a naphthyl group. ) represents a group represented by ] A uridine derivative represented by.