JP2001247551A - Method of producing 5-perfluoroalktluracil derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of producing a 5-perfluoroalkyluracil derivative in a high yield without decomposing the objective product in the method of producing the 5-perfluoroalkyluracil derivative. SOLUTION: In this method of reacting a 5-perfluoroalkyl-5,6-dihydrouracil derivative with an alkyl sulfoxide in the presence of a halogen and an acid catalyst, an alkyl sulfoxide decomposition product prepared as a by-product is removed out of the system.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 5-perfluoroalkyluracil derivative. More specifically, an improved method for producing a 5-perfluoroalkyluracil derivative by reacting a 5-perfluoroalkyl-5,6-dihydrouracil derivative with an alkyl sulfoxide in the presence of a halogen or an acid catalyst Is provided.

[0002]

2. Description of the Related Art 5-Perfluoroalkyluracil derivatives have been attracting attention for a long time in relation to uracil and thymine, which are bases of nucleic acids. These 5-perfluoroalkyluracil derivatives are important substances as intermediates of pharmaceuticals known as anticancer agents, antiviral agents and the like, particularly represented by trifluorothymidine and its derivatives. Therefore, many studies have been made on a method for producing a 5-perfluoroalkyluracil derivative.

Conventionally, as a method for producing a 5-perfluoroalkyluracil derivative, a method of reacting 5-hydroxycarbonyluracil with SF ₄ [M. P. Meri
te, et. al. , J. et al. Pahrm. Sci. , 5
2,508 (1963)]. However, this method has the drawback that must be used high dangerous SF ₄ toxicity.

A method of reacting 5-iodouracil with trifluoromethyl copper [Y. Kobayashi,
et. al. , J. et al. C. S. Perkin I, 275
5 (1980)], but it has been found that in this method, the reaction intermediate is extremely sensitive to air and the like, and thus there is a problem in the reaction conditions and yield.

Further, a method of subjecting uracil and trifluoroacetic acid to an electrolytic reaction [L. Hein, D .; Cech, Z .;
Chem. , 17, 415 (1977)], but this method is not satisfactory as an industrial production method because it has poor yield and current efficiency and requires an electrolytic facility that can withstand trifluoroacetic acid.

Furthermore, Japanese Patent Application Laid-Open No. 58-174371 discloses a method of reacting 5-trifluoromethyl-5,6-dihydrouracil with bromine, but requires twice or more the theoretical amount of bromine. There are many problems such as a poor yield.

Japanese Patent Application Laid-Open No. Sho 60-94971 discloses 5-
A method of reacting trifluoromethyl-5,6-dihydrouracil with cupric halide is disclosed. However, a large amount of copper salt remains after the reaction, which is not satisfactory as an industrial production method such as operability and post-treatment of copper salt.

Further, Japanese Patent Application Laid-Open No. 7-33750 discloses that
A method is disclosed in which 5-trifluoromethyl-5,6-dihydrouracil is reacted with an alkyl sulfoxide in the presence of a halogen and in the presence of an acid catalyst to obtain 5-trifluoromethyluracil. This method describes that 5-trifluoromethyluracil can be obtained in a relatively high yield of about 80%. As a result of careful re-examination by the present inventors based on the above-mentioned gazette, it was confirmed that about 80%
Although 5-trifluoromethyluracil can be taken out at a relatively high yield, the present inventors have studied the reaction conditions in detail, and as the reaction proceeds, the target product is decomposed as the reaction proceeds. It was found that there was a problem of lowering. Therefore, the conventional method is insufficient as an industrial production method for producing a 5-perfluoroalkyluracil derivative in a high yield, and thus a desired compound that is important in pharmaceuticals can be obtained in a high yield. There has been a demand for an improved manufacturing method.

[0009]

The problem to be solved by the present invention is to provide a method for producing a 5-perfluoroalkyluracil derivative in a high yield without decomposing the desired product. An object of the present invention is to provide a production method for obtaining a uracil derivative.

[0010]

Means for Solving the Problems The present inventors have found that 5-perfluoroalkyl-5,6 in the presence of halogens and an acid catalyst.
A method for producing a 5-perfluoroalkyluracil derivative by reacting a -dihydrouracil derivative with an alkyl sulfoxide was examined.
In the reaction method described in Japanese Patent Publication No. 50, there is a problem that water and by-products of alkylsulfoxide such as alkylsulfide decompose the desired target product and reduce the yield during the reaction. I understood. Further, from the viewpoint of production on an industrial scale, it was also found that hydrogen fluoride generated by the decomposition of the target product had a serious drawback that the material of the reactor was deteriorated and corroded. The present inventors, in view of such current situation, as a result of intensive study,
In a method of reacting a 5-perfluoroalkyl-5,6-dihydrouracil derivative with an alkyl sulfoxide in the presence of a halogen or an acid catalyst, an alkyl sulfoxide decomposition product by-produced is removed from the system to remove the target product. The present inventors have found a method for producing a 5-perfluoroalkyluracil derivative in a high yield while suppressing decomposition, and have completed the present invention.

That is, the present invention provides: 1) a compound represented by the general formula (1) in the presence of a halogen and an acid catalyst:

[0012]

Embedded image

(Wherein, R ¹ and R ² represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and Rf represents a 1 to 1 carbon atom.
0 represents a perfluoroalkyl group. 5-)
In a method of reacting a perfluoroalkyl-5,6-dihydrouracil derivative with an alkyl sulfoxide,
General formula (2) characterized in that a by-product alkylsulfoxide decomposition product is removed out of the system.

[0014]

Embedded image

(Wherein, R ¹ , R ² and Rf have the same meanings as described above). 2) The method according to 1) above, wherein the by-product alkylsulfoxide decomposed product is removed under azeotropic conditions when it is removed from the system. 3) The method according to 2) above, wherein an azeotropic solvent is used for removing the by-product alkylsulfoxide decomposition product out of the system, and toluene is used as the azeotropic solvent.

4) When a by-product alkylsulfoxide decomposition product is removed to the outside of the system, a condenser is used as a reactor, and the circulating liquid is used at a temperature equal to or higher than the boiling point of the by-product alkylsulfoxide decomposition product. Wherein the alkylsulfoxide decomposed product is removed out of the system.

5) The above-mentioned 1) to 1), wherein all of the by-product alkylsulfoxide decomposition products are removed out of the system.
4) The method according to the above. 6) In the formulas (1) and (2), R ¹ and R ² are hydrogen atoms, Rf is a trifluoromethyl group, and alkyl sulfoxide is dimethyl sulfoxide (1 to 5).
The described method. 7) The method according to 1) to 6) above, wherein the halogen is iodine and the acid catalyst is sulfuric acid.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. In the present invention, in the formulas (1) and (2), R ¹ and R ² are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and examples of the alkyl group having 1 to 6 carbon atoms include Methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group,
Examples thereof include a t-butyl group, an n-pentyl group, an n-hexyl group, and a cyclohexyl group.

In the formulas (1) and (2), Rf is
A perfluoroalkyl group having 1 to 6 carbon atoms, such as perfluoromethyl group, perfluoroethyl group, perfluoropropyl group, perfluoroisopropyl group, perfluorobutyl group, perfluoroisobutyl group, perfluoropentyl group, Perfluorohexyl groups and the like can be mentioned.

General formula (1) used as a raw material in the present invention
The 5-perfluoroalkyl-5,6-dihydrouracil derivative represented by the general formula (3)

[0021]

Embedded image

(In the formula, Rf has the same meaning as described above.)
Α-perfluoroalkylacrylic acid represented by the general formula (4)

[0023]

Embedded image

(Wherein, R ¹ and R ² have the same meanings as described above). For example, [T. Fuchiga
mi, et. al. , Synthesis, 766 (1
984)] shows a synthesis method thereof.

Examples of the alkyl sulfoxide used in the present invention include lower alkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and dipropyl sulfoxide. However, the alkyl group of the alkyl sulfoxide is not limited to these.
Preferably a lower alkyl group of C ₁ -C _4. Further, it is considered that arylsulfoxide, arylalkylsulfoxide and the like can be used for the reaction.

The amount of the alkyl sulfoxide to be used can be generally 1 equivalent or more based on the starting material 5-perfluoroalkyl-5,6-dihydrouracil derivative, but is preferably 2 equivalents or more and 10 equivalents or less. is there.

As halogens, iodine, chlorine, bromine,
Although iodine monochloride and the like can be mentioned, iodine is preferred.

The halogen can be used in an amount of usually 0.01 to 10 equivalents to the 5-perfluoroalkyl-5,6-dihydrouracil derivative as a raw material, but 0.05 equivalents is used. A range of not less than 0.5 equivalents is preferable.

As the acid catalyst, both organic acids and inorganic acids can be used, and there is no particular limitation. Examples of the organic acid include acetic acid, trifluoroacetic acid, camphorsulfonic acid, p-toluenesulfonic acid, and trimethylsilane chloride.Examples of the inorganic acid include phosphoric acid, phosphorus pentoxide, sulfuric acid, and hydrochloric acid. Preferably, sulfuric acid is used as the acid catalyst.

The amount of the acid catalyst can be generally used in the range of 0.01 to 1 equivalent relative to the starting material, 5-perfluoroalkyl-5,6-dihydrouracil derivative. A range of not less than equivalent and not more than 0.5 equivalent is preferable.

The actual reaction mode may be any condition as long as by-product water and alkylsulfoxide decomposition products such as alkylsulfides are removed from the system. Specifically, 1) a method of removing the decomposed product out of the system under reduced pressure, or 2) using a reactor equipped with, for example, a condenser (with a Dean-Stark tube) as a reactor, and azeotropically decomposing the decomposed product. Under such conditions, there may be mentioned a method of removing the compound out of the system. Preferably,
The method 2) is not particularly limited.

The reaction solvent may be either alkyl sulfoxide alone or a mixture with an azeotropic solvent, and is not particularly limited.

When an azeotropic solvent is used to remove the alkylsulfoxide decomposed product out of the system, the azeotropic solvent used may be any solvent that can be azeotropic with the by-product alkylsulfoxide decomposed product. , Toluene, xylene, hexane, octane, cyclohexane and the like, but are not particularly limited.
Preferably, toluene is used, but these azeotropic solvents may be used alone or as a mixture.

The amount of the azeotropic solvent can be generally used in a range of 0.1 to 10 times the alkyl sulfoxide. Preferably, the range is 0.5 times or more and 5 times or less.

When a condenser is used as a reactor for removing by-product alkylsulfoxide decomposition products out of the system, water is suitable as a circulating liquid to be circulated in the condenser, but it is particularly limited. Not something.

The temperature of the circulating liquid circulating in the condenser is usually from 0 ° C. to the boiling point of the reaction solvent or lower. Preferably, the temperature is not lower than the boiling point of the alkylsulfoxide decomposition product and not higher than the boiling point of the reaction solvent.

The reaction temperature is usually from 10 ° C. to the boiling point of the reaction solvent, preferably from 90 ° C. to 150 ° C. The reaction time is usually 0.5 to 72 hours.

The thus-obtained 5-perfluoroalkyluracil derivative represented by the general formula (2) according to the present invention can be separated and purified by usual means such as extraction, concentration, filtration, recrystallization, column chromatography and the like. Can be used for isolation and purification.

[0039]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Reference Example 1 Synthesis of 5-trifluoromethyl-5,6-dihydrouracil In a 1 L four-necked flask equipped with a stirrer, a dropping funnel, a thermometer and a condenser, 85.8 g (1.43 mol) of urea was added. And 294.0 g (2.88 mol) of acetic anhydride, and the temperature of the solution was raised to 90 ° C. while stirring. 100 g of trifluoromethacrylic acid (0.71
(Mole) at 90 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, sulfuric acid was added to hydrolyze impurities in the reaction solution, and 96.7 g (0.53 g) of 5-trifluoromethyl-5,6-dihydrouracil was obtained by cooling crystallization.
Mol).

Melting point 203-205 ° C. IR (KBr): 3700-2800 cm ⁻¹ (ν _NH )
1750, 1710 cm ^-1 (ν _{C = o} ) ¹ H-NMR (d ₆ -acetone: TMS): δ 3.4 to
4.2 (m, 3H) 7.0 (bs, 1H) 9.5
(Bs, 1H) ¹⁹ F-NMR (d ₆ -acetone: CFCl ₃ ): δ-6
6.6 (m).

Example 1 In a 200 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser (with a Dean-Stark tube), 20 g of 5-trifluoromethyl-5,6-dihydrouracil (0.2 g) was added.
11 mol), 40 g (0.51 mol) of dimethyl sulfoxide, 20 g of toluene, 1.36 g (0.005 g) of iodine.
Mol) and 1.04 g (0.011 mol) of concentrated sulfuric acid. Warm water at 60 ° C. was circulated through the condenser, and the reaction solution was heated to 120 ° C. with stirring to start the reaction. Dimethyl disulfide (boiling point: 37 ° C.) by-produced with the progress of the reaction was passed through the condenser in a gaseous state and was removed from the system. Dimethyl disulfide gas was trapped with a sodium hypochlorite solution, and water, which is also an alkylsulfoxide decomposition product, was removed from the system by azeotropic distillation with toluene. The refluxing toluene was returned to the reaction solution as needed, and the mixture was heated and stirred at a reaction temperature of 120 ° C. for 14 hours. The produced 5-trifluoromethyluracil and the remaining 5-trifluoromethyl-5,6-dihydrouracil were subjected to HPLC
The reaction yield was determined by analysis according to
Mole%. The HPLC analysis conditions for each compound are shown below.

HPLC analysis conditions for 5-trifluoromethyluracil and 5-trifluoromethyl-5,6-dihydrouracil Column: YMC A-312 Eluent: 20 mM KH ₂ PO ₄ (pH = adjusted with phosphoric acid): Methanol = 7: 3 Column temperature: 40 ° C. Detection: 210 nm Flow rate: 0.5 ml / min Injection volume: 1 μl

Example 2 In a 200 ml four-necked flask equipped with a stirrer, a thermometer and a condenser (with a Dean-Stark tube), 20 g of 5-trifluoromethyl-5,6-dihydrouracil (0.
11 moles) and 40 g (0.51) of dimethyl sulfoxide.
Mol), toluene 20 g, iodine 1.36 g (0.00
5 mol) and 1.04 g (0.011 mol) of concentrated sulfuric acid. Cold water was circulated through the condenser, and the reaction solution was heated to 120 ° C. with stirring to start the reaction. Dimethyl sulfide (boiling point 37
C) was cooled by a condenser and returned into the system, and the reaction was carried out while water, which is also an alkylsulfoxide decomposition product, was removed from the system by azeotropic distillation with toluene. The refluxing toluene was returned as needed, and the mixture was heated and stirred at a reaction temperature of 120 ° C. for 16 hours. The produced 5-trifluoromethyluracil and the remaining 5-trifluoromethyl-5,6-dihydrouracil were analyzed by HPLC to determine the reaction yield. As a result, the reaction yield was 90.9 mol%.

Comparative Example 1 In a 200 ml four-necked flask equipped with a stirrer and a thermometer,
5-trifluoromethyl-5,6-dihydrouracil 2
0 g (0.11 mol) and 40 g of dimethyl sulfoxide
(0.51 mol), 1.36 g (0.005 mol) of iodine, and 1.04 g (0.011 mol) of concentrated sulfuric acid. The reaction solution was heated to 120 ° C. with stirring to start the reaction. While trapping gas generated with the progress of the reaction in sodium hypochlorite, the reaction temperature was 120 ° C.
For 8 hours. The generated 5-trifluoromethyluracil and the remaining 5-trifluoromethyl-5,
6-Dihydrouracil was analyzed by HPLC to determine the reaction yield. As a result, the reaction yield was 89.3 mol%. The results of Examples and Comparative Examples are summarized in a table.

[0046]

[Table 1]

[0047]

According to the present invention, it has become possible to produce a 5-perfluoroalkyluracil derivative in high yield. That is, the feature of the present invention is to suppress the decomposition of the target product, 5-trifluoromethyluracil, by removing water and by-products of the alkyl sulfoxide such as alkyl sulfide, which are produced as a by-product in the reaction, out of the system. To obtain a 5-perfluoroalkyluracil derivative.
In addition, the method of the present invention not only obtains the target product in high yield, but also suppresses the deterioration and corrosion of the material of the reaction vessel by suppressing hydrogen fluoride generated during decomposition of the target product. It has become possible to stably produce a 5-perfluoroalkyluracil derivative as a pharmaceutical intermediate on a large scale.

Claims (7)

[Claims] 1. A compound of the general formula (1) in the presence of a halogen or an acid catalyst. (Wherein, R ¹ and R ² represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and Rf represents a perfluoroalkyl group having 1 to 10 carbon atoms). A method of reacting a -5,6-dihydrouracil derivative with an alkyl sulfoxide, wherein the by-product alkylsulfoxide decomposition product is removed out of the system. (In the formula, R ¹ , R ² and Rf have the same meaning as described above.)
A method for producing a 5-perfluoroalkyluracil derivative represented by the formula: 2. The method according to claim 1, wherein when the by-product alkylsulfoxide decomposition product is removed out of the system, it is removed under azeotropic conditions. 3. The method according to claim 2, wherein an azeotropic solvent is used to remove the by-product alkylsulfoxide decomposition product out of the system, and toluene is used as the azeotropic solvent. 4. A condenser is used as a reactor when removing by-product alkylsulfoxide decomposition products out of the system, and the condenser used is provided with a circulating liquid at a temperature not lower than the boiling point of the by-product alkylsulfoxide decomposition products. Circulates,
The method according to any one of claims 1 to 3, wherein the decomposition product of the alkyl sulfoxide is removed from the system. 5. The method according to claim 1, wherein all by-products of the alkylsulfoxide decomposition are removed from the system.
4. The method according to 4. 6. In the formulas (1) and (2), R ¹ and R ² are hydrogen atoms, Rf is a trifluoromethyl group,
The method according to claims 1 to 5, wherein the alkyl sulfoxide is dimethyl sulfoxide. 7. The method according to claim 1, wherein the halogen is iodine and the acid catalyst is sulfuric acid.