JPH08325238A - 5-trifluoromethyluracil derivative and its production - Google Patents

Abstract

PURPOSE: To easily obtain the subject compound useful as a synthetic intermediate for carcinostatic agent and antiviral agent from inexpensive raw materials in high yield by trifluoromethylating a halogenated uracil derivative having a specific structure. CONSTITUTION: The objective compound of formula II is produced by trifluoromethylating a 5-halogenated uracil derivative of formula I (R<1> and R<2> are each H, a 1-10C alkyl, benzyl, etc.; X is Cl, I or Br) with preferably 0.5-5 times mol (based on the compound of formula I) of 2,2- difluoro-2-(fluorosulfonyl)acetic acid methyl ester. Preferably, copper or copper iodide is used as a catalyst and DMF is used as a reaction solvent in the above reaction. The reaction is carried out at 50-150 deg.C for 3-10hr. N<1> ,N<3> -dibenzyl-5- trifluoromethyluracil of formula III is a new compound among the compounds of formula II. The compound of formula III can be produced e.g. from N<1> ,N<3> - dibenzyl-5-iodouracil.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 5-trifluoromethyluracil derivative and a novel 5-trifluoromethyluracil derivative produced by the method. The 5-trifluoromethyluracil derivative is a compound useful as an intermediate for pharmaceuticals, agricultural chemicals, etc., particularly as a synthetic intermediate for anticancer agents or antiviral agents such as 5-trifluoromethyluridines and 5-trifluoromethyldeoxyuridines. is there.

[0002]

The following methods have been proposed for the production of 5-trifluoromethyluracil derivatives. (1) Using 2-bromo-3,3,3-trifluoromethylpropane as a starting material in the presence of a Pd catalyst, ureido-carbo
nylation and then reacting with Br ₂ or CuBr ₂ to obtain a 5-trifluoromethyluracil derivative [Tetrahedron Letters, 23, 4099 (1982), Chemistry Le
Tters, 1595 (1984), JP-A-60-94971].

(2) 5-Protecting the oxygen part of uracil
CF in bromo-2,4-dimethoxypyrimidine in phosphoric acid hexamethyltriamide (hereinafter referred to as HMPA).
₃ Method of obtaining 5-trifluoromethyl-2,4-dimethoxypyrimidine by reacting with I / Cu at 110 ° C. for 40 hours [J. Chem. Soc. Perkin Trans1 2755 (1980)].
(3) 2,4-bis (trimethylsiloxy) pyrimidine in which the oxygen portion of uracil is protected with a trimethylsilyl group is reacted with bis (trifluoroacetyl) peroxide, 2,4-bis (trimethylsiloxy) -5-trifluoromethyluracil [J. Fluorine Chem. 63,43
(1995), JP-A-4-117367].

(4) A method of electrolytically reacting uracil with trifluoroacetic acid. [Z. Chem., 17, 415 (1977), DD119423].
(5) A method of photoreacting uracil with (CF ₃ ) ₂ Hg.
[J.Prakt.Chem.326,985 (1984), DD208150]. (6) 5
- a method of reacting hydroxycarbonyl uracil and _{SF 4 [. J.Pahrm.Sci, 52,508 (} 1963), USP3324126].
(7) A method for obtaining 5-trifluoromethyluracil by chlorinating and fluorinating thymine [JP-A-6-73023].

[0005]

However, the above method has various drawbacks. That is, in the reaction of (1),
It is necessary to carry out the reaction using carbon monoxide at a high pressure of 40 atm, and there is a problem that an expensive raw material is used as a starting material. In the reaction of (2), since the trifluoromethylating agent CF ₃ I is a gas at room temperature, it is difficult to handle, and the yield is low at 42%.

In the reaction (3), the starting material is unstable with respect to water, bis (trifluoroacetyl) peroxide is difficult to obtain, and the yield is low at 39%. The reaction (4) has drawbacks that the yield is low and that an electrolysis facility that can withstand trifluoroacetic acid is required. The reaction (5) also has drawbacks such as low yield.
The method (6) has a drawback that SF ₄ which is highly toxic and dangerous must be used. The method (7) has a drawback that the number of steps is large.

[0007]

The present invention has been made to solve various drawbacks of the prior art, and is a 5-trifluoromethyluracil derivative useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like. The present invention provides a method for producing a high-yield reagent which has a simple reaction operation and is easy to handle.

That is, according to the present invention, a 5-halogenated uracil derivative represented by the general formula (1) is represented by the general formula (2) by trifluoromethylating the halogen atom at the 5-position. Provided is a method for producing a trifluoromethyluracil derivative.

[0009]

Embedded image

In the formula, R ¹ and R ² may be the same or different and each is a hydrogen atom or a carbon number of 1 to 1.
10 alkyl group, allyl group, alkoxycarbonyl group, formyl group, acetyl group, tetrahydropyranyl group, methoxymethyl group, ethoxymethyl group, phenyl group, benzyl group, benzyloxymethyl group, diphenylmethyl group, triphenylmethyl group , A diphenyl-4-pyridylmethyl group or a 2,2-dimethylpropanoyloxymethyl group. However, when R ² is a hydrogen atom, R ¹ represents a group other than a hydrogen atom. Also, R ¹
And R ² is a group other than a hydrogen atom, one or more hydrogen atoms present in the group may be substituted with a halogen atom. When it is a phenyl group, a benzyl group, a benzyloxymethyl group, a diphenylmethyl group, a triphenylmethyl group, or a diphenyl-4-pyridylmethyl group, one or two or more bonded to the benzene ring in the group. The hydrogen atom of may be substituted with a nitro group, a methoxy group, or chlorine. X is a chlorine atom, a bromine atom,
Alternatively, it represents an iodine atom.

The present invention is also an invention which provides a novel compound produced by the above method, and provides N ¹ , N ³ -dibenzyl-5-trifluoromethyluracil represented by the formula (3). .

[0012]

[Chemical 4]

In N ¹ , N ³ -dibenzyl-5-trifluoromethyluracil represented by the following formula (3), both R ¹ and R ² in the general formula (2) are benzyl groups (--CH ₂ C ₆ H ₅ ).

The present invention will be described in detail below. In the following, the 5-halogenated uracil derivative represented by the general formula (1) will be referred to as the compound (1), and other compounds will be similarly described.

R ¹ in compound (1) and compound (2)
R ² and R ² may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an allyl group, an alkoxycarbonyl group, a formyl group, an acetyl group, a tetrahydropyranyl group, methoxymethyl. Group, ethoxymethyl group, phenyl group, benzyl group, benzyloxymethyl group, diphenylmethyl group, triphenylmethyl group, diphenyl-4-pyridylmethyl group, or 2,2
Represents a dimethylpropanoyloxymethyl group. However, when R ² is a hydrogen atom, R ¹ represents a group other than a hydrogen atom. Further, when R ¹ and R ² are groups other than hydrogen atoms, one or more hydrogen atoms present in the groups may be replaced by halogen atoms. When it is a phenyl group, a benzyl group, a benzyloxymethyl group, a diphenylmethyl group, a triphenylmethyl group, or a diphenyl-4-pyridylmethyl group, one or two or more bonded to the benzene ring in the group. The hydrogen atom of may be substituted with a nitro group, a methoxy group, or chlorine. X
Represents a chlorine atom, a bromine atom, or an iodine atom.

The alkyl group having 1 to 10 carbon atoms is preferably methyl group or ethyl group. As the alkoxycarbonyl group, a methoxycarbonyl group and a t-butoxycarbonyl group are preferable. As the tetrahydropyranyl group,
2-tetrahydropyranyl group, 3-tetrahydropyranyl group, and 4-tetrahydropyranyl group can be mentioned, but 2
-A tetrahydropyranyl group is preferred. As the group in which the hydrogen atom of the phenyl group is substituted, a 2,4-dinitrophenyl group is preferable. The group in which the hydrogen atom of the benzyl group is substituted is preferably a 3,4-dimethoxybenzyl group or an o-nitrobenzyl group. As the group in which the hydrogen atom of the diphenylmethyl group is substituted, a di (p-methoxyphenyl) methyl group and a (p-methoxyphenyl) diphenylmethyl group are preferable.

In the compound (1) of the present invention, R ¹ and R ² are preferably the same, and when they are not the same, it is preferable that either of them is a hydrogen atom. Further, R ¹ and R ² are preferably a hydrogen atom, a benzyl group, or a benzyloxymethyl group. However, it is excluded when both R ¹ and R ² are hydrogen atoms.

X represents a chlorine atom, a bromine atom or an iodine atom, preferably a bromine atom or an iodine atom, particularly preferably an iodine atom.

The compound (1) when X is a bromine atom is represented by the general formula (4), and the general formula (1) when X is an iodine atom is represented by the general formula (5).

[0020]

Embedded image

R ¹ in compound (4) and compound (5)
And R ² have the same meanings as above, but R ¹ and R 2
^{When 2} are the same, it is preferably a group shown in Table 1. Further, when R ¹ and R ² are different, it is preferable that either is a hydrogen atom, and the combinations shown in Table 2 or R ¹ in Table 2 are R ²
A combination in which ² is R ¹ is preferred.

[0022]

[Table 1]

[0023]

[Table 2]

The compound (1) is a known compound
It can be easily synthesized from halogenouracil according to a conventional method. Also, after protecting the nitrogen portion of uracil in the same manner, 5
It can also be easily synthesized by halogenating the position.

The trifluoromethylation of the present invention is 2,2
Preference is given to working with methyl difluoro-2- (fluorosulfonyl) acetate (FSO ₂ CF ₂ COOCH ₃ ). Methyl 2,2-difluoro-2- (fluorosulfonyl) acetate is a liquid that is easy to handle and is commercially available. In addition, publicly known (J. Am. Chem. Soc., 82, 6181 (296
It can also be synthesized according to the method of 0)).

The amount of methylfluorosulfonyldifluoroacetate used in trifluoromethylation is preferably 0.2 to 10 times mol, particularly preferably 0.5 to 5 times mol, of the compound (1).

In the trifluoromethylation,
Preferably, copper or copper halide is present as a catalyst. As the copper halide, copper (I) iodide and copper (I) bromide are preferable, and copper (I) iodide is particularly preferable. The amount of copper or copper halide may be a catalytic amount.
0.5 to 200 mol% is preferable, and about 1 to 50 mol% is particularly preferable.

Further, the reaction of the present invention is preferably carried out in the presence of a solvent. As the solvent, an aprotic polar solvent that does not participate in the reaction is preferable, and particularly from the viewpoint of yield, ether, chloroform, tetrahydrofuran (hereinafter referred to as THF), acetonitrile, dimethylformamide (hereinafter referred to as DMF), Dimethyl sulfoxide (hereinafter referred to as DMSO), sulfolane, N-methylpyrrolidone (hereinafter referred to as NMP), dimethylacetamide (hereinafter referred to as DMAc), HMPA, tetramethylurea (hereinafter referred to as TMU). Etc. are preferable, and DMF is particularly preferable. The amount of the solvent is represented by general formula (1)
It is desirable to adjust the concentration of the compound (1) to be in the range of 1 to 50% by weight based on the solvent.

Trifluoromethylation can be carried out at atmospheric pressure, and the reaction temperature is preferably 0 to 200 ° C, particularly preferably 50 to 150 ° C. Further, the reaction time is preferably 10 minutes to 20 hours, and when industrially carried out, it is preferably about 3 to 10 hours.

The reaction product obtained by the production method of the present invention is usually preferably purified to a high purity by a known method such as distillation, column chromatography or recrystallization.

The 5-trifluoromethyluracil derivative (compound (2)) synthesized by the present invention is prepared by subjecting the groups (R ¹ and R ² ) bonded to the nitrogen atoms at the 1- and 3-positions to a known deprotection reaction. It can be easily replaced with a hydrogen atom and converted into 5-trifluoromethyluracil which is useful as an intermediate for medicines and agricultural chemicals. In the deprotection reaction, R ¹ and R ² of the compound (2) may be identical, the one of R ¹ and R ² are hydrogen atoms it is preferable in terms of ease of deprotection reaction .

The obtained compound (2) can be used as 5-trifluoromethyluridines and 5-trifluoromethyldeoxyuridines which are useful as anticancer agents or antiviral agents.

[0033]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 N ¹ , N ³ -dibenzyl-5
-Synthesis example of trifluoromethyluracil. N ¹ four-necked flask 200 ml, N ³ - dibenzyl-5-iodo-uracil (X = I) 7.45g (17.8
mmol), 0.81 g of copper (I) iodide (4.3 mmo)
l), 7.84 g (40.8 mmol) of methyl 2,2-difluoro-2- (fluorosulfonyl) acetate and 60 ml of DMF as a solvent were added, and the mixture was placed under a nitrogen gas atmosphere at 1
The mixture was stirred at 00 ° C for 3 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was poured into ice water, ether was added for extraction, the organic layer was washed with water and dried. Finally, purification was performed by column chromatography (carrier: silica gel, eluent (weight ratio): methanol / chloroform = 1/30),
N ^1, N ³ - dibenzyl-5-trifluoromethyl-uracil 5.72 g (89% yield). The analysis results of the obtained compound are shown below.

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 4.92 (2H, S),
5.07 (2H, S), 7.39 (20H, m), 7.68 (1H, S). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ) δ (ppm): -64.2.MS m / e: 360 (M ⁺ ) .

[Example 2] N ¹ , N ³ -dibenzyl-5
-Synthesis example of trifluoromethyluracil. N ¹ , N ³ -dibenzyl-5-iodouracil was replaced with N ¹ ,
The reaction was performed in the same manner as in Example 1 except that N ³ -dibenzyl-5-bromouracil (X = Br) was used, and N ¹ , N ³
-Dibenzyl-5-trifluoromethyluracil was added to 5.
19 g (yield 81%) was obtained.

[Example 3] Synthesis example of N ¹ , N ³ -dibenzyloxymethyl-5-trifluoromethyluracil. N ¹ four-necked flask 200 ml, N ³ - di benzyloxymethyl-5-iodo uracil 5.10 g (10.
7 mmol), 0.49 g (2.6 mm) of copper (I) iodide
ol), methyl 2,2-difluoro-2- (fluorosulfonyl) acetate (4.73 g, 24.6 mmol) and 60 ml of DMF as a solvent were charged under a nitrogen gas atmosphere 1
The mixture was stirred at 00 ° C for 3 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was poured into ice water, ether was added for extraction, the organic layer was washed with water and dried. Finally, purification was carried out by column chromatography (carrier: silica gel, eluent (weight ratio: methanol / CHCl ₃ = 1/30), N 2
^1, N ³ - di benzyloxymethyl-5-trifluoromethyl uracil 4.24 g (94% yield). The analysis results of the obtained compound are shown below.

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 4.63 (2H, S),
4.69 (2H, S), 5.24 (2H, S), 5.44 (2H, S), 7.30 (20H, m), 7.66
(2H, S). ¹⁹ F NMR (CDCl ₃ , CFCl ₃ ) δ (ppm): -64.5.MS m / e: 420 (M ⁺ ).

[Example 4] Synthesis example of N ¹ , N ³ -dibenzyloxymethyl-5-trifluoromethyluracil. N ^1, N ³ - di benzyloxymethyl-5-iodo uracil N ^1, N ³ - was replaced by di-benzyloxymethyl-5-bromo-uracil A reaction was conducted in the same manner as in Example 3, N ^1, N 3.95 g (yield 88%) of ^3- dibenzyloxymethyl-5-trifluoromethyluracil was obtained.

[Example 5] Synthesis example of N ¹ , N ³ -di (4-tetrafudropyranyl) -5-trifluoromethyluracil. N ¹ , N ³ -dibenzyl-5-iodouracil was replaced with N ¹ ,
N ³ - was replaced by di (2-tetrahydropyranyl) -5-iodo-uracil A reaction was conducted in the same manner as in Example 1, N
^There was obtained 4.83 g (yield 78%) of ¹ , N ³ -di (2-tetrahydropyranyl) -5-trifluoromethyluracil. The analysis results are shown below. ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ) δ (ppm):-64.2.MS m / e: 348 (M ⁺ ).

Example 6 Synthesis example of N ¹ -benzyl-5-trifluoromethyluracil. In a 200 ml four-necked flask, 5.84 g (17.8 mmol) of N ¹ -benzyl-5-iodouracil, 0.61 g (4.3 mmol) of copper (I) bromide, 2,2-difluoro-2- (fluoro) were used. Sulfonyl) methyl acetate 7.84
g (40.8 mmol) and 60 DMG as solvent
Then, the solution was added in an amount of ml and stirred at 100 ° C. for 3 hours under a nitrogen gas atmosphere. After completion of the reaction, the reaction solution was filtered, the filtrate was poured into ice water, ether was added for extraction, the organic layer was washed with water and dried. Finally, purification was performed by column chromatography (carrier: silica gel, eluent (weight ratio): methanol /
CHCl ₃ = 1/10) and N ¹ -benzyl-5-trifluoromethyluracil 4.09 g (yield 85%) were obtained.
The analysis results of the obtained compound are shown below.

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 4.90 (2H, S),
7.40 (6H, m). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ) δ (ppm):-64.3.MS m / e: 270 (M ⁺ ).

Example 7 Synthesis example of N ¹ -benzyloxymethyl-5-trifluoromethyluracil. N ¹ - benzyl-5-iodo-uracil N ¹ - except that instead of benzyloxymethyl-5-iodo uracil A reaction was conducted in the same manner as in Example 6, N ¹ - benzyloxymethyl-5-trifluoromethyl uracil 4.81 g
(Yield 90%) was obtained. The analysis results are shown below. ¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 4.70 (2H, S), 5.27 (2H, S), 7.
35 (5H, m), 7.73 (2H, S). ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ) δ (ppm):-64.2.MS m / e: 300 (M ⁺ ).

[0044]

EFFECTS OF THE INVENTION According to the production method of the present invention, 5-trifluoromethyluridines, 5-trifluoromethyldeoxyuridines and the like useful as synthetic intermediates useful as anticancer agents or antiviral agents The fluoromethyluracil derivative can be obtained in high yield from an inexpensive compound.

Claims (7)

[Claims] 1. A method for producing a 5-trifluoromethyluracil derivative represented by the general formula (2) by trifluoromethylating a 5-halogenated uracil derivative represented by the general formula (1). Embedded image In the formula, R ¹ and R ² may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an allyl group, an alkoxycarbonyl group, a formyl group, an acetyl group, tetrahydropyrani Group, methoxymethyl group, ethoxymethyl group, phenyl group, benzyl group,
Benzyloxymethyl group, diphenylmethyl group, triphenylmethyl group, diphenyl-4-pyridylmethyl group,
Alternatively, it represents a 2,2-dimethylpropanoyloxymethyl group. However, when R ² is a hydrogen atom, R ¹ represents a group other than a hydrogen atom. Further, when R ¹ and R ² are groups other than hydrogen atoms, one or more hydrogen atoms present in the groups may be replaced by halogen atoms.
When it is a phenyl group, a benzyl group, a benzyloxymethyl group, a diphenylmethyl group, a triphenylmethyl group, or a diphenyl-4-pyridylmethyl group,
One or more hydrogen atoms bonded to the benzene ring in the group may be substituted with a nitro group, a methoxy group or chlorine. X represents a chlorine atom, a bromine atom, or an iodine atom. 2. The process according to claim 1, wherein the trifluoromethylation is carried out using methylfluorosulfonyldifluoroacetate. 3. The method according to claim 2, wherein the trifluoromethylation is carried out in the presence of copper or copper halide. 4. The method according to claim 2, wherein the trifluoromethylation is carried out in an aprotic polar solvent. 5. The production method according to claim 1, wherein X is an iodine atom or a bromine atom. 6. The method according to claim 1, wherein R ¹ and R ² are both benzyl group or benzyloxymethyl group. 7. N ¹ , N ³ -dibenzyl-5-trifluoromethyluracil represented by the formula (3). Embedded image