JP3032837B2 - Fluoroalkyl group-containing pyrimidine derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pyrimidine derivative containing a fluoroalkyl group and a method for producing the same.

[0002]

2. Description of the Related Art Compounds containing a fluoroalkyl group in an organic compound have been attracting attention as exhibiting useful properties such as heat resistance, water / oil repellency, and physiological activity. In particular, fluoroalkyl group-containing pyrimidine derivatives in which a fluoroalkyl group has been introduced into a pyrimidine compound are considered to be useful as pharmaceuticals, agricultural chemicals, and the like, particularly as synthetic intermediates for anticancer agents or antiviral agents, and have been receiving attention. However, at present, little is known about the fluoroalkyl group-containing pyrimidine derivative and its production method.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a fluoroalkyl group-containing pyrimidine derivative which can be used as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like, and a method for producing the same.

Another object of the present invention is to provide a method for producing a fluoroalkyl group-containing pyrimidine derivative easily and with high yield without using a reaction catalyst and a special apparatus.

[0005]

According to Means for Solving the Problems] The present invention, the following general formalized 4 (wherein R represents an oxygen atom or sulfur atom, Y represents a carbon atom or a nitrogen atom, Z is a hydrogen atom, a carbon X represents a hydrogen atom, a fluorine atom or a chlorine atom, n represents an integer of 1 to 10, m represents 0 or 1, provided that Y represents a hydrogen atom, a fluorine atom or a chlorine atom. A method for producing a fluoroalkyl group-containing pyrimidine derivative (hereinafter, referred to as pyrimidine derivative 1) represented by m represents 1 in the case of a carbon atom and m represents 0 in the case of Y being a nitrogen atom :

[0006]

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[0007] The following general formalized 5 (wherein X is a hydrogen atom, a fluorine atom or chlorine atom, n is an integer of 1 to 10) and di (haloacyl) peroxide represented by (hereinafter referred to as peroxide 2) , The following general formula 6 (wherein R
Represents an oxygen atom or a sulfur atom, Y represents a carbon atom or a nitrogen atom, A represents an alkyl group having 1 to 4 carbon atoms, Z represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or trifluoromethyl. Represents a group. M represents 0 or 1. However, when Y is a carbon atom, m represents 1.
A production method characterized by reacting with pyrimidines represented by the following formula (where m represents 0 when Y is a nitrogen atom) (hereinafter referred to as pyrimidines 3):

[0008]

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[0009]

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Hereinafter, the present invention will be described in more detail.

The fluoroalkyl group-containing pyrimidine derivative of the present invention is a pyrimidine derivative 1 represented by the above general formula (4). In the pyrimidine derivative 1, when Z is an alkyl group having 5 or more carbon atoms, production is difficult,
When n is 11 or more, it cannot be used because solubility in a solvent is reduced.

In the pyrimidine derivative 1, the applicable fluoroalkyl group, ie,-(CF ₂ ) n ₁ X, is specifically listed as F ₃ C—, F (CF ₂ ) ₂ —, F (C
F ₂ ) ₃ −, F (CF ₂ ) ₄ −, F (CF ₂ ) ₅ −, F (CF
_{2) 6 -, F (CF} 2) 7 -, F (CF 2) 8 -, F (C
_{F 2) 9 -, F (} CF 2) 10 -, HCF 2 -, H (CF 2) 2
_{-H (CF 2) 3 -,} H (CF 2) 4 -, H (CF 2) 5 -,
_{H (CF 2) 6 -,} H (CF 2) 7 -, H (CF 2) 8 -, H
_{(CF 2) 9 -, H} (CF 2) 10 -, ClCF 2 -, Cl
_{(CF 2) 2 -, Cl} (CF 2) 3 -, Cl (CF 2) 4 -,
_{Cl (CF 2) 5 -,} Cl (CF 2) 6 -, Cl (CF 2) 7
−, Cl (CF ₂ ) ₈ −, Cl (CF ₂ ) ₉ −, Cl (CF
₂ ) It is _10- .

The pyrimidine derivative 1 represented by the general formula 4 is, for example, 5- (trifluoromethyl)-
6-methyluracil, 5- (pentafluoroethyl)-
6-methyluracil, 5- (heptafluoropropyl)
-6-methyluracil, 5- (nonafluorobutyl)-
6-methyluracil, 5- (undecafluoropentyl) -6-methyluracil, 5- (tridecafluorohexyl) -6-methyluracil, 5- (pentadecafluoroheptyl) -6-methyluracil, 5- ( (Chlorodifluoromethyl) -6-methyluracil, 5- (2'-
Chlorotetrafluoroethyl) -6-methyluracil,
5- (3'-chlorohexafluoropropyl) -6-methyluracil, 5- (4'-chlorooctafluorobutyl) -6-methyluracil, 5- (5'-chlorodecafluoropentyl) -6-methyluracil , 5- (6′-
(Chlorododecafluorohexyl) -6-methyluracil, 5- (7'-chlorotetradecafluoroheptyl)
-6-methyluracil, 5- (H-difluoromethyl)
-6-methyluracil, 5- (2'-H-tetrafluoroethyl) -6-methyluracil, 5- (3'-H-hexafluoropropyl) -6-methyluracil, 5-
(4′-H-octafluorobutyl) -6-methyluracil, 5- (5′-H-decafluoropentyl) -6
Methyluracil, 5- (6′-H-dodecafluorohexyl) -6-methyluracil, 5- (7′-H-tetradecafluoroheptyl) -6-methyluracil, 5-
(Trifluoromethyl) -6-trifluoromethyluracil, 5- (pentafluoroethyl) -6-trifluoromethyluracil, 5- (heptafluoropropyl)-
6-trifluoromethyluracil, 5- (nonafluorobutyl) -6-trifluoromethyluracil, 5- (undecafluoropentyl) -6-trifluoromethyluracil, 5- (tridecafluorohexyl) -6-tri Fluoromethyluracil, 5- (pentadecafluoroheptyl) -6-trifluoromethyluracil, 5- (chlorodifluoromethyl) -6-trifluoromethyluracil, 5- (2'-chlorotetrafluoroethyl) -6
-Trifluoromethyluracil, 5- (3'-chlorohexafluoropropyl) -6-trifluoromethyluracil, 5- (4'-chlorooctafluorobutyl) -6
-Trifluoromethyluracil, 5- (5'-chlorodecafluoropentyl) -6-trifluoromethyluracil, 5- (6'-chlorododecafluorohexyl) -6
-Trifluoromethyluracil, 5- (7'-chlorotetradecafluoroheptyl) -6-trifluoromethyluracil, 5- (H-difluoromethyl) -6-trifluoromethyluracil, 5- (2'-H- Tetrafluoroethyl) -6-trifluoromethyluracil, 5-
(3′-H-hexafluoropropyl) -6-trifluoromethyluracil, 5- (4′-H-octafluorobutyl) -6-trifluoromethyluracil, 5-
(5′-H-decafluoropentyl) -6-trifluoromethyluracil, 5- (6′-H-dodecafluorohexyl) -6-trifluoromethyluracil, 5-
(7'-H-tetradecafluoroheptyl) -6-trifluoromethyluracil, 5- (trifluoromethyl)
-6-azauracil, 5- (pentafluoroethyl)-
6-azauracil, 5- (heptafluoropropyl)-
6-azauracil, 5- (nonafluorobutyl) -6
Azauracil, 5- (undecafluoropentyl) -6
-Azauracil, 5- (tridecafluorohexyl)-
6-azauracil, 5- (pentadecafluoroheptyl) -6-azauracil, 5- (chlorodifluoromethyl) -6-azauracil, 5- (2'-chlorotetrafluoroethyl) -6-azauracil, 5- (3 ' -Chlorohexafluoropropyl) -6-azauracil, 5-
(4′-chlorooctafluorobutyl) -6-azauracil, 5- (5′-chlorodecafluoropentyl) -6
-Azauracil, 5- (6'-chlorododecafluorohexyl) -6-azauracil, 5- (7'-chlorotetradecafluoroheptyl) -6-azauracil, 5-
(H-difluoromethyl) -6-azauracil, 5-
(2′-H-tetrafluoroethyl) -6-azauracil, 5- (3′-H-hexafluoropropyl) -6
Azauracil, 5- (4'-H-octafluorobutyl) -6-azauracil, 5- (5'-H-decafluoropentyl) -6-azauracil, 5- (6'-H-dodecafluorohexyl) -6 -Azauracil, 5-
(7'-H-tetradecafluoroheptyl) -6-azauracil, 5- (trifluoromethyl) -2-thiouracil, 5- (pentafluoroethyl) -2-thiouracil, 5- (heptafluoropropyl) -2- Thiouracil, 5- (nonafluorobutyl) -2-thiouracil,
5- (undecafluoropentyl) -2-thiouracil, 5- (tridecafluorohexyl) -2-thiouracil, 5- (pentadecafluoroheptyl) -2-thiouracil, 5- (chlorodifluoromethyl) -2-thiouracil , 5- (2'-chlorotetrafluoroethyl)
-2-thiouracil, 5- (3'-chlorohexafluoropropyl) -2-thiouracil, 5- (4'-chlorooctafluorobutyl) -2-thiouracil, 5-
(5'-chlorodecafluoropentyl) -2-thiouracil, 5- (6'-chlorododecafluorohexyl)-
2-thiouracil, 5- (7'-chlorotetradecafluoroheptyl) -2-thiouracil, 5- (H-difluoromethyl) -2-thiouracil, 5- (2'-H-tetrafluoroethyl) -2-thiouracil , 5- (3 '
-H-hexafluoropropyl) -2-thiouracil,
5- (4'-H-octafluorobutyl) -2-thiouracil, 5- (5'-H-decafluoropentyl) -2
-Thiouracil, 5- (6'-H-dodecafluorohexyl) -2-thiouracil, 5- (7'-H-tetradecafluoroheptyl) -2-thiouracil and the like can be preferably exemplified.

The process for producing a fluoroalkyl group-containing pyrimidine derivative according to the present invention is carried out using a specific di (haloacyl)
It is characterized by reacting peroxide with specific pyrimidines.

The di (haloacyl) peroxide used as a raw material component in the production method of the present invention is represented by the general formula
Is peroxide 2. When n is 11 or more, the peroxide 2 cannot be used because a problem occurs in the solubility of the peroxide 2 when reacting in the presence of a solvent.

In the production method of the present invention, the pyrimidine to be reacted with the peroxide 2 is the pyrimidine 3 represented by the general formula (6). The pyrimidines 3
In the above, when A is an alkyl group having 5 or more carbon atoms and Z is an alkyl group having 5 or more carbon atoms, production is difficult.

The pyrimidines 3 include, for example, 2,
4-bis (trimethylsiloxy) -6-methyl-pyrimidine, 2,4-bis (trimethylsiloxy) -6-trifluoromethyl-pyrimidine, 2,4-bis (trimethylsiloxy) -6-azapyrimidine, 2-trimethylsilyl Thio-4-trimethylsiloxypyrimidine and the like can be preferably mentioned.

In the production method of the present invention, the molar ratio of the peroxide 2 to the pyrimidines 3 is 1: 1:
The ratio is preferably from 0.2 to 10, particularly preferably from 1: 0.5 to 5. When the charged molar ratio of the pyrimidines 3 is less than 0.2, the yield of the resulting fluoroalkyl group-containing pyrimidine derivative is reduced, and when it exceeds 10, unreacted pyrimidines 3 after the reaction is completed. Undesirably remains in a large amount, making it difficult to isolate the desired product. The reaction can be carried out at normal pressure, and the reaction temperature is preferably in the range of 0 to + 150 ° C, particularly preferably in the range of 0 to 100 ° C. When the reaction temperature is less than 0 ° C., a long reaction time is required,
When the temperature exceeds ℃, the pressure at the time of the reaction becomes high and the reaction operation is difficult, which is not preferable. Further, the reaction time is 30 minutes to 20 minutes.
The range of time is preferable, and the range of 3 to 10 hours is particularly preferable industrially.

In the production method of the present invention, the desired fluoroalkyl group-containing pyrimidine derivative can be produced by reacting the peroxide 2 with the pyrimidines 3 under the various reaction conditions. In order to handle and react the peroxide 2 more smoothly, the reaction is preferably performed using a solvent.
As the solvent, a halogenated aliphatic solvent, specifically, for example, 2-chloro-1,2-dibromo-1,1,2-trifluoroethane, 1,2-dibromohexafluoropropane, 1,2-dibromo Tetrafluoroethane, 1,
1-difluorotetrachloroethane, 1,2-difluorotetrachloroethane, fluorotrichloromethane, heptafluoro-2,3,3-trichlorobutane, 1,
1,1,3-tetrachlorotetrafluoropropane,
1,1,1-trichloropentafluoropropane, 1,
Preferred are 1,2-trichlorotrifluoroethane and the like, and particularly industrially, 1,1,2-trichlorotrifluoroethane is preferred. The amount of the solvent to be charged is preferably adjusted so that the concentration of the peroxide 2 is in the range of 1 to 30% by weight based on the solvent.

The reaction product obtained by the production method of the present invention can be purified by a known method such as distillation, column chromatography, recrystallization and the like.

[0021]

Industrial Applicability The fluoroalkyl group-containing pyrimidine derivative of the present invention is useful as a pharmaceutical, a pesticide and the like, particularly as a synthetic intermediate for an anticancer agent and an antiviral agent. Further, in the production method of the present invention, a fluoroalkyl group-containing pyrimidine derivative can be produced in a short time, at a high yield and easily, without using a reaction catalyst and a special device.

[0022]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

[0023]

Example 1 Under an argon atmosphere, 0.76 g (6.03 mmol) of 6-methyluracil was suspended in 30 ml of dry dioxane, and then 1.83 g of trimethylamine.
(18.1 mmol), and finally 1.96 g (18.0 mmol) of trimethylchlorosilane was added to carry out a reaction.
2,4-Bis (trimethylsiloxy) -6-methyl-pyrimidine was obtained quantitatively. Next, 30 ml of 1,1,2-trichlorotrifluoroethane was added to the resulting mixed solution to completely dissolve the suspension. Then, while maintaining the temperature of the obtained solution at 30 ° C, 51.3 solution of 1,1,2-trichlorotrifluoroethane containing 2.57 g (6.03 mmol) of bis (heptafluorobutyryl) peroxide.
7 g was dropped from the dropping funnel. Next, after stirring at the same temperature for 2 hours, reflux was performed for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of water was added, and the mixture was stirred for 2 hours. Then, 150 ml of ethyl acetate was added for extraction, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over magnesium sulfate.
Finally, purification was performed by column chromatography to obtain 5- (heptafluoropropyl) -6-methyluracil in a yield of 36%. Table 1 shows the results of various analyzes of the obtained compound.

[0024]

[Table 1]

[0025]

Example 2 The reaction and purification were carried out in the same manner as in Example 1 except that bis (heptafluorobutyryl) peroxide was replaced with bis (pentadecafluoroheptanoyl) peroxide, to obtain 5- (pentadecafluorohexyl) peroxide. −
6-Methyluracil was obtained in a yield of 40%. Table 2 shows the analysis results.

[0026]

[Table 2]

[0027]

Example 3 Example 1 was repeated except that bis (heptafluorobutyryl) peroxide was replaced with bis (trifluoroacetyl) peroxide at a reaction temperature of 30 ° C. to 70 ° C., and the reaction was carried out in a pressure-resistant ampoule. The reaction and purification were carried out in the same manner as in the above to give 5- (trifluoromethyl) -6-methyluracil in a yield of 36%. Table 3 shows the analysis results.

[0028]

[Table 3]

[0029]

Example 4 The reaction and purification were carried out in the same manner as in Example 1 except that bis (heptafluorobutyryl) peroxide was replaced with bis (chlorodifluoroacetyl) peroxide, to give 5- (chlorodifluoromethyl) -6- Methyluracil was obtained in a yield of 41%. Table 4 shows the analysis results.

[0030]

[Table 4]

[0031]

Example 5 2,4-bis (trimethylsiloxy) -6
The reaction and purification were carried out in the same manner as in Example 1, except that -methyl-pyrimidine was replaced with 2,4-bis (trimethylsiloxy) -6-trifluoromethylpyrimidine.
-(Heptafluoropropyl) -6-trifluoromethyluracil was obtained in a yield of 41%. Table 5 shows the analysis results.

[0032]

[Table 5]

[0033]

Example 6 2,4-bis (trimethylsiloxy) -6
Example 1 except that -methyl-pyrimidine was replaced by 2,4-bis (trimethylsiloxy) -6-azapyrimidine
The reaction and purification were carried out in the same manner as in the above to give 5- (heptafluoropropyl) -6-azauracil at a yield of 13%. The results of the analysis are shown in Table 6.

[0034]

[Table 6]

[0035]

Example 7 2,4-bis (trimethylsiloxy) -6
-Methyl-pyrimidine is converted to 2-trimethylsilylthio-4
The reaction and purification were carried out in the same manner as in Example 1 except for using -trimethylsiloxypyrimidine, to obtain 5- (heptafluoropropyl) -2-thiouracil in a yield of 20%. Table 7 shows the analysis results.

[0036]

[Table 7]

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yuo Hayakawa 4-33, Yamabushi, Nishiimajuku, Jimaji-cho, Kaifu-gun, Aichi Prefecture (72) Inventor Hideo Sawada 2-24-5, Umezono, Tsukuba, Ibaraki Prefecture (72) Inventor Motohiro Mitani 2-17-1 Kasuga, Tsukuba, Ibaraki Pref. (72) Inventor Masayo Nakayama 1132-9, Ekuni, Tsuchiura, Ibaraki Examiner Shunichi Yokoo (56) References JP-A 4-117367 (JP, A) 1984-39875 (JP, A) Chemical Abstracts; vol. 85 (No. 9) p560 Abstract No. 63022h Tetrahedron Letters; vol. 23 (No. 40) p4099-5000 (1982) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 239/553 C07D 239/56 C07D 253/075 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A following general formalized 1 (wherein R represents an oxygen atom or sulfur atom, Y represents a carbon atom or a nitrogen atom, Z is a hydrogen atom, an alkyl group or trifluoromethyl having 1 to 4 carbon atoms X represents a hydrogen atom, a fluorine atom or a chlorine atom, n represents an integer of 1 to 10, and m represents 0 or 1. However, when Y is a carbon atom, m represents 1. Wherein m is 0 when Y is a nitrogen atom), wherein the pyrimidine derivative containing a fluoroalkyl group is represented by the following formula : Wherein X is a hydrogen atom, a fluorine atom or a salt
And n represents an integer of 1 to 10)
Di (haloacyl) peroxide and the following general formula 3
(Wherein R represents an oxygen atom or a sulfur atom, and Y represents
A represents an atom or a nitrogen atom, and A represents an atom having 1 to 4 carbon atoms.
And Z represents a hydrogen atom, an alkyl having 1 to 4 carbon atoms.
Or a trifluoromethyl group. M is 0
Or 1 is shown. However, when Y is a carbon atom, m is 1
And when Y is a nitrogen atom, m represents 0)
Characterized by reacting with pyrimidines
Construction method. Embedded image Embedded image