JPH04257565A - Polyfluoroalkyl group-containing pyrimidine derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new polyfluoroalkyl group-containing pyrimidine derivative useful as a medicine, agricultural chemical, water and oil repelling agent, etc., especially as a synthetic intermediate of anticancer agent and antiviral agent. CONSTITUTION:A compound, e.g. 5-(perfluoro-1'-methyl-2'-oxapentyl)-6- methyluracyl, expressed by formula I (X is O or S; Y is C or N; Z is H, 1-4C alkyl or trifluoromethyl; (n) is 0-8; (m) is 0 or 1; when Y is C, (m) is 1 and when Y is N, (m) is O). The compound is readily obtained in high yield without using a reaction catalyst and special device by reacting a peroxypolyfluoroalk, anoyl expressed by formula II with pyrimidines expressed by formula III (A is 1-4C alkyl) in a solvent (e.g. 1,1,2-trichlorotrifluoroethane) at 0-150 deg.C.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to a polyfluoroalkyl group-containing pyrimidine derivative and a method for producing the same.

0002

BACKGROUND OF THE INVENTION Among organic compounds, compounds containing fluoroalkyl groups have attracted attention as they exhibit useful properties such as heat resistance, water and oil repellency, and physiological activity. In particular, pyrimidine derivatives containing a fluoroalkyl group, in which a fluoroalkyl group is introduced into a pyrimidine compound, are attracting attention because they are thought to be useful as medicines, agricultural chemicals, etc., and especially as synthetic intermediates for anticancer agents or antiviral agents. However, at present, little is known about the polyfluoroalkyl group-containing pyrimidine derivatives and their production methods.

0003

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

Another object of the present invention is to provide a method for easily producing polyfluoroalkyl group-containing pyrimidine derivatives in high yield without using a reaction catalyst or special equipment.

[0005]

[Means for Solving the Problems] According to the present invention, it is represented by the following general formula 4 (wherein, X represents an oxygen atom or a sulfur atom, Y represents a carbon atom or a nitrogen atom, and Z
represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a trifluoromethyl group. In addition, n represents an integer from 0 to 8,
m represents 0 or 1. However, when Y is a carbon atom, m indicates 1, and when Y is a nitrogen atom, m indicates 0)
A polyfluoroalkyl group-containing pyrimidine derivative represented by (hereinafter referred to as pyrimidine derivative 1) is provided.

[0006]

[C4]

Further, according to the present invention, a polyfluoroalkanoyl peroxide (hereinafter referred to as alkanoyl 2) represented by the following general formula 5 (wherein n represents an integer of 0 to 8);
The following general formula 6 (in the formula, X 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, and Z represents a hydrogen atom, a carbon number 1 ~4 represents an alkyl group or trifluoromethyl group. Also, m represents 0 or 1. However, when Y is a carbon atom, m represents 1, and when Y is a nitrogen atom, m represents 0.
There is provided a method for producing the pyrimidine derivative 1, which comprises reacting the pyrimidines represented by (hereinafter referred to as pyrimidines 3).

[0008]

[C5]

[0009]

[C6]

The present invention will be explained in more detail below.

The polyfluoroalkyl group-containing pyrimidine derivative of the present invention is the pyrimidine derivative 1 represented by the general formula 4 above. In the pyrimidine derivative 1,
When Z is an alkyl group having 5 or more carbon atoms, it is difficult to manufacture, and when n is 9 or more, the solubility in a solvent decreases, so that it cannot be used.

In the pyrimidine derivative 1, applicable polyfluoroalkyl groups, ie, the following general formula 7, are specifically listed as the following chemical formulas 8, 9, 10,
These are chemical formula 11, chemical formula 12, chemical compound 13, chemical compound 14, chemical compound 15, and chemical compound 16.

[0013]

[C7]

[0014]

[Chemical formula 8]

[0015]

[Chemical formula 9]

[0016]

[Chemical formula 10]

[0017]

[Chemical formula 11]

[0018]

[Chemical formula 12]

[0019]

[Chemical formula 13]

[0020]

[Chemical formula 14]

[0021]

[Chemical formula 15]

[0022]

[Chemical formula 16]

Examples of the pyrimidine derivative 1 represented by the general formula 4 include 5-(perfluoro-1'-methyl-2'-oxapentyl)-6-methyluracil,
5-(perfluoro-1',4'-dimethyl-2',5
'-dioxaoctyl)-6-methyluracil, 5-(
Perfluoro-1',4',7'-trimethyl-2',
5',8'-trioxaundecyl)-6-methyluracil, 5-(perfluoro-1',4',7',10'
-tetramethyl-2',5',8',11'-tetraoxa-tetradecyl)-6-methyluracil, 5-(perfluoro-1',4',7',10',13'-pentamethyl-2' , 5', 8', 11', 14'-pentaoxa-pentadecyl)-6-methyluracil, 5-(
perfluoro-1'-methyl-2'-oxapentyl)
-6-trifluoromethyluracil, 5-(perfluoro-1',4'-dimethyl-2',5'-dioxaoctyl)-6-trifluoromethyluracil, 5-(perfluoro-1',4', 7'-trimethyl-2',5'
, 8'-trioxaundecyl)-6-trifluoromethyluracil, 5-(perfluoro-1',4',7'
,10'-tetramethyl-2',5',8',11'-
Tetraoxa-tetradecyl)-6-trifluoromethyluracil, 5-(perfluoro-1',4',7',
10',13'-pentamethyl-2',5',8',1
1',14'-pentaoxa-pentadecyl)-6-trifluoromethyluracil, 5-(perfluoro-1'
-Methyl-2'-oxapentyl)-6-azauracil, 5-(perfluoro-1',4'-dimethyl-2',
5'-dioxaoctyl)-6-azauracil, 5-(
Perfluoro-1',4',7'-trimethyl-2',
5',8'-trioxaundecyl)-6-azauracil, 5-(perfluoro-1',4',7',10'-
Tetramethyl-2',5',8',11'-tetraoxa-tetradecyl)-6-azauracil,5-(perfluoro-1',4',7',10',13'-pentamethyl-2',5 ',8',11',14'-pentaoxa-pentadecyl)-6-azauracil, 5-(perfluoro-1'-methyl-2'-oxapentyl)-2-
Thiouracil, 5-(perfluoro-1',4'-dimethyl-2',5'-dioxaoctyl)-2-thiouracil, 5-(perfluoro-1',4',7'-trimethyl-2',5 ',8'-trioxaundecyl)-2
-thiouracil, 5-(perfluoro-1',4',7
',10'-tetramethyl-2',5',8',11'
-tetraoxa-tetradecyl)-2-thiouracil,
5-(perfluoro-1', 4', 7', 10', 13
'-Pentamethyl-2', 5', 8', 11', 14'
-Pentaoxa-pentadecyl)-2-thiouracil and the like can be preferably mentioned.

The method for producing a polyfluoroalkyl group-containing pyrimidine derivative according to the present invention is characterized by reacting a specific polyfluoroalkanoyl peroxide with a specific pyrimidine.

The polyfluoroalkanoyl peroxide used as a raw material component in the production method of the present invention is alkanoyl 2 represented by the general formula 5 above. In the alkanoyl 2, when n is 9 or more, a problem arises in the solubility of the dipolyfluoroalkanoyl peroxide when reacting in the presence of a solvent, so it cannot be used.

In the production method of the present invention, the pyrimidine to be reacted with the alkanoyl 2 is the pyrimidine 3 represented by the general formula 6. The above pyrimidines 3
In the case where 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 Preferable examples include thio-4-trimethylsiloxypyrimidine.

In the production method of the present invention, the molar ratio of the alkanoyl 2 and the pyrimidine 3 is 1:
The ratio is preferably 0.2 to 10, particularly preferably 1:0.5 to 5. The charging molar ratio of the pyrimidines 3 is 0
．． When it is less than 2, the yield of the polyfluoroalkyl group-containing pyrimidine derivative to be produced decreases, and when it is more than 10, unreacted pyrimidines 3
This is not preferable since a large amount of remains, making it difficult to isolate the desired product. Further, 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. If the reaction temperature is less than 0°C, the reaction time will take a long time, and the
If the temperature exceeds .degree. C., the pressure during the reaction becomes high and the reaction operation becomes difficult, which is not preferable. Furthermore, the reaction time is 30 minutes to 20 minutes.
The time range is preferable, and industrially, the range of 3 to 10 hours is particularly preferable.

In the production method of the present invention, the desired polyfluoroalkyl group-containing pyrimidine derivative can be produced by reacting the alkanoyl 2 with the pyrimidine 3 under the various reaction conditions described above. In order to more smoothly handle and react the alkanoyl 2, it is preferable to carry out the reaction using a solvent. The solvent is a halogenated aliphatic solvent, specifically, for example, methylene chloride, 2-chloro-1,2-dibromo-
1,1,2-trifluoroethane, 1,2-dibromohexafluoropropane, 1,2-dibromotetrafluoroethane, 1,1-difluorotetrachloroethane, 1
, 2-difluorotetrachloroethane, fluorotrichloromethane, heptafluoro-2,3,3-trichlorobutane, 1,1,1,3-tetrachlorotetrafluoropropane, 1,1,1-trichloropentafluoropropane, 1, Preferred examples include 1,2-trichlorotrifluoroethane, and particularly industrially, 1,1,
2-Trichlorotrifluoroethane is preferred. Further, the amount of the solvent to be charged is desirably adjusted so that the concentration of the alkanoyl 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 known methods such as distillation and column chromatography.

[0031]

Effects of the Invention The polyfluoroalkyl group-containing pyrimidine derivative of the present invention is a novel compound, and can be used for pharmaceuticals, agricultural chemicals,
It is useful as a water and oil repellent, particularly as a synthetic intermediate for anticancer agents and antiviral agents. Further, in the production method of the present invention, a polyfluoroalkyl group-containing pyrimidine derivative can be produced easily in a short time with high yield and without using a reaction catalyst or special equipment.

[0032]

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

[0033]

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 1.0 g (6.03 mmol) of 6-methyluracil was suspended in 30 ml of dry dioxane.
After adding 83 g (18.1 mmol), 1.96 g (18.0 mmol) of trimethylchlorosilane was finally added to react, and 2,4-bis(trimethylsiloxy)
-6-Methyl-pyrimidine was obtained quantitatively. Next, 30 ml of 1,1,2-trichlorotrifluoroethane was added to the obtained mixed solution to completely dissolve the suspension. Then, while maintaining the temperature of the obtained solution at 30°C, diperfluoro-2-methyl-3-oxahexanoyl peroxide 3
．． 51.37 g of a 1,1,2-trichlorotrifluoroethane solution containing 97 g (6.03 mmol) was added dropwise from the dropping funnel. Next, the mixture was stirred at the same temperature for 2 hours, and then refluxed for 1.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, 100 ml of water was added, and the mixture was stirred for 2 hours. Next, 150 ml of ethyl acetate was added to perform extraction, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and then dried using magnesium sulfate. Finally, purification was performed by column chromatography, and 5-(perfluoro-1'-methyl-2'-oxapentyl)-
6-Methyluracil was obtained with a yield of 51%. Table 1 shows various analysis results of the obtained compound.

[0034]

[Table 1]

[0035]

[Example 2] Diperfluoro-2-methyl-3-peroxide
Oxahexanoyl peroxide diperfluoro-2,5-
The reaction and purification were carried out in the same manner as in Example 1 except that dimethyl-3,6-dioxanonanoyl was used, and 5-(
Perfluoro-1',4'-dimethyl-2',5'-dioxaoctyl)-6-methyluracil was obtained in a yield of 47%. The analysis results are shown in Table 2.

[0036]

[Table 2]

[0037]

[Example 3] Diperfluoro-2-methyl-3-peroxide
Oxahexanoyl, diperfluoro-2,5 peroxide
, 8-Trimethyl-3,6,9-trioxadodecanoyl was used, but the reaction and purification were carried out in the same manner as in Example 1, and 5-(perfluoro-1',4',7'-trimethyl- 2',5',8'-trioxaundecyl)
-6-Methyluracil was obtained in a yield of 55%. The analysis results are shown in Table 3.

[0038]

[Table 3]

[0039]

[Example 4] 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-trifluoromethyl-pyrimidine.
Yield of 5-(perfluoro-1'-methyl-2'-oxapentyl)-6-trifluoromethyluracil 43%
I got it from The analysis results are shown in Table 4.

[0040]

[Table 4]

[0041]

[Example 5] 2,4-bis(trimethylsiloxy)-6
Example 1, except that -methyl-pyrimidine was replaced with 2,4-bis(trimethylsiloxy)-6-azapyrimidine
Reaction and purification were carried out in the same manner as above to obtain 5-(perfluoro-1'-methyl-2'-oxapentyl)-6-azauracil in a yield of 29%. The analysis results are shown in Table 5.

[0042]

[Table 5]

[0043]

[Example 6] 2,4-bis(trimethylsiloxy)-6
-methyl-pyrimidine to 2-trimethylsilylthio-4
The reaction and purification were carried out in the same manner as in Example 1 except that -trimethylsiloxypyrimidine was used, and 5-(perfluoro-1'-methyl-2'-oxapentyl)-2-
Thiouracil was obtained in a yield of 31%. The analysis results are shown in Table 6.

[0044]

[Table 6]

Claims (2)

[Claims] Claim 1: A compound represented by the following general formula 1 (wherein X represents an oxygen atom or a sulfur atom, Y represents a carbon atom or a nitrogen atom, and Z represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) or represents a trifluoromethyl group.Also, n
represents an integer of 0 to 8, and m represents 0 or 1. (provided that when Y is a carbon atom, m represents 1, and when Y is a nitrogen atom, m represents 0). [Chemical formula 1] 2. A polyfluoroalkanoyl peroxide represented by the following general formula 2 (wherein n represents an integer of 0 to 8) and a polyfluoroalkanoyl peroxide represented by the following general formula 3 (wherein X 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,
It represents an alkyl group or trifluoromethyl group having 1 to 4 carbon atoms. Further, m represents 0 or 1. 2. The polyfluorinated polyfluoride according to claim 1, wherein m is 1 when Y is a carbon atom, and m is 0 when Y is a nitrogen atom. A method for producing an alkyl group-containing pyrimidine derivative. [Chemical formula 2] [Chemical formula 3]