JP3032781B2 - Method for producing pyrimidine derivative containing fluoroalkyl group - Google Patents

Description

The present invention relates to a method for producing a fluoroalkyl group-containing pyrimidine derivative.

<Conventional Technology> A compound containing a fluoroalkyl group in an organic compound has attracted attention as a compound exhibiting useful properties such as heat resistance, water / oil repellency, and physiological activity. In particular, in a pyrimidine compound, a fluoroalkyl group-containing pyrimidine derivative in which a fluoroalkyl group has been introduced is used as a drug, a pesticide, or the like.
In particular, it is considered to be useful as an intermediate for synthesizing anticancer drugs or antiviral drugs, and has attracted attention. However, at present, little is known about the fluoroalkyl group-containing pyrimidine derivative and its production method.

<Problem to be Solved by the Invention> It is an object of the present invention to provide a method for producing a fluoroalkyl group-containing pyrimidine derivative which can be used as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and the like.

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

<Means for Solving the Problems> According to the present invention, the following general formula (I) (In the formula, R ₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X represents a fluorine atom, a chlorine atom, or a hydrogen atom.
However, when R ₁ is a hydrogen atom, X is a hydrogen atom or a chlorine atom. n represents an integer of 1 to 10), which is a method for producing a pyrimidine derivative containing a fluoroalkyl group represented by the following general formula (II): Wherein X and n are the same as defined above, and a di (haloacyl) peroxide represented by the following general formula (III) (Wherein R ₂ represents an alkyl group having 1 to 4 carbon atoms, a trialkylsilyl group or a diphenyl-t-butylsilyl group)
And a method for producing a fluoroalkyl group-containing pyrimidine derivative, characterized by reacting with a pyrimidine represented by the formula:

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

The fluoroalkyl group-containing pyrimidine derivative obtained by the production method of the present invention can be represented by the following general formula (I): In the formula, R ₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X represents a fluorine atom, a chlorine atom or a hydrogen atom.
However, when R ₁ is a hydrogen atom, X is a hydrogen atom or a chlorine atom. N represents an integer of 1 to 10. In this case, when R ₁ is an alkyl group having 5 or more carbon atoms, production is difficult, and when n is 11 or more, the solubility in a solvent is reduced, so that it cannot be used. Examples of the fluoroalkyl group-containing pyrimidine derivative represented by the general formula (I) include, for example, 2,4-dimethoxy-5-trifluoromethylpyrimidine, 2,4-dimethoxy-5-pentafluoroethylpyrimidine, 2,4- Dimethoxy-5-heptafluoropropylpyrimidine, 2,4-dimethoxy-5-nonafluorobutylpyrimidine, 2,4-dimethoxy-5-undecafluoropentylpyrimidine, 2,4-dimethoxy-5-tridecafluorohexylpyrimidine, 2,4-dimethoxy-5-pentadecafluoroheptylpyrimidine, 2,4-
Dimethoxy-5-chlorodifluoromethylpyrimidine,
2,4-dimethoxy-5- (2'-chlorotetrafluoroethyl) pyrimidine, 2,4-dimethoxy-5- (3'-
Chlorohexafluoropropyl) pyrimidine, 2,4-dimethoxy-5- (4'-chlorooctafluorobutyl)
Pyrimidine, 2,4-dimethoxy-5- (5'-chlorodecafluoropentyl) pyrimidine, 2,4-dimethoxy-
5- (6'-chlorododecafluorohexyl) pyrimidine, 2,4-dimethoxy-5- (7'-chlorotetradecafluoroheptyl) pyrimidine, 2,4-dimethoxy-5
-Hydrodifluoromethylpyrimidine, 2,4-dimethoxy-5- (2'-hydrotetrafluoroethyl) pyrimidine, 2,4-dimethoxy-5- (3'-hydrohexafluoropropyl) pyrimidine, 2,4-dimethoxy- 5-
(4'-hydrooctafluorobutyl) pyrimidine, 2,
4-dimethoxy-5- (5'-hydrodecafluoropentyl) pyrimidine, 2,4-dimethoxy-5- (6'-hydrododecafluorohexyl) virimidine, 2,4-dimethoxy-5- (7'-hydrotetra Decafluoroheptyl) pyrimidine, 2,4-dihydroxy-5-chlorodifluoromethylpyrimidine, 2,4-dihydroxy-5
(2'-chlorotetrafluoroethyl) pyrimidine, 2,
4-dihydroxy-5- (3'-chlorohexafluoropropyl) pyrimidine, 2,4-dihydroxy-5
(4'-chlorooctafluorobutyl) pyrimidine, 2,
4-dihydroxy-5- (5'-chlorodecafluoropentyl) pyrimidine, 2,4-dihydroxy-5- (6 '
-Chlorododecafluorohexyl) pyrimidine, 2,4-
Dihydroxy-5- (7'-chlorotetradecafluoroheptyl) pyrimidine, 2,4-dihydroxy-5-hydrodifluoromethylpyrimidine, 2,4-dihydroxy-
5- (2'-hydrotetrafluoroethyl) pyrimidine, 2,4-dihydroxy-5- (3'-hydrohexafluoropropyl) pyrimidine, 2,4-dihydroxy-5
-(4'-hydrooctafluorobutyl) bilimidine,
2,4-dihydroxy-5- (5'-hydrodecafluoropentyl) pyrimidine, 2,4-dihydroxy-5
(6′-hydrododecafluorohexyl) pyrimidine,
Preferred examples include 2,4-dihydroxy-5- (7'-hydrotetradecafluoroheptyl) pyrimidine.

The method for producing a fluoroalkyl group-containing pyrimidine derivative according to the present invention is characterized by reacting a specific di (haloacyl) peroxide with a specific pyrimidine.

The di (haloacyl) peroxide used as a raw material component in the production method of the present invention can be represented by the following general formula (II): X represents a fluorine atom, a chlorine atom or a hydrogen atom,
N represents an integer of 1 to 10. In this case, when n is 11 or more, it cannot be used because a problem occurs in the solubility of the di (haloacyl) peroxide when reacting in the presence of a solvent. The X (CF _{2 n} of di (haloacyl) peroxide represented by the general formula (II), when specifically _{enumerated, CF 3 -, F (CF} 2 2, F (CF 2 3, F (CF 2 4, _{F (CF 2 5, F (} CF 2 6, F (CF 2 7, F (CF 2 8, F (CF 2 9, F (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 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 It is ₁₀ .

In the production method of the present invention, the pyrimidine to be reacted with the di (haloacyl) peroxide can be represented by the following general formula (III): In the formula, R ₂ represents an alkyl group having 1 to 4 carbon atoms, a trialkylsilyl group or a diphenyl-t-butylsilyl group. In this case, when R ₂ is an alkyl group having 5 or more carbon atoms or a trialkylsilyl group having an alkyl group having 5 or more carbon atoms, production is difficult.

Examples of the pyrimidine compound represented by the general formula (III) include, for example, 2,4-dimethoxypyrimidine, 2,4-diethoxypyrimidine, 2,4-dipropoxypyrimidine, 2,4
-Dibutoxypyrimidine, 2,4-bis (diphenyl-t
-Butylsiloxy) pyrimidine, 2,4-bis (trimethylsiloxy) pyrimidine, 2,4-bis (triethylsiloxy) pyrimidine, 2,4-bis (tripropylsiloxy) pyrimidine, 2,4-bis (tributylsiloxy) pyrimidine And the like.

In the production method of the present invention, the charged molar ratio of the di (haloacyl) peroxide and the pyrimidine is 1:
It is preferably from 0.2 to 10, particularly preferably from 1: 0.5 to 5. When the charged molar ratio of the pyrimidines is less than 0.2, the yield of the resulting fluoroalkyl group-containing pyrimidine derivative is reduced, and when it exceeds 10, a large amount of unreacted pyrimidines remains after the reaction is completed. However, it is not preferable because isolation of the desired product becomes difficult. The reaction can be carried out at normal pressure, and the reaction temperature is preferably in the range of -20 to + 150 ° C, particularly preferably in the range of 0 to 100 ° C. When the reaction temperature is lower than −20 ° C., a long time is required for the reaction time. When the reaction temperature is higher than 150 ° C., the pressure during the reaction increases, and the reaction operation is difficult. Further, the reaction time is preferably in the range of 30 minutes to 20 hours, and particularly preferably in the range of 3 to 10 hours industrially.

In the production method of the present invention, the desired fluoroalkyl group-containing pyrimidine derivative can be produced by reacting the di (haloacyl) peroxide with the pyrimidine under the various reaction conditions. In order to handle and react the di (haloacyl) peroxide 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-dibromotetrafluoroethane,
1,1-difluorotetrachloroethane, 1,2-difluorotetrachloroethane, fluorotrichloromethane, heptafluoro-2,3,3-trichlorobutane, 1,1,1,3-tetrachlorotetrafluoropropane, 1,1, Preferred are 1-trichloropentafluoropropane, 1,1,2-trichlorotrifluoroethane and the like. In particular, 1,1,2-trichlorotrifluoroethane is preferred industrially. The amount of the solvent to be charged is preferably adjusted so that the concentration of the fluoroalkanoyl is in the range of 1 to 30% by weight based on the solvent.

Further, in the fluoroalkyl group-containing pyrimidine derivative represented by the general formula (I), when R ₁ is a hydrogen atom, in addition to the above-mentioned production method, R ₁ obtained by the above production method is an alkyl group. It can also be obtained by treating an alkyl group-containing pyrimidine derivative under acidic conditions such as glacial acetic acid in the presence of sodium iodide.

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.

<Effect of the Invention> The fluoroalkyl group-containing pyrimidine derivative obtained by the production method of the present invention is useful as a pharmaceutical, a pesticide and the like, particularly as a synthetic intermediate of 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.

<Examples> Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 Under an argon atmosphere, 1.28 g of 2,4-bis (trimethylsiloxy) pyrimidine was dissolved in 20 ml of 1,1,2-trichlorotrifluoroethane. The temperature of the resulting solution is then
Keep at 30 ° C and contain 1.1 g of bis (heptafluorobutyryl) peroxide (0.5 equivalents to pyrimidines).
21.6 g of a 1,2-trichlorotrifluoroethane solution was dropped from the dropping funnel over about 1 minute. Then, at the same temperature, 3
After stirring for an hour, the mixture was refluxed for 2 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 sodium sulfate. Finally, purification was performed by column chromatography.
0.40 g (57% yield) of 4-dihydroxy-5-heptafluoropropylpyrimidine was obtained. The results of various analyzes of the obtained compound are shown below.

mp: 258-259 ° C MS m / z 280 (M ⁺ ), 261,161 IR (cm ^-1 ) 3160 (NH), 1680, 1750 (C = O), 1360 (C
F ₃ ), 1230 (CF ₂ ) ¹ H-NMR (d ⁶ -DMSO) δ 7.99 (s, 1H) ¹⁹ F-NMR (d ⁶ -DMSO; ext.CF ₃ COOH) δ -1.52 (3F, t, J = 8.68, γ-CF ₃ ), -30.67 (2F, q,
J = 9.93, α-CF ₂ ), -46.87 (2F, s, β-CF ₂ ) The obtained 2,4-dihydroxy-5-heptafluoropropylpyrimidine is, as shown below, It is a tautomer of fluorouracil.

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 give 2,4-dihydroxy-5-pentadeca. 0.67 g (yield 38%) of fluorohexylpyrimidine was obtained. The analysis results are shown below.

mp: 277-278 ° C MS m / z 430 (M ⁺ ), 411,161 IR (cm ^-1 ) 3240 (NH), 1670, 1760 (C = O), 1325 (C
F ₃ ) 1255 (CF ₂ ) ¹ H-NMR (d ⁶ -DMSO) δ 7.98 (s, 1H) ¹⁹ F-NMR (d ⁶ -DMSO; ext. CF ₃ COOH) δ-2.08 (3F, t, J = 8.69, ζ−CF ₃ ), − 29.94 (2F, t,
_{J = 13.65, ε-CF 2} ), - 42.60 (2F, br s, δ-CF 2), -
43.39 (2F, br s, γ-CF ₂ ), -44.21 (2F, br s, β-C
F ₂ ), -47.53 (2F, q, J = 7.44, α-CF ₂ ) Example 3 Bis (trifluoroacetyl) peroxide was used in place of bis (heptafluorobutyryl) peroxide, and the reaction temperature was 70 ° C. The reaction and purification were carried out in the same manner as in Example 1 except that the reaction was carried out in a pressure-resistant ampoule, to obtain 0.17 g (yield 31%) of 2,4-dihydroxy-5-trifluoromethylpyrimidine. The analysis results are shown below.

mp: 236-237 ° C MS m / z 180 (M ⁺ ), 137 IR (cm ^-1 ) 3240 (NH), 1680, 1715, 1750 (C = O), 1350
(CF ₂ ) ¹ H-NMR (d ⁶ -DMSO) δ 7.98 (s, 1 H) ¹⁹ F-NMR (d ⁶ -DMSO; ext. CF ₃ COOH) δ 16.90 (3 F, s) Example 4 Bis (hepta) The reaction and purification were carried out in the same manner as in Example 1 except that bis (chlorodifluoroacetyl) peroxide was used instead of (fluorobutyryl) peroxide.
-Dihydroxy-5-chlorodifluoromethylpyrimidine was obtained in a yield of 50%. The analysis results are shown below.

MS m / z 157 (M ⁺ ) IR (cm- ¹ ) 3240 (NH), 1680, 1715, 1750 (C = O), 1240
(CF ₂ ) ¹ H-NMR (d ⁶ -DMSO) δ 7.93 (s, 1 H) ¹⁹ F-NMR (d ⁶ -DMSO; ext. CF ₃ COOH) δ -37.00 (2 F, s) 4-bis (trimethylsiloxy) pyrimidine is converted to 2,4-
The reaction and purification were carried out in the same manner as in Example 1 except that dimethoxypyrimidine was used instead of 2,4-dimethoxy-5-
0.73 g of heptafluoropropylpyrimidine (yield 47
%)Obtained.

 The analysis results are shown below.

mp: 214-215 ° C MS m / z 308 (M ⁺ ), 278,189 IR (cm ^-1 ) 1340 (CF ₃ ), 1235 (CF ₂ ) ¹ H-NMR (d ⁶ -DMSO) δ 4.50 (3H, s ), 4.08 (3H, s),
7.99 (1H, s) ¹⁹ F-NMR (d ⁶ -DMSO; ext. CF ₃ COOH) δ −3.31 (3F, t, J = 9.93, γ-CF ₃ ), −32.64) 2F, q,
J = 9.92, α-CF ₂ ),-48.93 (2F, s, β-CF ₂ ) Example 6 0.50 g of 2,4-dimethoxy-5-heptafluoropropylpyrimidine obtained in Example 5 was added to 20 ml of glacial acetic acid. And sodium iodide (1.34 g, 2,4-dimethoxy-5).
-Heptafluoropropylpyrimidine) (5 times the molar amount with respect to heptafluoropropylpyrimidine) and reacted at 100 ° C for 5 hours. After completion of the reaction, acetic acid was removed, and the obtained product was washed with benzene and dissolved in warm water. Then, after adding sodium thiosulfate, the aqueous solution was cooled and 2,4-dihydroxy-5 was added.
-Heptafluoropropylpyrimidine was obtained in a yield of 88%.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yoshio Hayakawa 4-33, Nishi-Imajuku, Yamaji, 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-57-85377 (JP, A) 50-49287 (JP, A) U.S. Pat. No. 3,324,126 (US, A) Tetrahedron Letters, Vol. 23 (No. 40) P4099-1400 (1982) Nucleic Acids Research, Vol. 2 (No. 11) P 2183-2192 (1975) Chemical Abstracts Vol. 85 (No. 9) p560 Abstract No. 63022h (1976) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 239/52 C07D 239/54 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound represented by the following general formula (I) (In the formula, R ₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and X represents a fluorine atom, a chlorine atom, or a hydrogen atom.
However, when R ₁ is a hydrogen atom, X is a hydrogen atom or a chlorine atom. n represents an integer of 1 to 10), which is a method for producing a pyrimidine derivative containing a fluoroalkyl group represented by the following general formula (II): (Wherein X represents a fluorine atom, a chlorine atom or a hydrogen atom, and n represents an integer of 1 to 10), and a di (haloacyl) peroxide represented by the following general formula (III) (Wherein R ₂ represents an alkyl group having 1 to 4 carbon atoms, a trialkylsilyl group or a diphenyl-t-butylsilyl group)
A process for producing a pyrimidine derivative containing a fluoroalkyl group, characterized by reacting with a pyrimidine represented by the formula: