JP2015227318A - 4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine derivative and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a 4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine derivative useful as a pharmaceutical and agrochemical intermediate and electronic material intermediate, and to provide a production method of the pyrimidine derivative.SOLUTION: A 4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine derivative is represented by formula (1), and a production method of the pyrimidine derivative comprises a step of synthesizing with reaction of 2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine, and metal alkoxide or metal phenoxide. In the formula (1), R is a methyl group, ethyl group, linear, branched or cyclic alkyl group having 3 to 6 carbon atoms, phenyl group or benzyl group.

Description

  The present invention relates to a novel 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative and a method for producing the same. The 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative of the present invention is a compound useful as a raw material for synthesizing various medical and agricultural chemicals and electronic materials.

Conventionally, the 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative of the present invention and the production method thereof have not been known.
As similar compounds, 2- (4-nitrophenoxy) -4-chloro-5- (trifluoromethyl) pyrimidine and its production method (see, for example, Patent Document 1) and 2-methoxy-4-chloro-5- (tri Fluoromethyl) pyrimidine and a method for producing the same (see, for example, Patent Document 2) are known.

However, the method described in Patent Document 1 has a problem that it is limited to a method of obtaining 2- (4-nitrophenoxy) -4-chloro-5- (trifluoromethyl) pyrimidine using 4-nitrophenol.
On the other hand, the method described in Patent Document 2 includes the target 2-methoxy-4-chloro-5- (trifluoromethyl) pyrimidine and the isomer 4-methoxy-2-chloro-5- (trifluoromethyl) pyrimidine. The target 2-methoxy-4-chloro-5- (trifluoromethyl) pyrimidine is obtained by silica gel column purification, and it is necessary to purify the silica gel column, which is difficult to implement industrially. was there.

  Furthermore, when various metal alkoxides are reacted with 2,4-dichloro-5- (trifluoromethyl) pyrimidine, the composition varies depending on the type of metal alkoxide to be reacted, but the product is substituted at the 2-position. There was a problem that it became a mixture of the one and 4-position substituted.

Special table 2013-501759 gazette Special table 2008-528613

  The present invention is useful as a raw material for synthesizing 5- (trifluoromethyl) pyrimidine derivatives substituted at 2-position or 4-position, and 4- (2,2,2-trifluoroethoxy substituted at 2-position. ) -5- (trifluoromethyl) pyrimidine derivatives and methods for producing the same.

  The present inventors use 2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine as a raw material, and react with metal alkoxide or metal phenoxide to achieve a very high selection. Thus, it was found that a novel 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative substituted with alkoxy at the 2-position was obtained, and the present invention was completed. It was.

  That is, the present invention provides the following general formula (1)

(In the formula (1), R represents a methyl group, an ethyl group, a linear branched or cyclic alkyl group having 3 to 6 carbon atoms, a phenyl group, or a benzyl group)
4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative represented by the following formula (2)

2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine represented by the following general formula (3)
RO-M (3)
(In the formula (3), R is the same as the formula (1))
The metal alkoxide or metal phenoxide represented by these is made to react, and the manufacturing method is provided.

  INDUSTRIAL APPLICABILITY According to the present invention, a novel 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative useful as a synthetic raw material for medical and agricultural chemicals and a highly selective production method thereof can be provided.

Hereinafter, the present invention will be described in detail.
Specific examples of the 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) of the present invention include 2-methoxy-4- ( 2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-ethoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-n -Propoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-iso-propoxy-4- (2,2,2-trifluoroethoxy) -5- (tri Fluoromethyl) pyrimidine, 2-n-butoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-sec-butoxy-4- (2, , 2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-iso-butoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-tert- Butoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-n-pentoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoro Methyl) pyrimidine, 2-cyclo-pentoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-n-hexyloxy-4- (2,2,2-tri) Fluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-cylo-hexyloxy-4- (2,2,2-trifluoroethoxy) -5- ( (Rifluoromethyl) pyrimidine, 2-phenoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine, 2-benzyloxy-4- (2,2,2-trifluoroethoxy) Examples include -5- (trifluoromethyl) pyrimidine.

  2,4-bis (2,2,2-trifluoroethoxy) -5 represented by the formula (2) used for the production of the 5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) of the present invention -(Trifluoromethyl) pyrimidine is obtained by, for example, dehydrating and chlorinating commercially available 5- (trifluoromethyl) uracil from phosphorus oxychloride and the like to produce 2,4-dichloro-5- (trifluoromethyl) pyrimidine Can be prepared by reacting a metal salt of 2,2,2-trifluoroethanol.

  As the metal alkoxide or metal phenoxide represented by the general formula (3) applicable to the production of the 5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) of the present invention, specifically, for example, lithium methoxy Sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium-n-propoxide, sodium-n-propoxide, potassium-n-propoxide, lithium-iso-propoxide, Sodium-iso-propoxide, potassium-iso-propoxide, lithium-n-butoxide, sodium-n-butoxide, potassium-n-butoxide, lithium-iso-butoxide, sodium-iso-butoxide, potassium-iso-butoxide, Lichiu -Sec-butoxide, sodium-sec-butoxide, potassium-sec-butoxide, lithium-tert-butoxide, sodium-tert-butoxide, potassium-tert-butoxide, lithium-n-pentoxide, sodium-n-pentoxide, potassium-n -Pentoxide, lithium-n-hexyl oxide, sodium-n-hexyl oxide, potassium-n-hexyl oxide, lithium-cyclo-hexyl oxide, sodium-cyclo-hexyl oxide, potassium-cyclo-hexyl oxide, lithium phenoxide, sodium phenoxide Potassium phenoxide, lithium benzyloxide, sodium benzyloxide, potassium benzyloxide and the like.

  The amount of the metal alkoxide or metal phenoxide represented by the general formula (3) applicable to the production of the 5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) of the present invention is determined by the formula ( 2) In the range of 1.0 mol times to 1.5 mol times the amount of 2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine represented by 2) is there.

  If the metal alkoxide or metal phenoxide represented by the general formula (3) applicable to the production of the 5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) of the present invention is commercially available, it is used as it is. Those that are not commercially available may be used as appropriate alcohols or phenols, for example, lithium hydride, sodium hydride, potassium hydride, n-butyl lithium, tert-butyl lithium, lithium hexamethyldisilazide. Metal reagents such as sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc. may be prepared by using 0.7 mol times to 1.0 mol times the amount of alcohol or phenol.

  As the solvent applicable to the production of the 5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) of the present invention, any solvent can be used as long as it is inert to the reaction. Ether solvents such as diethyl ether, di-iso-propyl ether, methyl-tert-butyl ether, methyl-cyclo-pentyl ether, tetrahydrofuran, aliphatic hydrocarbon solvents such as pentane, hexane, cyclo-hexane, benzene, toluene, Examples include aromatic hydrocarbon solvents such as ethylbenzene, xylene, mesitylene, cumene, etc., and 2,4-bis (2,2,2-trifluoroethoxy) -5 represented by the formula (2) included in the reaction. 2 to 100 times the amount of (trifluoromethyl) pyrimidine is used. Moreover, you may use these solvents in mixture of 2 or more types.

The reaction temperature and time for producing the 5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) of the present invention vary depending on the type of metal alkoxide used in the reaction, the type of solvent, and the substrate concentration. The reaction is completed by carrying out the reaction for 1 hour to 48 hours in a temperature range of 20 ° C to 80 ° C.
The post-treatment after the production of the 5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) of the present invention can be carried out by a well-known method, such as neutralization with a saturated aqueous ammonium chloride solution, dichloromethane or the like. The 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative represented by the general formula (1) was obtained by extraction with a solvent of the above, drying over sodium sulfate, filtration, and concentration. obtain.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited only to these examples.
The following equipment was used for the analysis.
¹ H-NMR, ¹⁹ F-NMR, ¹³ C-NMR: AVANCE II 400 manufactured by Bruker.
GC-MS: Shimadzu GCMS-QP2010Plus.
Elemental analysis: CHN coder MT-6 manufactured by Yanaco.

Reference Example 1 Preparation of 2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine In a 200 mL eggplant-shaped flask equipped with a stirrer under a nitrogen stream, 2,2, 2-Trifluoroethanol (5.99 g, 59.9 mmol) and tetrahydrofuran (85 mL) were charged, cooled to −20 ° C., and then n-butyllithium (1.6 M-hexane solution, 34.5 mL, 55.2 mmol). And stirred at the same temperature for 30 minutes. Next, 2,4-dichloro-5- (trifluoromethyl) pyrimidine (5.00 g, 23.0 mmol) was added thereto, and the mixture was stirred at the same temperature for 30 minutes, then warmed and reacted at 40 ° C. for 24 hours. Went.

After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, concentrated under reduced pressure, extracted with dichloromethane (30 ml × 3 times), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
The obtained crude product was purified by silica gel bed (10 g, eluent dichloromethane) and concentrated to give the desired 2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl). Pyrimidine (7.22 g, 21.0 mmol, 91% yield) was obtained as a colorless transparent liquid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.60 (d, J = 0.8 Hz, 1H), 4.91 (q, J = 4.9 Hz, 2H), 4.85 (q, J = 4. 8Hz, 2H).
¹⁹ F-NMR (CDCl ₃ , 376 MHz) δ-63.80, −74.82 (t, J = 7.5 Hz), −74.89 (t, J = 7.5 Hz).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ 167.07, 165.00, 158.38 (q, J = 4.7 Hz), 122.99 (q, J = 275.8 Hz), 122.74 (q, J = 275.6 Hz), 122.28 (q, J = 269.4 Hz), 108.05 (q, J = 34.7 Hz), 64.39 (q, J = 36.7 Hz), 63.39 ( q, J = 37.2 Hz).
GC-MS (m / z): 344 (M ⁺ , 45), 325 (58), 275 (100), 246 (93), 163 (90), 83 (95).
Elemental analysis calculated: carbon (31.41%), hydrogen (1.46%), nitrogen (8.14%).
Measurements: carbon (31.32%), hydrogen (1.46%), nitrogen (8.16%).

  Example 1 Preparation of 2-benzyloxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (4)

Benzyl alcohol (0.310 g, 2.91 mmol) and tetrahydrofuran (20 mL) were charged into a 50 mL eggplant type flask equipped with a stir bar and purged with nitrogen. After cooling to −20 ° C., n-butyllithium (1.6 M -Hexane solution, 1.82 mL, 2.91 mmol) was added, and the mixture was stirred at the same temperature for 30 minutes. Next, 2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (1.00 g, 2.91 mmol) prepared in Reference Example 1 was added, and 30 at the same temperature. After stirring for a minute, the temperature was returned to room temperature and the reaction was carried out for 12 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride (10 mL) is added. Tetrachlorofuran is distilled off by concentration under reduced pressure, extraction with dichloromethane (10 mL × 3 times), the organic layers are combined, dried over sodium sulfate, filtered, and concentrated. This gave crude 2-benzyloxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine as a slightly pale yellow solid (1.21 g). In ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard, the obtained crude product was converted into 95% by 92% yield and by-product 2- (2,2,2-trifluoroethoxy). -4-Benzyloxy-5- (trifluoromethyl) pyrimidine contained 1.2% in terms of yield.

Further, the obtained crude product was recrystallized from ethylbenzene-hexane to obtain purified 2-benzyloxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine in white. Obtained as a solid (0.77 g, 75% yield, 99% purity).
¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.58 (d, J = 0.8 Hz, 1H), 7.47-7.35 (m, 5H), 5.47 (s, 2H), 4.85 (Q, J = 8.0 Hz, 2H).
¹⁹ F-NMR (CDCl ₃ , 376 MHz) δ-63.71, −75.03 (t, J = 7.5 Hz).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ 166.58, 166.28, 158.45 (q, J = 4.7 Hz), 135.52, 128.84, 128.73, 128.40, 122.82 (Q, J = 275.2 Hz), 122.58 (q, J = 269.2 Hz), 106.49 (q, J = 34.5 Hz), 70.60, 63.01 (q, J = 37. 0 Hz).
GC-MS (m / z) 352 (10, M ⁺ ), 351 (8), 269 (7), 246 (35), 107 (6), 91 (100), 65 (21).
Elemental analysis calculated: carbon (47.74%), hydrogen (2.86%), nitrogen (7.95%).
Measurements: carbon (47.62%), hydrogen (2.87%), nitrogen (7.93%).

Example 2 Preparation of 2-Benzyloxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine In the same reactor as in Example 1, sodium hydride (60% oily, 0. 163 g, 4.07 mmol) and tetrahydrofuran (40 mL) were charged, and after cooling to 0 ° C., benzyl alcohol (0.450 g, 4.22 mmol) was added and stirred at the same temperature for 30 minutes. Next, 2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (1.00 g, 2.91 mmol) prepared in Reference Example 1 was added, and 24 hours at the same temperature. Time reaction was performed. After the reaction yield, the same post-treatment operation as in Example 1 was carried out, and crude 2-benzyloxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine was obtained as a slightly pale yellow solid. (1.27 g). The obtained crude product was subjected to ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard. The conversion was 100%, the yield was 96%, and the byproduct 2- (2,2,2-trifluoroethoxy)- 4-Benzyloxy-5- (trifluoromethyl) pyrimidine contained 1.5% in terms of yield.

Example 3 Preparation of 2-benzyloxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine To the same reactor as in Example 1, benzyl alcohol (0.403 g, 3.78 mmol) was prepared. ) And tetrahydrofuran (10 mL), and after cooling to −10 ° C., potassium hexamethyldisilazide (1.0 M-tetrahydrofuran solution, 3.06 mL, 3.06 mmol) was added and stirred at the same temperature for 30 minutes. . Next, 2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (1.00 g, 2.91 mmol) prepared in Reference Example 1 was added, and 24 hours at the same temperature. Time reaction was performed. After the reaction yield, the same post-treatment operation as in Example 1 was carried out, and crude 2-benzyloxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine was obtained as a slightly pale yellow solid. (1.19 g). The obtained crude product was subjected to ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard. The conversion was 99%, the yield was 95%, and the byproduct 2- (2,2,2-trifluoroethoxy)- 4-Benzyloxy-5- (trifluoromethyl) pyrimidine contained 1.8% in terms of yield.

  Example 4 Preparation of 2-methoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (5)

The same operation as in Example 1 was carried out except that methanol (0.092 g, 2.91 mmol) was used instead of benzyl alcohol (0.310 g, 2.91 mmol) in Example 1, and 2-methoxy-4- (2 , 2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (0.82 g) was obtained as a colorless transparent liquid. In the ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard, the obtained crude product was converted into a by-product 2- (2,2,2-trifluoroethoxy) with a conversion rate of 92% and a yield of 89%. -4-Methoxy-5- (trifluoromethyl) pyrimidine was contained 2.3% in terms of yield.
¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.58 (d, J = 0.8 Hz, 1H), 4.90 (q, J = 8.1 Hz, 2H), 4.08 (s, 3H).
¹⁹ F-NMR (CDCl ₃ , 376 MHz) δ-63.60, −74.94 (t, J = 8.1 Hz).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ 166.93, 166.54, 158.49 (q, J = 4.7 Hz), 122.86 (q, J = 275.6 Hz), 122.63 (q, J = 268.9 Hz), 106.25 (q, J = 34.5 Hz), 62.88 (q, J = 37.1 Hz), 55.86.
GC-MS m / z 276 (49, M ⁺ ), 275 (27), 257 (24), 246 (100), 163 (37), 143 (32), 91 (27), 83 (23), 69 ( 21).
Elemental analysis calculated: carbon (34.80%), hydrogen (2.19%), nitrogen (10.14%).
Measurements: carbon (34.71%), hydrogen (2.19%), nitrogen (10.13%).

  Example 5 Preparation of 2-iso-propoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (6)

The same procedure as in Example 1 was performed except that iso-propanol (0.175 g, 2.91 mmol) was used instead of benzyl alcohol (0.310 g, 2.91 mmol) in Example 1, and 2-iso-propoxy- A crude product (0.98 g) of 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine was obtained as a colorless transparent liquid. The obtained crude product was subjected to a ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard. The conversion was 96%, the yield was 94%, and the byproduct 2- (2,2,2-trifluoroethoxy)- 4-iso-propoxy-5- (trifluoromethyl) pyrimidine contained 1.3% in terms of yield.
¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.55 (d, J = 0.8 Hz, 1H), 5.35 (dq, J = 6.4, 6.3 Hz, 1H), 4.90 (q, J = 8.1 Hz, 2H), 1.42 (d, J = 6.4 Hz, 6H).
¹⁹ F-NMR (CDCl ₃ , 376 MHz) δ-63.30, −74.82 (t, J = 9.4 Hz).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ 166.52, 166.11, 158.43 (q, J = 4.7 Hz), 122.89 (q, J = 275.7 Hz), 122.69 (q, J = 268.7 Hz), 105.83 (q, J = 34.0 Hz), 72.58, 62.89 (q, J = 37.0 Hz), 21.75.
GC-MS (m / z) 304 (2, M ⁺ ), 289 (12), 263 (94), 246 (100), 243 (27), 223 (16), 193 (35), 164 (28) 136 (33), 83 (23).
Elemental analysis calculated: carbon (39.48%), hydrogen (3.31%), nitrogen (9.21%).
Measurements: carbon (39.42%), hydrogen (3.31%), nitrogen (9.19%).

  Example 6 Preparation of 2-tert-butoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (7)

The same operation as in Example 1 was performed except that tert-butanol (0.216 g, 2.91 mmol) was used instead of benzyl alcohol (0.310 g, 2.91 mmol) in Example 1, and 2-tert-butoxy- A crude product (0.94 g) of 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine was obtained as a colorless transparent liquid. The obtained crude product was subjected to ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard. The conversion was 93%, the yield was 93%, and the by-product 2- (trifluoroethoxy) -4-tert-butoxy- 5- (Trifluoromethyl) pyrimidine was not observed.
¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.54 (d, J = 0.8 Hz, 1H), 4.85 (q, J = 8.1 Hz, 2H), 1.66 (s, 9H).
¹⁹ F-NMR (CDCl ₃ , 376 MHz) δ-63.70, −74.87 (t, J = 9.4 Hz).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ 166.12 (d, J = 1.3 Hz), 165.96, 158.06 (q, J = 4.7 Hz), 122.91 (q, J = 275. 5 Hz), 122.79 (q, J = 268.7 Hz), 105.51 (q, J = 34.5 Hz), 69.03, 62.98 (q, J = 36.9 Hz), 28.30.
GC-MS (m / z) 303 (4), 263 (91), 243 (15), 223 (8), 83 (9), 57 (100).

  Example 7 Preparation of 2-cyclo-hexyloxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (8)

The same operation as in Example 1 was carried out except that cyclohexanol (0.291 g, 2.91 mmol) was used instead of benzyl alcohol (0.310 g, 2.91 mmol) in Example 1, and 2-cyclo-hexyloxy was used. A crude product of -4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (1.25 g) was obtained as a colorless transparent liquid. The obtained crude product was subjected to ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard. The conversion was 97%, the yield was 96%, and the by-product 2- (trifluoroethoxy) -4-cyclo-hexyloxy was obtained. -5- (Trifluoromethyl) pyrimidine contained 0.7% in terms of yield.
¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.54 (d, J = 0.8 Hz, 1H), 5.12-5.02 (m, 1H), 4.87 (q, J = 8.1 Hz, 2H), 2.07-1.27 (m, 10H).
¹⁹ F-NMR (CDCl ₃ , 376 MHz) δ-63.55, −74.99 (t, J = 8.1 Hz).
¹³ C-NMR (CDCl ₃ , 100 MHz) δ 166.53, 166.12, 158.38 (q, J = 4.7 Hz), 122.89 (q, J = 275.7 Hz), 122.69 (q, J = 268.9 Hz), 105.79 (q, J = 34.4 Hz), 77.55, 62.90 (q, J = 37.0 Hz), 31.62, 25.49, 23.98.
GC-MS (m / z) 263 (100), 247 (21), 246 (20), 243 (16), 223 (7), 83 (22%).
Elemental analysis calculated: carbon (45.36%), hydrogen (4.10%), nitrogen (8.14%).
Measurements: carbon (45.31%), hydrogen (4.11%), nitrogen (8.12%).

  Example 8 Preparation of 2-phenoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine (9)

The same operation as in Example 1 was performed except that phenol (0.274 g, 2.91 mmol) was used instead of benzyl alcohol (0.310 g, 2.91 mmol) in Example 1 and the reaction was performed at 60 ° C. for 36 hours. , 2-phenoxy-4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine crude product (1.18 g) was obtained as a colorless transparent liquid. The obtained crude product was subjected to ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard, and the conversion was 65%, the yield was 58%, and the by-product 2- (trifluoroethoxy) -4-phenoxy-5- (Trifluoromethyl) pyrimidine contained 0.5% in terms of yield.
¹ H-NMR (CDCl ₃ , 400 MHz) δ 8.56 (d, J = 0.4 Hz, 1H), 7.47-6.46 (m, 5H), 4.92 (q, J = 8.1 Hz, 2H).
¹⁹ F-NMR (CDCl ₃ , 376 MHz) δ-63.27, −74.75 (t, J = 7.5 Hz).
GC-MS (m / z) 338 (60, M ⁺ ), 319 (16), 269 (11), 246 (38), 192 (15), 104 (20), 93 (100), 77 (87% ).

Comparative Example 1 Reaction of 2,4-dichloro-5- (trifluoromethyl) pyrimidine and lithium benzyloxide Using the same reaction apparatus as in Example 1, 2,4-bis (2,2,2-trichloroethoxy) -5 (Trifluoromethyl) pyrimidine (1.00 g, 2.91 mmol) was used instead of 2,4-dichloro-5- (trifluoromethyl) pyrimidine (0.63 g, 2.91 mmol), and the reaction was performed at 0 ° C. for 6 hours. The same operation as in Example 1 was carried out except that the crude product (0.86 g) was obtained. In ¹⁹ F-NMR measurement using hexafluorobenzene as an internal standard, the obtained crude product was converted into 2-benzyloxy-4-chloro-5- (trifluoromethyl) pyrimidine at a conversion rate of 95% in a yield conversion of 57%. %, 2-chloro-5-benzyloxy-5- (trifluoromethyl) pyrimidine was a mixture containing 35% in terms of yield.

  The novel 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative of the present invention can be used as a synthetic intermediate for various pharmaceuticals, and 5- (trifluoromethyl) pyrimidine Expected to be a skeleton introduction agent.

Claims (3)

The following general formula (1)

(In the formula (1), R represents a methyl group, an ethyl group, a linear branched or cyclic alkyl group having 3 to 6 carbon atoms, a phenyl group, or a benzyl group)
A 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative represented by: Following formula (2)

2,4-bis (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine represented by the following general formula (3)
RO-M (3)
(In the formula (3), R is the same as the formula (1))
The method for producing a 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative according to claim 1, wherein the metal alkoxide or metal phenoxide represented by the formula is reacted. The method for producing a 4- (2,2,2-trifluoroethoxy) -5- (trifluoromethyl) pyrimidine derivative according to claim 2, wherein the metal is lithium, sodium or potassium.