JPH0656817A - 5-trifluoromethyl-1,3-dioxin-4-one derivative - Google Patents

Abstract

(57) [Summary] [Structure] [In the formula, R ₁ and R ₂ are the same or different and each is an alkyl group having 1 to 5 carbon atoms, or R ₁ and R ₂ together are 3 to 3 carbon atoms.
6 represents an alkylene group. R ₃ represents a hydrogen atom or an alkyl group or aryl group having 1 to 6 carbon atoms. ] The 5-trifluoromethyl-1,3-dioxin-4-one derivative shown by these. [Effect] This compound is useful as an antitumor agent or antiviral agent by reacting with a urea derivative.
Giving the trifluoromethyluracil derivative in high yield. Further, the compound of the present invention is equivalent to a β-keto-α-trifluoromethylacetic acid derivative, and by reacting with various alcohols, a trifluoromethyl group at the α-position useful as an intermediate for pharmaceuticals and agricultural chemicals is obtained. The carboxylic acid derivative having is provided in high yield.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 1,3-dioxynone derivative. More specifically, it relates to a 1,3-dioxin-4-one derivative having a trifluoromethyl group at the 5-position, which is useful as a synthetic chemical synthon for pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art 1,3-dioxin-4-one derivatives are useful synthons for the synthesis of various compounds in organic chemistry which produce acyl ketene by heating. Acyl ketene is a compound useful as an intermediate for medicines and agricultural chemicals, and is used in various syntheses, but a compound having a trifluoromethyl group has not been known so far.

[0003]

The present invention has the general formula (I)

[Chemical 2] (In the formula, R ₁ and R ₂ are the same or different and are an alkyl group having 1 to 5 carbon atoms, or R ₁ and R ₂ together are 3 to 3 carbon atoms.
6 represents an alkylene group. R ₃ represents a hydrogen atom or an alkyl group or aryl group having 1 to 6 carbon atoms. ), Which provides a 5-trifluoromethyl-1,3-dioxin-4-one derivative.

The compound represented by the formula (I) can be generally synthesized by the following reaction.

[Chemical 3] (In the above formula, R ₁ , R ₂ , and R ₃ have the same meanings as described above. X represents a halogen atom such as chlorine, bromine, or iodine.)

The compound of the formula (II) is disclosed, for example, in JP-A-62-62.
It can be synthesized by the method described in -205075 Publication.

The trifluoromethyl copper used in the trifluoromethylation in this reaction is used without isolation of the one synthesized in the known reaction. Trifluoromethylation is usually performed in an inert solvent. Preferred solvents are hexamethylphosphoric triamide, dimethylformamide, dimethylacetamide, dimethylimidazolidinone, N-methylpyrrolidone and the like.

The reaction temperature is generally room temperature to 70 ° C., preferably 40 to 50 ° C. The obtained product can be purified by a conventional method such as vacuum distillation or recrystallization.

[0008]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited thereto.

Example 1 4-oxo-5-trifluoromethyl-4H-1,3-
Preparation of dioxin-2-spin Russia cyclohexane

A mixture of 0.75 g of copper powder, 1.80 g of iodotrifluoromethane and 5 ml of hexamethylphosphoric triamide (HMPA) heated at 120 ° C. for 5 hours was added to 5-iodo-4-oxo-4H-1,3. -Add 147 mg of dioxin-2-spirocyclohexane and add 4
The reaction was carried out at 5 ° C for 18 hours. Then, the reaction solution is 20 ml of water,
It was developed in 10 ml of ether and the insoluble matter was filtered off. The mother liquor was extracted with 10 ml of ether, the organic layer was washed twice with 10 ml of water and then dried over magnesium sulfate, and the solvent was distilled off.
The residue was purified by silica gel chromatography (hexane: methylene chloride = 1: 1) to obtain 75 mg of the title compound. Recrystallization from ether-hexane gave colorless needle crystals. Melting point: 77.5 to 78.0 ° C

IR (CHCl ₃ ) 2950, 1750
and 1645 cm ^-1 NMR (CDCl ₃ ) δ: 1.3-2.3 (10H,
m), 7.70 (1H, brs). High Resolution MS: C ₁₀ H ₁₁
F ₃ O ₃ as 236.0660 Found 236.
0656

[0011]

Example 1 6-Methyl-4-oxo-5-trifluoromethyl-4
H-1,3-dioxin-2-spirocyclohexane
Manufacturing method

A mixture of 4.57 g of copper powder, 8.82 g of iodotrifluoromethane and 18 ml of HMPA heated at 120 ° C. for 2 hours was added to 5-iodo-6-methyl-4-oxo-4H-1,3-dioxin-2-. 1.54 g of spirocyclohexane was added, and the mixture was reacted at 50 ° C. for 3 hours. Next, the reaction solution was developed in 100 ml of ice water, neutralized with a saturated aqueous solution of sodium carbonate, and the insoluble matter was filtered off. The filtered product was washed with ether, and the aqueous layer and the ether washing solution were combined and extracted with ether. The organic layer was washed twice with 30 ml of water and dried over magnesium sulfate, and the solvent was distilled off. The residue was chromatographed on silica gel (hexane: methylene chloride =
1: 1) and the title compound 0.67 as a colorless oil.
g was obtained.

IR (CHCl ₃ ) 2960, 1740
and 1630 cm ^-1 NMR (CDCl ₃ ) δ: 1.3-2.3 (10H,
m), 2.27 (3H, q, J = 2Hz). High Resolution MS: C ₁₁ H ₁₃
F ₃ O ₃ as 250.0816 Found 250.
0817

[0014]

Example 3 2,2,6-Trimethyl-5-trifluoromethyl-
Process for producing 1,3-dioxin-4-one

A mixture obtained by heating 1.37 g of copper powder, 2.65 g of iodotrifluoromethane and 5.4 ml of HMPA at 115 ° C. for 2 hours and 30 minutes was added to 5-iodo-2,2,6-trimethyl-1,3-dioxin-. 0.40 g of 4-one was added and reacted at 50 ° C. for 5 hours. Then, the reaction solution is ice water 3
It was developed into 0 ml and 30 ml of ether, and the insoluble matter was filtered off. The filtered product was washed with ether, and the aqueous layer and the ether washing solution were combined and extracted with ether. 2 ml of organic layer with 20 ml of water
After washing twice, it was dried over magnesium sulfate and the solvent was distilled off. The residue was chromatographed on silica gel (hexane:
Purification with ethyl acetate = 10: 1) gave 0.168 g of the title compound as a colorless oil.

IR (CHCl ₃ ) 1750, 1630
and 1400 cm ^-1 NMR (CDCl ₃ ) δ: 1.73 (6H, s), 2.
27 (3H, m). High Resolution MS: C ₈ H ₉ F ₃
As O ₃ , 210.0504 measured value 210.05
43

[0017]

Example 4 2,2-dimethyl-6-phenyl-5-trifluoromethyl-1,3-Jioki Shin-4-one of formula

A mixture of 1.37 g of copper powder, 2.65 g of iodotrifluoromethane and 5.4 ml of HMPA heated at 120 ° C. for 2 hours and 30 minutes was added to 5-iodo-2,2-dimethyl-6-phenyl-1,3-. Dioxin-4-one 49
5 mg was added and reacted at 60 ° C. for 2 hours. Then, the reaction solution was developed in 30 ml of ice water and 30 ml of ether, and the insoluble matter was filtered off. The filtered product was washed with ether, and the aqueous layer and the ether washing solution were combined and extracted with ether. The organic layer is 20m
It was washed twice with 1 and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (hexane: methylene chloride = 1: 1) to give the title compound 2
16 mg was obtained. Recrystallization from ethyl acetate-hexane gave colorless needle crystals. Melting point 111.5-112.5 [deg.] C.

IR (CHCl ₃ ) 1740, 161
5, 1385 and 1375 cm ^-1 NMR (CDCl ₃ ) δ: 1.87 (6H, s), 7.
60 (5H, s). High Resolution MS: C ₁₃ H ₁₁
272.0660 as F ₃ O ₃ measured value 272.0
658

[0020]

INDUSTRIAL APPLICABILITY By reacting the compound of the present invention with a urea derivative, a 5-trifluoromethyluracil derivative useful as an antitumor agent or antiviral agent is provided in a high yield. Further, the compound of the present invention is equivalent to a β-keto-α-trifluoromethylacetic acid derivative, and by reacting with various alcohols, a trifluoromethyl group at the α-position useful as an intermediate for pharmaceuticals and agricultural chemicals is obtained. The carboxylic acid derivative having is provided in high yield.

[0021]

Reference Example 1 of 1,3-dimethyl-5-trifluoromethyluracil
Synthesis

To a solution of 35.2 mg N, N'-dimethylurea and 2 ml toluene, under reflux, 4oxo-5-trifluoromethyl-4H-1,3-dioxin-2-spirocyclohexane 47.2 mg toluene. 2 ml of solution
Was added dropwise over 2 hours. After the dropping, the mixture was refluxed for another 30 minutes, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain 35 mg of the title compound. Recrystallization from ethyl acetate-ether gave colorless plate crystals. Melting point: 108-
109 ° C

IR (CHCl ₃ ) 1725,1690
and 1680 cm ^-1 NMR (CDCl ₃ ) δ: 3.37 (3H, s),
3.50 (3H, s), 7.70 (1H, m). High Resolution MS: C ₇ H ₇ F ₃
As N ₂ O ₂ , 208.0460 Found 208.
0473

[0024]

Reference Example 2 (E) -3-Hydroxy-2-trifluoromethylac
Synthesis of benzyl phosphate

4-oxo-5-trifluoromethyl-4
H-1,3-dioxin-2-spirocyclohexane 4
After refluxing 7.2 mg, benzyl alcohol 22.7 mg, and toluene 0.5 ml for 30 minutes, the solvent, excess benzyl alcohol, and by-product cyclohexanone were distilled off under reduced pressure to obtain 42 mg of the title compound as a colorless oil.

IR (CHCl ₃ ) 1680,142
0,1190 and 1140 cm ^-1 NMR (CDCl ₃ ) δ: 5.37 (2H, s),
7.40 (5H, s), 7.76 (1H, brd, J =
13 Hz), 12.35 (1 H, d, J = 13 Hz). High Resolution MS: C ₁₁ H ₉ F
As ₃ O ₃ 246.0504 embodiment Value 246.05
12

[0027]

[Reference Example 3] Combination of benzyl 3-oxo-2-trifluoromethylbutyrate
Success

4-oxo-5-trifluoromethyl-4
H-1,3-dioxin-2-spirocyclohexane 5
After refluxing 0 mg, benzyl alcohol 22.7 mg, and xylene 0.5 ml for 20 minutes, the solvent, excess benzyl alcohol, and by-produced cyclohexanone were distilled off under reduced pressure.
53 mg of the title compound was obtained as a colorless oil.

IR (CHCl ₃ ) 1760,173
5,1260 and 1160 cm ^-1 NMR (CDCl ₃ ) δ: 2.30 (3H, s), 4.
23 (1Hx0.9, q, J = 8Hz), 5.27 (2
H, s), 7.37 (5H, s), 14.00 (1Hx
0.1, s). High Resolution MS: C ₁₂ H ₁₁
260.0660 actual value 260.0 as F ₃ O ₃
647

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ₁ and R ₂ are the same or different and are an alkyl group having 1 to 5 carbon atoms, or R ₁ and R ₂ together are 3 to 3 carbon atoms.
6 represents an alkylene group. R ₃ represents a hydrogen atom or an alkyl group or aryl group having 1 to 6 carbon atoms. ), A 5-trifluoromethyl-1,3-dioxin-4-one derivative.