JPH0692958A - 5-fluoro-1,3-dioxin-4-one derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an intermediate for medicines and agricultural chemicals. CONSTITUTION:The compound of formula I (R1 and R2 are 1-5C alkyl or together represent 3-6C alkylene; R3 is 1-6C alkyl, aryl or trifluoromethyl), e.g. 5-fluoro-6-methyl-4-oxo-4H-1,3-dioxin-2-spirocyclohexane. This compound of formula I is obtained by fluorinating a compound of formula II with fluorine gas, providing a difluoro derivative of formula III and then treating the resultant compound with a base such as triethylamine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 1,3-dioxynone derivative. More specifically, 1,3-dioxin-4- having a fluorine atom at the 5-position and a substituent at the 6-position, which is useful as a synthetic chemical synthon for pharmaceuticals and agricultural chemicals, etc.
An on derivative.

[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,
It is used in various syntheses. To date, 5-fluoro-1,3-dioxin-4-one derivatives having no 6-position substituent are known, but 5-fluoro-1,3 having a substituent at the 6-position, which is more versatile, is known. -Dioxin-4-one derivatives are unknown.

[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 an alkyl group having 1 to 6 carbon atoms, an aryl group or a trifluoromethyl group. ), Which provides a 5-fluoro-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. ) The compound of the formula (II) can be obtained, for example, from Chemical and Pharmaceutical Bretanes (Chemical a).
nd Pharmaceutical Bulleti
n) Vol. 31, No. 6, pp. 1896-1901 (1983)
Year)).

The fluorine gas used for fluorination in this reaction is diluted with an inert gas such as nitrogen, argon or helium to a fluorine concentration of 5 to 20% by volume. Fluorination is usually carried out in a solvent which is relatively inert to fluorine. Preferred solvents are acetonitrile, methanol, acetic acid, methylene chloride, chloroform and the like.

The reaction temperature is generally -70 to 0 ° C, preferably -40 to -10 ° C. The difluoro derivative as an intermediate is isolated or treated with a base without isolation to give the compound of the present invention. As a base,
Tertiary amines such as triethylamine, N, N-dimethylaminopyridine, 1,8-diazabicyclo [5,5
4,0] undecane-7-ene (DBU), 1,4-diazabicyclo [2,2,0] octane (DABCO) and the like are preferable.

As the solvent, methylene chloride, chloroform, tetrahydrofuran, acetonitrile, toluene and the like are preferably used. The reaction temperature is usually 0 to 40 ° C,
It is preferably 15 to 35 ° C., and the reaction time is usually 10
~ 30 minutes. The obtained product can be purified by a conventional method, for example, vacuum distillation, recrystallization and the like.

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

【Example】

[0009]

Example 1 5-Fluoro-6-methyl-4-oxo-4H-1,3
-Process for producing dioxin-2-spirocyclohexane

6-methyl-4-oxo-4H-1,3-
910 mg of dioxin-2-spirocyclohexyne was dissolved in 50 ml of acetonitrile and cooled to -20 ° C. Fluorine gas 22 diluted with this solution to 5% by volume with nitrogen gas
40 ml was passed. Then, nitrogen gas was passed through for 10 minutes to remove fluorine gas, 80 ml of chloroform was added to the reaction solution, and then washed with 30 ml of a saturated aqueous solution of sodium hydrogen carbonate. Further, the mixture was washed twice with 30 ml of water, the organic layer was dried over magnesium sulfate (MgSO ₄ ), and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of hexane: ether = 10: 1 to elute 5,6-difluoro-6-methyl-40oxo-1,3-dioxane-2-spiro. Cyclohexane 30
6 mg was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.0-
2.1 (10H, m), 1.72 (3H, dd, J =
2,27Hz), 4.87 (1H, dd, J = 23, 4)
7Hz)

The resulting 5,6-difluoro-6-
306 mg of methyl-4-oxo-1,3-dioxane-2-spirocyclohexane was dissolved in 5 ml of methylene chloride, 228 mg of DBU was added at room temperature, and the mixture was stirred for 30 minutes. Next, the reaction solution was washed 3 times with 5 ml of water, and the organic layer was washed with M
After drying with gSO ₄ , the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of hexane: ethyl acetate = 5: 1 to give the title compound 19
3 mg was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.2-
2.0 (10H, m), 2.07 (3H, d, J = 4H
z) IR (CHCl ₃ ): 2960, 1745, 168
0,1415,1180 cm ⁻¹ High-Resolution MS: C ₁₀ H ₁₃
FO ₃ , calculated value 200.0849, measured value 200.
0853

[0014]

Example 2 5-Fluoro-2,2-dimethyl-6-phenyl-1,
Process for producing 3-dioxin-4-one

2,2-dimethyl-6-phenyl-1,3
-Dioxin-4-one 408 mg in acetonitrile 2
It was dissolved in 0 ml and cooled to -30 ° C. 900 ml of fluorine gas diluted to 5% by volume with nitrogen gas was passed through this solution, and then nitrogen gas was passed through for 10 minutes to remove the fluorine gas. The reaction solution was returned to room temperature and triethylamine 1.01 was added.
g and stirred for 30 minutes. Ethyl acetate 20 in the reaction solution
ml was added, washed three times with saturated saline, and the organic layer was MgSO 4.
After drying at ₄ , the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of hexane: ethyl acetate = 10: 1 to give the title compound 168.
mg was obtained. Recrystallization from ether-hexane gave colorless needle crystals.

Melting point: 75-76 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.87 (6H,
_{s), 7.2-8.0 (5H, m} ) IR (CHCl 3): 1740,1395,119
0 cm ⁻¹ elemental analysis: calculated value as C ₁₂ H ₁₁ FO ₃ C; 6
4.86 H; 4.99 found C; 64.90 H; 5.03

[0017]

Example 3 5-Fluoro-4-oxo-6-phenyl-4H-1,
Process for producing 3-dioxin-2-spirocyclohexane

4-oxo-6-phenyl-4H-1,3
-610 mg of dioxin-2-spirocyclohexane was dissolved in 25 ml of acetonitrile and cooled to -40 ° C. 1120 ml of fluorine gas diluted to 5% by volume with nitrogen gas was passed through this solution, and then nitrogen gas was passed through for 10 minutes to remove the fluorine gas. Methylene chloride was added to the reaction solution, which was washed twice with a saturated aqueous sodium hydrogen carbonate solution and then three times with water. The organic layer was dried over MgSO ₄ , the solvent was distilled off, and 5,6-difluoro-4-oxo-6-phenyl-
1,3-dioxane-2-spirocyclohexane 563
mg was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.2-
2.5 (10H, m), 4.98 (1H, dd, J = 2)
3,47Hz), 7.53 (5H, s)

To the resulting solution of 5,6-difluoro-4-oxo-6-phenyl-1,3-dioxane-2,563 mg of spirocyclohexane dissolved in 10 ml of methylene chloride was added 505 mg of tritylamine, and the mixture was stirred at room temperature for 3 times.
Stir for 0 minutes. The same treatment as in Example 1 was carried out to obtain 399 mg of the title compound. Recrystallization from ether-hexane gave colorless needle crystals. Melting point: 70.5-71.0 ° C

¹ H-NMR (CDCl ₃ ) δ: 1.2
-2.0 (10H, m), 7.0-8.0 (5H, m) IR (CHCl 3): 2980,1740,139
0,1190,1040 cm ⁻¹ Elemental analysis: Calculated value as C ₁₅ H ₁₅ FO ₃ C; 6
8.69 H; 5.77 Found C; 68.45 H; 5.89

[0021]

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

4-oxo-6-trifluoromethyl-4
H-1,3-dioxin-2-spicyclohexane 70
8 mg was melt | dissolved in 30 ml of acetonitrile, and it cooled at -35 degreeC. 3200 ml of fluorine gas diluted with nitrogen gas to 5% by volume was passed through this solution, and the same post-treatment and base treatment as in Example 3 were carried out to obtain 148 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.2-
2.4 (10H, m) 1R (CHCl ₃ ): 2960,1770,126
5,1165 cm ⁻¹ High-Resolution MS: C ₁₀ H ₁₀
Calculated value 254.0566 as F ₄ O ₃ , measured value 25
4.0591

[0024]

The compound obtained according to the present invention gives various fluorine-containing heterocycles expected to have physiological activity in high yield.

[0025]

[Reference Example] 2-dimethylamino-5-fluoro-4-oxo-6-
Process for producing phenyl-1,3-oxazin-4-one

5-Fluoro-4-oxo-6-phenyl-4H-1,3-dioxin-2-spirocyclohexane (44.4 mg) and dimethylcyanamide (28 mg) were dissolved in mesitylene (0.5 ml) and heated under reflux for 1.5 hours. . The reaction mixture was purified by silica gel column chromatography (ethyl acetate: ethanol = 4: 1) to give the title compound 42.
mg was obtained. Recrystallization from ethyl acetate gave colorless needle crystals. Melting point: 159-160.5 ° C

¹ H NMR (CDCl ₃ ) δ: 3.23
_{(6H, s), 7.2-7.9 (} 5H, m) IR (CHCl 3): 1660,1595,139
0 cm ⁻¹ elemental analysis: calculated value as C ₁₂ H ₁₁ FN ₂ O ₂ C;
61.53 H; 4.73 N; 11.96 Found C; 61.43 H; 4.75 N; 11.9.
8

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 an alkyl group having 1 to 6 carbon atoms, an aryl group or a trifluoromethyl group. ), Which is a 5-fluoro-1,3-dioxin-4-one derivative.