Improved synthesis method for 2-perfluoroalkyl-4h-pyran-4-one derivative

Abstract

A synthesis method is provided, using acetylacetone enol ether (1) and perfluoroalkyl acyl chloride (2) as raw materials, obtaining an intermediate (3) from an addition reaction under alkaline conditions, and then performing ring closure under acidic conditions, to synthesize a 2-perfluoroalkyl-4H-pyran-4-one derivative (4). The present method uses perfluoroalkyl acyl chloride to carry out an addition reaction, effectively improving the yield of the addition reaction; by means of a trifluoroacetic acid / ethanol system, efficient ring closure is achieved at room temperature. The method avoids the use of high-temperature conditions and drug precursor reagents, and has prospects for industrial use.

Description

Improved Synthesis Method of 2-Perfluoroalkyl-4H-pyran-4-one Derivatives Technical Field

[0001] The present invention belongs to the technical field of organic fluorides and relates to a method for synthesizing a perfluoroalkylated six-membered heterocycle, and in particular to an improved method for synthesizing a 2-perfluoroalkyl-4H-pyran-4-one derivative. Background Art

[0002] Perfluoroalkylated heterocyclic compounds have attracted considerable attention due to their remarkable biological activity, specific chemical reactivity, and physical properties. In particular, perfluoroalkylated six-membered heterocycles have important applications in medicine, agronomy, and dye chemistry. Therefore, efficient and economical methods for the regioselective introduction of short-chain perfluoroalkyl groups into heterocycle synthesis are highly desirable.

[0003] Perfluoroalkylated heterocyclic compounds have attracted considerable attention due to their remarkable biological activity, specific chemical reactivity, and physical properties. In particular, perfluoroalkylated six-membered heterocycles have important applications in medicine, agronomy, and dye chemistry. Therefore, efficient and economical methods for the regioselective introduction of short-chain perfluoroalkyl groups into heterocyclic synthesis are highly desirable. Among perfluoroalkylated six-membered heterocycles, 2-perfluoroalkyl-4H-pyran-4-one is a representative compound that has been extensively studied.

[0004] There are two main synthetic routes for 2-perfluoroalkyl-4H-pyran-4-one reported in the literature. The first synthetic method was reported by Tyvorakii et al. (Tetrahedron, 1998, 54, 2819-2826), and the route is as follows:

[0005] This route involves the addition of acetylacetone enol ether to ethyl perfluoroalkanoate, followed by cyclization under hydrochloric acid conditions to obtain the target product. The total yield of this two-step method is less than 40%, and hydrochloric acid, a precursor reagent, is required.

[0006] The second synthesis method was reported by Usachev et al. (Russian Chemical Bulletin, 2010, 59, 845-847), and the route is as follows:

[0007] This route requires a high-temperature deacidification reaction (over 250°C), which limits its industrial application.

[0008] Therefore, there is a need to further develop an improved synthetic method with milder conditions and higher yields.

[0009] Summary of the Invention

[0010] To address the shortcomings of existing synthesis methods, such as difficulty in scalable application and low yield, the present invention provides an improved synthesis method for 2-perfluoroalkyl-4H-pyran-4-one derivatives. This method has mild conditions, few by-products, high product purity, and high product yield.

[0011] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0012] A method for synthesizing a 2-perfluoroalkyl-4H-pyran-4-one derivative comprises using acetylacetone enol ether 1 and perfluoroalkyl acyl chloride 2 as raw materials, adding an intermediate 3 under alkaline conditions, and then ring closing under acidic conditions to synthesize a 2-perfluoroalkyl-4H-pyran-4-one derivative 4. The reaction formula is as follows:

[0013] Where R1 is C 1-6 Alkyl; R2 is C 1-6 Perfluoroalkyl; characterized in that

[0014] (1) dissolving a base in an aprotic solvent, adding 4-alkoxy-3-butene-2-one 1 dropwise, and then adding a perfluoroalkyl acyl chloride 2 dissolved in an aprotic solvent dropwise to the above solution at low temperature;

[0015] (2) After the addition is complete, the temperature is raised to room temperature. The reaction is completed and quenched with ammonium chloride aqueous solution to obtain intermediate 3;

[0016] (3) Intermediate 3 was subjected to a ring-closure reaction using trifluoroacetic acid. After the reaction was completed, it was distilled under reduced pressure to obtain a 2-perfluoroalkyl-4H-pyran-4-one derivative 4.

[0017] Preferably, the base in step (1) is selected from any one or more of sodium hydride, lithium aluminum tetrahydride, potassium tert-butoxide, sodium tert-butoxide, and sodium ethoxide.

[0018] Preferably, the aprotic solvent in step (1) is selected from any one or more of tetrahydrofuran, 2-methyltetrahydropyran, acetonitrile, diethyl ether, acetone or butanone.

[0019] Preferably, the low temperature of step (1) is -20 to 0°C.

[0020] Preferably, the room temperature in step (1) is 20-30°C.

[0021] Preferably, the mass of the aprotic solvent in step (1) is 4-10 times the mass of 4-alkoxy-3-butene-2-one 1.

[0022] Preferably, the molar ratio of the 4-alkoxy-3-butene-2-one 1 to the perfluoroalkyl acyl chloride 2 in step (1) is 1:1.1-5.0.

[0023] Preferably, the molar ratio of the 4-alkoxy-3-butene-2-one 1 to the base in step (1) is 1:2.0-3.0.

[0024] Preferably, the reaction completion endpoint of step (2) is the disappearance of the starting material 1 as detected by gas chromatography.

[0025] Preferably, the trifluoroacetic acid used in step (3) is a trifluoroacetic acid / ethanol system.

[0026] Preferably, the volume ratio of trifluoroacetic acid to ethanol in step (3) is 1:3.0-5.0.

[0027] Preferably, the reaction completion endpoint of step (3) is the disappearance of the intermediate 3 detected by gas chromatography.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1) The present invention uses perfluoroalkyl acyl chloride to carry out the addition reaction, which effectively improves the yield of the addition reaction.

[0030] 2) The present invention achieves efficient ring closure at room temperature through a trifluoroacetic acid / ethanol system.

[0031] 3) The present invention avoids the use of high temperature conditions and easily produced drug reagents, and has industrial application prospects. DETAILED DESCRIPTION

[0032] The present invention is further described below with reference to the examples, which do not limit the application of the present invention. Unless otherwise specified, the percentages in the examples are all by mass.

[0033] Example 1:

[0034] The first step is to dissolve potassium tert-butoxide (224g, 2mol) in 800mL of dry tetrahydrofuran at -20 to 0°C under a nitrogen atmosphere, and add 4-methoxy-3-butene-2-one (100g, 1mol) dropwise over 30 minutes, keeping the reaction temperature at no more than 5°C during the addition process. Subsequently, trifluoroacetyl chloride (662g, 5mol) gas is slowly introduced into the above reaction solution. After ventilation is completed, the temperature is naturally raised to 20 to 25°C and the reaction is kept warm for 1-2 hours. The raw material 4-methoxy-3-butene-2-one disappears when detected by gas phase detection. A 10% aqueous ammonium chloride solution (1000mL) is added to the reaction solution to quench the reaction, separate the organic phase, dry it over anhydrous magnesium sulfate, and concentrate to remove the solvent to obtain intermediate 3;

[0035] In the second step, intermediate 3 obtained in the previous step was dissolved in 2000 mL of ethanol. Trifluoroacetic acid (400 mL) was added at 25°C and stirred at 25°C for 2-4 hours. Gas chromatography revealed the disappearance of intermediate 3. The solvent was then concentrated to obtain the crude product. The crude product was distilled using short-path distillation at 40-45°C and a vacuum of 130-400 Pa to afford 2-trifluoromethyl-4H-pyran-4-one (119.2 g, 73%) as a bright yellow oil.

[0036] 1 H NMR (CDCl3, 400MHz) δ: 6.48 (m, 1H, H (5)); 6.76 (d, 1H, H (3)); 7.85 (dd, 1H, H (6)).

[0037] Example 2:

[0038] The first step is to dissolve sodium ethoxide (136g, 2mol) in 800mL of dry tetrahydrofuran at -20 to 0°C under a nitrogen atmosphere, and add 4-methoxy-3-butene-2-one (100g, 1mol) dropwise over 30 minutes, keeping the reaction temperature below 5°C during the addition process. Subsequently, trifluoroacetyl chloride (662g, 5mol) gas is slowly introduced into the above reaction solution. After ventilation is completed, the temperature is naturally raised to 20 to 25°C and the reaction is kept warm for 1-2 hours. The raw material 4-methoxy-3-butene-2-one disappears when detected by gas phase detection. A 10% aqueous ammonium chloride solution (1000mL) is added to the reaction solution to quench the reaction, separate the organic phase, dry it over anhydrous magnesium sulfate, and concentrate to remove the solvent to obtain intermediate 3;

[0039] In the second step, intermediate 3 obtained in the previous step was dissolved in 2000 mL of ethanol. Trifluoroacetic acid (400 mL) was added at 25°C and stirred at 25°C for 2-4 hours. Gas chromatography revealed the disappearance of intermediate 3. The solvent was then concentrated to obtain the crude product. The crude product was distilled using short-path distillation at 40-45°C and a vacuum of 130-400 Pa to afford 2-trifluoromethyl-4H-pyran-4-one (98.4 g, 60%) as a bright yellow oil.

[0040] 1 H NMR (CDCl3, 400MHz) δ: 6.48 (m, 1H, H (5)); 6.76 (d, 1H, H (3)); 7.85 (dd, 1H, H (6)).

[0041] Example 3:

[0042] The first step is to dissolve potassium tert-butoxide (224g, 2mol) in 800mL of dry tetrahydrofuran at -20 to 0°C under a nitrogen atmosphere, and add 4-methoxy-3-butene-2-one (100g, 1mol) dropwise over 30 minutes, keeping the reaction temperature below 5°C during the addition process. Subsequently, trifluoroacetyl chloride (662g, 5mol) gas is slowly introduced into the above reaction solution. After ventilation is completed, the temperature is naturally raised to 20 to 25°C and the reaction is kept warm for 1-2 hours. The raw material 4-methoxy-3-butene-2-one disappears during gas phase detection. A 10% aqueous ammonium chloride solution (1000mL) is added to the reaction solution to quench the reaction, separate the organic phase, dry it over anhydrous magnesium sulfate, and concentrate to remove the solvent to obtain intermediate 3;

[0043] In the second step, intermediate 3 obtained in the previous step was dissolved in 2000 mL of ethanol. Trifluoroacetic acid (400 mL) was added at 25°C and stirred at 25°C for 2-4 hours. Gas chromatography revealed the disappearance of intermediate 3. The solvent was then concentrated to obtain the crude product. The crude product was subjected to short-path distillation at 40-45°C and a vacuum of 130-400 Pa to afford 2-trifluoromethyl-4H-pyran-4-one (105 g, 64%) as a bright yellow oil.

[0044] 1 H NMR (CDCl3, 400MHz) δ: 6.48 (m, 1H, H (5)); 6.76 (d, 1H, H (3)); 7.85 (dd, 1H, H (6)).

[0045] Example 4:

[0046] The first step is to dissolve potassium tert-butoxide (224g, 2mol) in 800mL of dry tetrahydrofuran at -20 to 0°C under a nitrogen atmosphere, and add 4-methoxy-3-butene-2-one (100g, 1mol) dropwise over 30 minutes, keeping the reaction temperature below 5°C during the addition process. Subsequently, trifluoroacetyl chloride (662g, 5mol) gas is slowly introduced into the above reaction solution. After ventilation is completed, the temperature is naturally raised to 20 to 25°C and the reaction is kept warm for 1-2 hours. The raw material 4-methoxy-3-butene-2-one disappears during gas phase detection. A 10% aqueous ammonium chloride solution (1000mL) is added to the reaction solution to quench the reaction, separate the organic phase, dry it over anhydrous magnesium sulfate, and concentrate to remove the solvent to obtain intermediate 3;

[0047] In the second step, intermediate 3 obtained in the previous step was dissolved in 2000 mL of ethanol. Trifluoroacetic acid (400 mL) was added at 25°C and stirred at 25°C for 2-4 hours. Gas chromatography revealed the disappearance of intermediate 3. The solvent was then concentrated to obtain the crude product. The crude product was subjected to short-path distillation at 40-45°C and a vacuum of 130-400 Pa to afford 2-trifluoromethyl-4H-pyran-4-one (115 g, 70%) as a bright yellow oil.

[0048] 1 H NMR (CDCl3, 400MHz) δ: 6.48 (m, 1H, H (5)); 6.76 (d, 1H, H (3)); 7.85 (dd, 1H, H (6)).

[0049] Example 5:

[0050] The first step is to dissolve potassium tert-butoxide (224g, 2mol) in 800mL of dry tetrahydrofuran at -20 to 0°C under a nitrogen atmosphere, and add 4-methoxy-3-butene-2-one (100g, 1mol) dropwise over 30 minutes, keeping the reaction temperature below 5°C during the addition process. Subsequently, pentafluoropropionyl chloride (662g, 5mol) liquid is slowly dripped into the above reaction solution. After the addition is complete, the temperature is naturally raised to 20 to 25°C and the reaction is kept warm for 1-4 hours. The raw material 4-methoxy-3-butene-2-one disappears during gas phase detection, and 10% ammonium chloride aqueous solution (1000mL) is added to the reaction solution to quench the reaction. The organic phase is separated, dried over anhydrous magnesium sulfate, and concentrated to remove the solvent to obtain intermediate 3;

[0051] In the second step, the intermediate 3 obtained in the previous step was dissolved in 2000 mL of ethanol. Trifluoroacetic acid (400 mL) was added at 25°C and stirred at 25°C for 2-4 hours. Gas chromatography revealed the disappearance of intermediate 3. The solvent was then concentrated to obtain a crude product. The crude product was subjected to short-path distillation at 45-50°C and a vacuum of 130-400 Pa. After cooling, distillation was performed to obtain 2-pentafluoroethyl-4H-pyran-4-one (147 g, 69%) as a yellow solid.

[0052] 1 H NMR (CDCl3, 400MHz) δ: 6.51 (m, 1H, H (5)); 6.82 (d, 1H, H (3)); 7.87 (dd, 1H, H (6)).

[0053] Example 6:

[0054] The first step is to dissolve potassium tert-butoxide (224g, 2mol) in 800mL of dry tetrahydrofuran at -20 to 0°C under a nitrogen atmosphere, and add 4-methoxy-3-butene-2-one (100g, 1mol) dropwise over 30 minutes, keeping the reaction temperature below 5°C during the addition process. Subsequently, heptafluorobutyryl chloride (662g, 5mol) liquid is slowly dripped into the above reaction solution. After the addition is complete, the temperature is naturally raised to 20 to 25°C and the reaction is kept warm for 1-4 hours. The raw material 4-methoxy-3-butene-2-one disappears when detected by gas phase detection. A 10% aqueous ammonium chloride solution (1000mL) is added to the reaction solution to quench the reaction, the organic phase is separated, dried over anhydrous magnesium sulfate, and concentrated to remove the solvent to obtain intermediate 3;

[0055] In the second step, the intermediate 3 obtained in the previous step was dissolved in 2000 mL of ethanol. Trifluoroacetic acid (400 mL) was added at 25°C and stirred at 25°C for 2-4 hours. Gas chromatography revealed the disappearance of intermediate 3. The solvent was then concentrated to obtain a crude product. The crude product was subjected to short-path distillation at 48-55°C and a vacuum of 130-400 Pa. After cooling, distillation was performed to obtain 2-heptafluoropropyl-4H-pyran-4-one (190 g, 72%) as a yellow-green solid.

[0056] 1 H NMR (CDCl3, 400MHz) δ: 6.52 (m, 1H, H (5)); 6.83 (d, 1H, H (3)); 7.88 (dd, 1H, H (6)).

[0057] It should be understood that the specific embodiments of the present invention are intended only to illustrate the spirit and principles of the present invention and are not intended to limit the scope of the present invention. Furthermore, it should be understood that after reading the contents of the present invention, those skilled in the art may make various changes, substitutions, deletions, corrections, or adjustments to the technical solutions of the present invention, and that such equivalent technical solutions also fall within the scope defined by the claims of the present invention.

Claims

1. A method for synthesizing a 2-perfluoroalkyl-4H-pyran-4-one derivative, comprising taking acetylacetone enol ether (1) and perfluoroalkyl acyl chloride (2) as raw materials, performing addition reaction under alkaline conditions to obtain an intermediate (3), and then performing ring closure under acidic conditions to synthesize a 2-perfluoroalkyl-4H-pyran-4-one derivative (4); the reaction formula is as follows: in, R1 is C 1-6 Alkyl; R2 is C 1-6 Perfluoroalkyl; characterized in that (1) dissolving a base in an aprotic solvent, adding 4-alkoxy-3-butene-2-one (1) dropwise, and then adding a perfluoroalkyl acid chloride (2) dissolved in an aprotic solvent dropwise to the above solution at low temperature; (2) After the addition is complete, the temperature is raised to room temperature. After the reaction is complete, an aqueous solution of ammonium chloride is added to quench the reaction to obtain an intermediate (3); (3) The intermediate (3) is subjected to a ring-closing reaction using trifluoroacetic acid. After the reaction is completed, it is distilled under reduced pressure to obtain a 2-perfluoroalkyl-4H-pyran-4-one derivative (4).

2. The synthesis method according to claim 1, wherein The base in step (1) is selected from any one or more of sodium hydride, lithium aluminum tetrahydride, potassium tert-butoxide, sodium tert-butoxide, and sodium ethoxide.

3. The synthesis method according to claim 1, wherein The aprotic solvent in step (1) is selected from any one or more of tetrahydrofuran, 2-methyltetrahydropyran, acetonitrile, diethyl ether, acetone or butanone.

4. The synthesis method according to claim 1, wherein The low temperature of step (1) is -20 to 0°C.

5. The synthesis method according to claim 1, wherein The room temperature of step (1) is 20-30°C.

6. The synthesis method according to claim 1, wherein The mass of the aprotic solvent in step (1) is 4-10 times the mass of 4-alkoxy-3-butene-2-one (1).

7. The synthesis method according to claim 1, wherein The molar ratio of the 4-alkoxy-3-butene-2-one (1) to the perfluoroalkyl acid chloride (2) in step (1) is 1:1.1-5.

0.

8. The synthesis method according to claim 1, wherein The molar ratio of the 4-alkoxy-3-butene-2-one (1) to the base in step (1) is 1:2.0-3.

0.

9. The synthesis method according to claim 1, wherein The trifluoroacetic acid used in step (3) is a trifluoroacetic acid / ethanol system.

10. The synthesis method according to claim 1, wherein The volume ratio of trifluoroacetic acid to ethanol in step (3) is 1:3.0-5.0.

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