Method for synthesizing difluorocyclobutenedione based on ruthenium catalyzed carbonylation reaction

Abstract

The application belongs to the technical field of medicine preparation, and particularly relates to a method for synthesizing difluorocyclobutenedione based on ruthenium catalyzed carbonylation reaction, and the specific steps are as follows: in step one, aromatic alkyne, ruthenium catalyst, base, tetrahydrofuran and difluorodibromomethane are put into an autoclave, and carbon monoxide 10 atm is introduced for reaction, the reaction time is 12 h, and the reaction temperature is 80-100 DEG C; in step two, chloromethane is used to dilute the reaction liquid, then the organic solvent is removed by rotary evaporation, and the remaining product is separated and purified by column chromatography to obtain difluorocyclobutenedione; only two steps are needed to effectively synthesize difluorocyclobutenedione, the reaction flow is simple, the operation is convenient, the whole reaction temperature range is controlled in 80-100 DEG C, the reaction does not need high-temperature reaction conditions, the reaction energy consumption is low, the reaction cost is reduced, and energy saving and environmental protection are promoted.

Description

[Technical Field]

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction. [Background Technology]

[0002] Difluorocyclobutenones are widely used as intermediates in the synthesis of other organic compounds. Through further functional group transformations, difluorocyclobutenones can be converted into the target product, thus they are widely used in drug development and research. For example, fluphenazine, an antipsychotic drug, can be synthesized using difluorocyclobutenone as an intermediate for reaction activation; nitroglycerin, a vasodilator used to treat angina, can also be synthesized using difluorocyclobutenone as an intermediate; and moxifloxacin, a broad-spectrum antibiotic commonly used to treat bacterial infections, uses difluorocyclobutenone as an activator and reaction intermediate in its synthesis.

[0003] Currently, there is a lack of routes for the efficient synthesis of difluorocyclobutenones. [Summary of the Invention]

[0004] This invention provides a method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction, thereby solving the problem of how to synthesize difluorocyclobutenone in the prior art.

[0005] This invention is achieved through the following technical solution: a method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction is provided.

[0006] The specific steps of a method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction are as follows:

[0007] Step 1: Aromatic alkynes, ruthenium catalyst, base, tetrahydrofuran and difluorodibromomethane are placed in a high-pressure reactor and carbon monoxide is introduced at 10 atm to carry out the reaction. The reaction time is 12 hours and the reaction temperature is 80-100℃.

[0008] Step 2: The reaction solution was diluted with chloromethane, and then the organic solvent was removed by rotary evaporation. The remaining product was purified by column chromatography to obtain difluorocyclobutenone.

[0009] Further, in step one, the mass ratio of aromatic alkyne, ruthenium catalyst, base, difluorodibromomethane and solvent is 1:0.05:4:4:2.

[0010] Furthermore, in step one, the aromatic alkyne is any one of p-methoxyphenylacetylene, phenylacetylene, 4-fluorophenylacetylene, and 4-methylphenylacetylene.

[0011] Furthermore, the ruthenium catalyst is any one of dodecyltriruthenium, ruthenium acetylacetonate, ruthenium triphenylphosphine chloride, hexaammineruthenium chloride, p-cymene ruthenium dichloride dimer, (1,5-cyclooctadiene) ruthenium dichloride, and dichlorophenylruthenium(II) dimer.

[0012] Furthermore, the base is any one of potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, triethylamine, cesium acetate, and N,N-diethylaniline.

[0013] Furthermore, in step two, during chromatographic separation, a 100-200 mesh silica gel column is used for separation and purification.

[0014] Furthermore, in step two, the eluent used for chromatographic separation is a mixture of petroleum ether and ethyl acetate.

[0015] Furthermore, in step one, the aromatic alkyne is p-methoxyphenylacetylene, the ruthenium catalyst is dodecyltriruthenium, and the base is potassium bicarbonate; in step two, the ratio of petroleum ether to ethyl acetate is 30:1-10:1.

[0016] Furthermore, in step one, the aromatic alkyne is p-phenylacetylene, the ruthenium catalyst is dodecyltriruthenium carbonyl, and the base is potassium bicarbonate; in step two, the ratio of petroleum ether to ethyl acetate is 30:1-8:1.

[0017] Furthermore, in step one, p-phenylacetylene is selected as the 4-fluorophenylacetylene, dodecacarbonyltriruthenium is selected as the ruthenium catalyst, and potassium bicarbonate is selected as the base; in step two, the ratio of petroleum ether to ethyl acetate is 30:1-10:1.

[0018] The beneficial effects are: difluorocyclobutenone can be synthesized effectively in just two steps, the reaction process is simple and convenient, the entire reaction temperature range is controlled within 80-100℃, high-temperature reaction conditions are not required, the reaction energy consumption is low, which helps to reduce reaction costs and promote energy conservation and environmental protection.

Detailed Implementation Methods

[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below.

[0020] The method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction provided in this embodiment is implemented according to the following steps:

[0021] Step 1: Aromatic alkynes, ruthenium catalyst, base, tetrahydrofuran, and difluorodibromomethane are placed in a high-pressure reactor and carbon monoxide is introduced at 10 atm for reaction. The reaction time is 12 hours, and the reaction temperature is 80-100℃. After the reaction is completed, the carbon monoxide is stopped, and the next step is carried out. The mass ratio of aromatic alkynes, ruthenium catalyst, base, difluorodibromomethane, and solvent is 1:0.05:4:4:2.

[0022] Step 2: Dilute the reaction solution with chloromethane, then remove the organic solvent by rotary evaporation. The remaining product is purified by column chromatography to obtain difluorocyclobutenone. A 200-300 mesh silica gel column is used for column chromatography purification.

[0023] In step one, the aromatic alkyne is any one of p-methoxyphenylacetylene, phenylacetylene, 4-fluorophenylacetylene, 4-methylphenylacetylene; the ruthenium catalyst is any one of dodecyltriruthenium, ruthenium acetylacetonate, ruthenium triphenylphosphine chloride, hexaammineruthenium chloride, p-cymene ruthenium dichloride dimer, (1,5-cyclooctadiene) ruthenium dichloride, and dichlorophenylruthenium(II) dimer; the base is any one of potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, triethylamine, cesium acetate, and N,N-diethylaniline.

[0024] In step two, the eluent used for chromatographic separation is a mixture of petroleum ether and ethyl acetate.

[0025] Specific Example 1 of a method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction provided by the present invention:

[0026] In this embodiment, the specific steps of the method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction are as follows:

[0027] Step 1: Place p-methoxyphenylacetylene, dodecyltriruthenium carbonyl, potassium bicarbonate, tetrahydrofuran, and difluorodibromomethane into a high-pressure reactor, and introduce carbon monoxide at 10 atm. React for 12 hours at a temperature of 100°C.

[0028] Step 2: Dilute the reaction solution with dichloromethane, then remove the organic solvent by rotary evaporation. The remaining product is purified by separation using a 100-200 mesh silica gel column to obtain difluorocyclobutenone.

[0029] In this embodiment, the eluent used for chromatographic separation is a mixture of petroleum ether and ethyl acetate, with a petroleum ether:ethyl acetate ratio of 30:1 to 10:1, as shown below:

[0030] 1H NMR (400MHz, Acetone) δ7.28 (d, J=8.6Hz, 2H), 6.86 (d, J=8.6Hz, 2H), 6.19 (s, 1H), 3.80 (s, 3H).

[0031] 13C NMR (101MHz, Acetone) δ197.05, 138.61, 134.75, 131.10, 122.68, 110.14, 77.51, 54.80;

[0032] 19F NMR (376MHz, Acetone) δ-71.42;

[0033] HRMS(ESI)m / z:[M+H]+calcd.for C11H9F2O2211.0554; found:211.0555.

[0034] Specific Example 2 of the method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction provided by the present invention:

[0035] In this embodiment, the specific steps of the method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction are as follows:

[0036] Step 1: Phenylacetylene, dodecyltriruthenium carbonyl, potassium bicarbonate, tetrahydrofuran and difluorodibromomethane are placed in a high-pressure reactor for reaction, and carbon monoxide is introduced at 10 atm. The reaction time is 12 hours and the reaction temperature is 100℃.

[0037] Step 2: Dilute the reaction solution with dichloromethane, remove the organic solvent by rotary evaporation, and then separate and purify the remaining product using a 100-200 mesh silica gel column to obtain difluorocyclobutenone.

[0038] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent, with a petroleum ether:ethyl acetate ratio of 30:1 to 8:1, as shown in the following data:

[0039] 1H NMR (400MHz, Acetone) δ7.38–7.25 (m, 5H), 6.24 (s, 1H);

[0040] 13C NMR (101MHz, Acetone) δ196.85, 138.60, 135.07, 130.75, 129.94, 128.87, 128.49, 110.80, 77.87.

[0041] 19F NMR (376MHz, Acetone) δ-71.32.

[0042] HRMS(ESI)m / z:[M+H]+calcd.for C10H7F2O 811.0837; found:811.0762.

[0043] Specific Example 3 of the method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction provided by the present invention:

[0044] In this embodiment, the specific steps of the method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction are as follows:

[0045] Step 1: 4-fluorophenylacetylene, dodecyltriruthenium carbonyl, potassium bicarbonate, tetrahydrofuran and difluorodibromomethane are added to a high-pressure reactor for reaction, and carbon monoxide is introduced at 10 atm. The reaction time is 12 hours and the reaction temperature is 100℃.

[0046] Step 2: Dilute the reaction solution with dichloromethane, remove the organic solvent by rotary evaporation, and then separate and purify the remaining product using a 100-200 mesh silica gel column to obtain difluorocyclobutenone.

[0047] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent, with a petroleum ether:ethyl acetate ratio of 30:1 to 10:1, as shown in the following data:

[0048] 1H NMR (400MHz, Acetone) δ7.27 (dd, J=9.0, 5.3Hz, 2H), 6.96 (t, J=8.8Hz, 2H), 6.14 (s, 1H);

[0049] 13C NMR (101MHz, Acetone) δ196.64, 163.98, 161.52, 135.02, 132.69, 126.92, 115.54, 109.83, 77.86;

[0050] 19F NMR (376MHz, Acetone) δ-71.17;

[0051] HRMS(ESI)m / z:[M+H]+calcd.for C10H6F3O 282.0820; found:199.0326.

[0052]

[0053]

[0054] Compound 1

[0055] 1H NMR (400MHz, Acetone) δ7.28 (d, J=8.6Hz, 2H), 6.86 (d, J=8.6Hz, 2H), 6.19 (s, 1H), 3.80 (s, 3H).

[0056] 13C NMR (101 MHz, Acetone) δ 197.05, 138.61, 134.75, 131.10, 122.68, 110.14, 77.51, 54.80;

[0057] 19F NMR (376 MHz, Acetone) δ -71.42;

[0058] HRMS (ESI) m / z: [M+H]+ calcd. for C11H9F2O2 211.0554; found: 211.0555.

[0059] Compound 2

[0060] 1H NMR (400 MHz, Acetone) δ 7.38–7.25 (m, 5H), 6.24 (s, 1H);

[0061] 13C NMR (101 MHz, Acetone) δ 196.85, 138.60, 135.07, 130.75, 129.94, 128.87, 128.49, 110.80, 77.87.

[0062] 19F NMR (376 MHz, Acetone) δ -71.32.

[0063] HRMS (ESI) m / z: [M+H]+ calcd. for C10H7F2O 811.0837; found: 811.0762.

[0064] Compound 3

[0065] 1H NMR (400 MHz, Acetone) δ 7.27 (dd, J = 9.0, 5.3 Hz, 2H), 6.96 (t, J = 8.8 Hz, 2H), 6.14 (s, 1H);

[0066] 13C NMR (101 MHz, Acetone) δ 196.64, 163.98, 161.52, 135.02, 132.69, 126.92, 115.54, 109.83, 77.86;

[0067] 19F NMR (376 MHz, Acetone) δ -71.17;

[0068] HRMS (ESI) m / z: [M+H]+ calcd. for C10H6F3O 282.0820; found: 199.0326.

Claims

1. A method for synthesizing difluorocyclobutenone based on ruthenium-catalyzed carbonylation reaction, characterized in that, The specific steps are as follows: Step 1: Aromatic alkynes, ruthenium catalyst, base, tetrahydrofuran and difluorodibromomethane are placed in a high-pressure reactor and carbon monoxide is introduced at 10 atm to carry out the reaction. The reaction time is 12 hours and the reaction temperature is 80-100℃. Step 2: Dilute the reaction solution with dichloromethane, then remove the organic solvent by rotary evaporation. The remaining product is separated and purified by a 100-200 mesh silica gel column using a mixture of petroleum ether and ethyl acetate as the eluent to obtain difluorocyclobutenone. Its features are: The aromatic alkyne is p-methoxyphenylacetylene, phenylacetylene, or 4-fluorophenylacetylene; The ruthenium catalyst is dodecacarbonyltriruthenium; The alkali is potassium bicarbonate; The mass ratio of the aromatic alkyne, ruthenium catalyst, base, difluorodibromomethane, and tetrahydrofuran is 1:0.05:4:4:

2.

2. The method according to claim 1, characterized in that, When the aromatic alkyne is p-methoxyphenylacetylene, the volume ratio of petroleum ether to ethyl acetate in the rinsing agent in step two is 30:1 to 10:

1.

3. The method according to claim 1, characterized in that, When the aromatic alkyne is phenylacetylene, the volume ratio of petroleum ether to ethyl acetate in the rinsing agent in step two is 30:1 to 8:

1.

4. The method according to claim 1, characterized in that, When the aromatic alkyne is 4-fluorophenylacetylene, the volume ratio of petroleum ether to ethyl acetate in the rinsing agent in step two is 30:1 to 10:1.

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