Preparation method of 1-aryl-2-acetone compound

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of a 1-aryl-2-acetone compound, and the preparation method of the 1-aryl-2-acetone compound comprises the following steps: in the presence of an organic solvent, an alkaline reagent and a composite catalyst, reacting a compound II with acetylacetone to prepare a compound I; the composite catalyst comprises cuprous halide and proline. According to the preparation method, the proline and the cuprous halide are adopted as the composite catalyst, so that the reaction yield can be greatly improved, and even if aryl bromide is adopted as a raw material, the reaction yield can reach 70% or above and is improved by 20% or above compared with the prior art. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to a method for preparing 1-aryl-2-propanone compounds. Background Art

[0002] 1-aryl-2-propanone compounds are important pharmaceutical intermediates. For example, 1-phenyl-2-propanone can be used to synthesize selegiline hydrochloride for treating Parkinson's syndrome, and can also be used to synthesize the anti-angina drug xantinol nicotinate (CN110590529A); 1-(4-biphenyl)-2-propanone can be used to synthesize amikacin acid derivatives for treating and preventing hypercholesterolemic sepsis, hyperlipidemia, arteriosclerosis, etc. (US5488149A).

[0003] In the prior art, there are mainly the following two methods for preparing corresponding 1-aryl-2-propanone compounds using aryl halides as raw materials:

[0004] The first one: Palladium-Catalyzed Mono-α-arylation of Acetone at Room Temperature (Chem. Eur. J. 2015, 21, 11006-11009) discloses that 1-(4-biphenyl)-2-propanone is prepared in a yield of 87% by reacting 4-bromo-1,1'-biphenyl under the action of a suitable palladium ligand. However, this preparation method requires the use of expensive palladium reagents and is difficult to apply to large-scale industrial production.

[0005]

[0006] The second one: Copper Catalyzed Arylation / C-C Bond Activation: An Approach toward α-Aryl Ketones (J. Am. Chem. Soc. 2010, 132, 8273-8275) discloses a series of reactions of haloarenes with acetylacetone to form α-aryl ketones. The applicant found that under the reaction conditions provided in this paper, when there are non-hydrogen substituents at the para position of the halogen in the haloarene, the reaction yields of iodoarenes are higher than those of bromoarenes. For example:

[0007] 1-methyl-4-iodobenzene reacts with acetylacetone under the action of cuprous iodide and potassium phosphate to obtain 1-(4-methylphenyl)-2-propanone in a yield of 74%.

[0008]

[0009] When the raw material uses the corresponding bromide 1-methyl-4-bromobenzene and the reaction conditions are kept unchanged, even if the reaction temperature is increased to 110 °C, the yield can only reach 42%.

[0010]

[0011] However, the stability of iodoarenes is worse than that of bromoarenes, and the production of iodoarenes is more difficult, resulting in generally higher prices. Therefore, the technical solution recorded in this paper is difficult to be applied in large-scale industrial production. SUMMARY OF THE INVENTION

[0012] The present invention is made to solve the above problems, and the purpose is to provide a preparation method of 1-aryl-2-propanone compounds using aryl bromides as raw materials, which is simple and convenient to operate, has inexpensive raw materials and high yields.

[0013] The present invention provides a preparation method of 1-aryl-2-propanone compounds, and the steps are as follows: in the presence of an organic solvent, a basic reagent and a composite catalyst, compound II reacts with acetylacetone to obtain compound I;

[0014]

[0015] wherein, R 1 and R 3 are each independently H, C 1-6 alkyl or C 1-6 alkoxy;

[0016] R 2 is C 1-6 alkyl, C 1-6 alkoxy or phenyl, and the phenyl is optionally substituted by one or more C 1-6 alkyl, and the plurality is 2, 3, 4 or 5;

[0017] The composite catalyst includes: cuprous halide and proline.

[0018] In the preparation method, the composite catalyst further includes alkali metal iodide.

[0019] In the preparation method, in R 1 , R 2 and R 3 , the C 1-6 alkyl is preferably C 1-3 alkyl, such as methyl, ethyl, propyl or isopropyl.

[0020] In the preparation method, in R 1 , R 2 and R 3 , the C 1-6The alkoxy group is preferably C 1-3 alkoxy group, such as methoxy, ethoxy, propoxy or isopropoxy.

[0021] In the preparation method, the "phenyl group is optionally substituted by one or more C 1-6 alkyl groups", and the C 1-6 alkyl group is preferably C 1-3 alkyl group, such as methyl, ethyl, propyl or isopropyl.

[0022] In the preparation method, R 1 and R 3 are each independently H, C 1-3 alkyl group or C 1-3 alkoxy group;

[0023] R 2 is C 1-3 alkyl group, C 1-3 alkoxy group or phenyl group, the phenyl group is optionally substituted by one or more C 1-3 alkyl groups, and the plurality is 2, 3, 4 or 5.

[0024] In the preparation method, compound II is preferably Compound I is preferably

[0025] In the preparation method, the organic solvent can be one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide, preferably dimethyl sulfoxide and / or N-methylpyrrolidone.

[0026] In the preparation method, the cuprous halide can be cuprous fluoride, cuprous chloride, cuprous bromide or cuprous iodide.

[0027] In the preparation method, the basic reagent can be an alkali metal carbonate or an alkali metal phosphate, preferably an alkali metal phosphate, for example, potassium phosphate.

[0028] In the preparation method, the alkali metal iodide can be sodium iodide.

[0029] In the preparation method, the proline can be L-proline, D-proline, or a mixture of L-proline and D-proline.

[0030] In the preparation method, the molar ratio of the composite catalyst to compound II can be (0.1-0.5):1, preferably (0.2-0.3):1.

[0031] In the preparation method, the molar ratio of cuprous halide, proline and alkali metal halide in the composite catalyst can be (1 - 3):(1 - 3):(0 - 3), preferably 1:1:1 or 1:1:0.

[0032] In one embodiment, the composite catalyst includes cuprous halide and proline. Preferably, the molar ratio of cuprous chloride to proline is (1 - 3):(1 - 3), such as 1:1.

[0033] In another embodiment, the composite catalyst includes cuprous halide, proline and alkali metal iodide. Preferably, the molar ratio of cuprous halide, proline and alkali metal iodide is (1 - 3):(1 - 3):(1 - 3), such as 1:1:1.

[0034] In the preparation method, the mass ratio of compound II to the organic solvent can be 1:(1 - 10), preferably 1:(4 - 6).

[0035] In the preparation method, the molar ratio of the basic reagent to compound II can be (1 - 5):1, preferably (2 - 4):1, such as 3:1.

[0036] In the preparation method, the reaction temperature of the reaction can be 80 - 130 °C, preferably 90 - 110 °C.

[0037] In the preparation method, the reaction time of the reaction can be 5 - 24 h.

[0038] In one embodiment, the preparation method of the 1 - aryl - 2 - propanone compound is as follows: In the presence of an organic solvent, a basic reagent and a composite catalyst, 4 - bromo - 1,1'-biphenyl reacts with acetylacetone to obtain 1-(4 - biphenylyl)-2 - propanone;

[0039]

[0040] The composite catalyst includes cuprous halide and proline.

[0041] In another embodiment, the preparation method of the 1 - aryl - 2 - propanone compound is as follows: In the presence of an organic solvent, a basic reagent and a composite catalyst, 4 - bromo - 1,1'-biphenyl reacts with acetylacetone to obtain 1-(4 - biphenylyl)-2 - propanone;

[0042]

[0043] The composite catalyst includes cuprous halide, proline and alkali metal iodide.

[0044] In the described preparation method, after the reaction is completed, the following post-treatment steps are further included: acidification, extraction, and recrystallization.

[0045] Among them, the reagent used for acidification can be dilute hydrochloric acid; the solvent used for extraction can be methyl tert-butyl ether; the reagent used for recrystallization can be a mixed solvent of methyl tert-butyl ether and n-heptane.

[0046] In the described preparation method, the post-treatment includes the following steps: after the reaction system is cooled, it is acidified with dilute hydrochloric acid, extracted with methyl tert-butyl ether, the organic phase is concentrated and then recrystallized with a mixed reagent of methyl tert-butyl ether and n-heptane, and the solid is obtained by filtration.

[0047] In a certain embodiment, the preparation method of the 1-aryl-2-propanone compound is as follows: in the presence of an organic solvent, copper halide, potassium phosphate, sodium iodide, and proline, 4-bromo-1,1'-biphenyl reacts with acetylacetone at 80-130 °C for 5-24 h. After the reaction system is cooled, it is acidified with dilute hydrochloric acid and extracted with methyl tert-butyl ether. The organic phase is taken, concentrated, recrystallized with a mixed reagent of methyl tert-butyl ether and n-heptane, and the solid is obtained by filtration to prepare 1-(4-biphenylyl)-2-propanone.

[0048] Functions and effects of the invention

[0049] For the preparation method of the 1-aryl-2-propanone compound involved in the present invention, the applicant unexpectedly found that for raw materials such as aryl bromides, using proline and copper halide as a composite catalyst can greatly improve the reaction yield, reaching more than 70%, which is more than 20% higher than the prior art. Specific embodiments

[0050] In order to make the technical means, creative features, achieved purposes, and effects of the present invention easy to understand, the present invention will be specifically described below in conjunction with embodiments.

[0051] In the following embodiments, unless otherwise specified, each raw material is a commercially available product.

[0052] Example 1

[0053]

[0054] Add 226 kg of 4-bromo-1,1'-biphenyl (969.5 mol, 1.0 eq), 291 kg of acetylacetone (2906.5 mol, 3.0 eq), 775.2 kg of potassium phosphate trihydrate (2910.9 mol, 3.0 eq), 11.3 kg of cuprous chloride (114.1 mol, 0.12 eq), 14.7 kg of sodium iodide (98.1 mol, 0.1 eq), 1243 kg of dimethyl sulfoxide and 11.3 kg of DL-proline (98.1 mol, 0.1 eq) into the reaction kettle. After purging with nitrogen three times, heat up to 90 °C and keep the reaction at this temperature for 12 h. Cool down the reaction system to 40 °C, add dilute hydrochloric acid with a mass fraction of 6 wt% until the pH reaches 6, stir and cool down to 5 °C, then add methyl tert-butyl ether for extraction. Take the methyl tert-butyl ether phase and concentrate it until there is no distillate, obtaining an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 156.5 kg of 1-(4-methylphenyl)-2-propanone solid, with a yield of 76.8% and a purity of 99.1%.

[0055] Example 2

[0056]

[0057] Add 100 g of 4-bromo-1,1'-biphenyl (0.43 mol, 1.0 eq), 129.2 g of acetylacetone (1.29 mol, 3.0 eq), 343.5 g of potassium phosphate trihydrate (1.29 mol, 3.0 eq), 8.2 g of cuprous iodide (0.043 mol, 0.1 eq), 6.4 g of sodium iodide (0.043 mol, 0.1 eq), 550 g of dimethyl sulfoxide and 5.0 g of DL-proline (0.043 mol, 0.1 eq) into the reaction kettle. After purging with nitrogen three times, heat up to 90 °C and keep the reaction at this temperature for 12 h. Cool down the reaction system to 40 °C, add dilute hydrochloric acid with a mass fraction of 6 wt% until the pH reaches 6, stir and cool down to 5 °C, then add methyl tert-butyl ether for extraction. Take the methyl tert-butyl ether phase and concentrate it until there is no distillate, obtaining an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 69.5 g of 1-(4-methylphenyl)-2-propanone solid, with a yield of 77.0% and a purity of 99.3%.

[0058] Example 3

[0059]

[0060] Add 100 g of 4-bromo-1,1'-biphenyl (0.43 mol, 1.0 eq), 129.2 g of acetylacetone (1.29 mol, 3.0 eq), 343.5 g of potassium phosphate trihydrate (1.29 mol, 3.0 eq), 4.3 g of cuprous chloride (0.043 mol, 0.1 eq), 6.4 g of sodium iodide (0.043 mol, 0.1 eq), 550 g of dimethyl sulfoxide and 5.0 g of DL-proline (0.043 mol, 0.1 eq) into the reaction kettle. After purging with nitrogen three times, heat up to 110 °C and keep the temperature for reaction for 8 h. Cool down the reaction system to 40 °C, add dilute hydrochloric acid with a mass fraction of 6 wt% until the pH is 6, stir and cool down to 5 °C, add methyl tert-butyl ether for extraction. Take the methyl tert-butyl ether phase, concentrate until there is no distillate, and obtain an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 68.6 g of 1-(4-methylphenyl)-2-propanone solid, with a yield of 76.0% and a purity of 98.2%.

[0061] Example 4

[0062]

[0063] Add 100 g of 4-bromo-1,1'-biphenyl (0.43 mol, 1.0 eq), 129.2 g of acetylacetone (1.29 mol, 3.0 eq), 343.5 g of potassium phosphate trihydrate (1.29 mol, 3.0 eq), 8.2 g of cuprous iodide (0.043 mol, 0.1 eq), 6.4 g of sodium iodide (0.043 mol, 0.1 eq), 550 g of N-methylpyrrolidone and 5.0 g of DL-proline (0.043 mol, 0.1 eq) into the reaction kettle. After purging with nitrogen three times, heat up to 90 °C and keep the temperature for reaction for 12 h. Cool down the reaction system to 40 °C, add dilute hydrochloric acid with a mass fraction of 6 wt% until the pH is 6, stir and cool down to 5 °C, add methyl tert-butyl ether for extraction. Take the methyl tert-butyl ether phase, concentrate until there is no distillate, and obtain an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 69.3 g of 1-(4-methylphenyl)-2-propanone solid, with a yield of 76.8% and a purity of 98.7%.

[0064] Example 5

[0065]

[0066] Add 100 g of 4-bromo-1,1'-biphenyl (0.43 mol, 1.0 eq), 129.2 g of acetylacetone (1.29 mol, 3.0 eq), 343.5 g of potassium phosphate trihydrate (1.29 mol, 3.0 eq), 8.2 g of cuprous iodide (0.043 mol, 0.1 eq), 6.4 g of sodium iodide (0.043 mol, 0.1 eq), 550 g of dimethyl sulfoxide and 5.0 g of L-proline (0.043 mol, 0.1 eq) into the reaction kettle. After purging with nitrogen three times, heat up to 90 °C and hold the reaction for 12 h. Cool down the reaction system to 40 °C, add 6 wt% dilute hydrochloric acid until the pH is 6, stir and cool down to 5 °C, add methyl tert-butyl ether for extraction. Take the methyl tert-butyl ether phase and concentrate until there is no distillate to obtain an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 68.8 g of 1-(4-methylphenyl)-2-propanone solid, with a yield of 76.3% and a purity of 99.2%.

[0067] Example 6

[0068]

[0069] Add 100 g of 4-bromo-1,1'-biphenyl (0.43 mol, 1.0 eq), 129.2 g of acetylacetone (1.29 mol, 3.0 eq), 343.5 g of potassium phosphate trihydrate (1.29 mol, 3.0 eq), 8.2 g of cuprous iodide (0.043 mol, 0.1 eq), 550 g of dimethyl sulfoxide and 5.0 g of DL-proline (0.043 mol, 0.1 eq) into the reaction kettle. After purging with nitrogen three times, heat up to 90 °C and hold the reaction for 12 h. Cool down the reaction system to 40 °C, add 6 wt% dilute hydrochloric acid until the pH is 6, stir and cool down to 5 °C, add methyl tert-butyl ether for extraction. Take the methyl tert-butyl ether phase and concentrate until there is no distillate to obtain an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 64.4 g of 1-(4-methylphenyl)-2-propanone solid, with a yield of 71.4% and a purity of 98.3%.

[0070] Example 7

[0071]

[0072] Add 100 g of 4-bromo-1,1'-biphenyl (0.43 mol, 1.0 eq), 129.2 g of acetylacetone (1.29 mol, 3.0 eq), 343.5 g of potassium phosphate trihydrate (1.29 mol, 3.0 eq), 4.3 g of copper(I) chloride (0.043 mol, 0.1 eq), 550 g of dimethyl sulfoxide, and 5.0 g of DL-proline (0.043 mol, 0.1 eq) into the reaction kettle. After displacing with nitrogen three times, heat up to 90 °C and keep the temperature for reaction for 12 h. Cool down the reaction system to 40 °C, add dilute hydrochloric acid with a mass fraction of 6 wt% until the pH is 6, stir and cool down to 5 °C, add methyl tert-butyl ether for extraction, take the methyl tert-butyl ether phase, concentrate until there is no distillate, and obtain an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 63.4 g of 1-(4-methylphenyl)-2-propanone solid, with a yield of 70.3% and a purity of 98.5%.

[0073] Comparative Example 1

[0074]

[0075] Add 100 g of 4-bromo-1,1'-biphenyl (0.43 mol, 1.0 eq), 129.2 g of acetylacetone (1.29 mol, 3.0 eq), 343.5 g of potassium phosphate trihydrate (1.29 mol, 3.0 eq), 4.3 g of copper(I) chloride (0.043 mol, 0.1 eq), 6.4 g of sodium iodide (0.043 mol, 0.1 eq), and 550 g of dimethyl sulfoxide into the reaction kettle. After displacing with nitrogen three times, heat up to 90 °C and keep the temperature for reaction for 12 h. Cool down the reaction system to 40 °C, add dilute hydrochloric acid with a mass fraction of 6 wt% until the pH is 6, stir and cool down to 5 °C, add methyl tert-butyl ether for extraction, take the methyl tert-butyl ether phase, concentrate until there is no distillate, and obtain an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 45.4 g of 1-(4-methylphenyl)-2-propanone solid, with a yield of 50.3% and a purity of 98.9%.

[0076] Comparative Example 2

[0077]

[0078] Add 100 g of 4-bromo-1,1'-biphenyl (0.43 mol, 1.0 eq), 129.2 g of acetylacetone (1.29 mol, 3.0 eq), 343.5 g of potassium phosphate trihydrate (1.29 mol, 3.0 eq), 24.6 g of cuprous iodide (0.13 mol, 0.3 eq) and 550 g of dimethyl sulfoxide into the reaction kettle. After replacing the nitrogen three times, heat up to 110 °C and keep the temperature for reaction for 20 h. Cool down the reaction system to 40 °C, add dilute hydrochloric acid with a mass fraction of 6 wt% until the pH is 6, stir and cool down to 5 °C, add methyl tert-butyl ether for extraction. Take the methyl tert-butyl ether phase and concentrate it until there is no distillate to obtain an oily substance. The obtained oily substance is recrystallized with methyl tert-butyl ether / n-heptane (V / V = 1:3), filter to obtain the solid, and dry it in a vacuum oven at 30 ± 5 °C to obtain 47.5 g of 1-(4-methylphenyl)-2-propanone solid, with a yield of 52.7% and a purity of 99.0%.

[0079] For the preparation method of 1-aryl-2-propanone compounds involved in the above examples, the applicant unexpectedly found that for raw materials such as aryl bromides, using proline and cuprous halide as a composite catalyst can significantly improve the reaction yield, reaching more than 70%, which is more than 20% higher than the prior art.

[0080] Furthermore, the applicant unexpectedly found that on the basis of the composite catalyst composed of proline and cuprous halide, adding a small amount of sodium iodide can further improve the reaction yield.

[0081] Furthermore, only 0.1 - 0.5 eq of the composite catalyst used in the reaction is required to achieve a significant increase in the above-mentioned yield.

[0082] Even further, according to the preparation method of 1-aryl-2-propanone compounds involved in the above examples, the applicant also developed a recrystallization method. Using methyl tert-butyl ether / n-heptane to recrystallize the oily crude product can effectively obtain a solid product with high purity.

[0083] The above embodiments are preferred cases of the present invention and are not used to limit the protection scope of the present invention.

Claims

1. A method for preparing a 1-aryl-2-propanone compound, characterized in that: The steps are as follows: in the presence of an organic solvent, an alkaline reagent and a composite catalyst, compound II reacts with acetylacetone to obtain compound I; Among them, R 1 and R 3 Each independently is H, C 1-6 Alkyl or C 1-6 Alkoxy; R 2 C 1-6 Alkyl, C 1-6 Alkoxy or phenyl, the phenyl group is optionally substituted by 1 or more C 1-6 Alkyl substitution, the plurality is 2, 3, 4 or 5; The composite catalyst comprises cuprous halide and proline.

2. The preparation method according to claim 1, characterized in that The composite catalyst also includes alkali metal iodide.

3. The preparation method according to claim 2, characterized in that: The alkali metal iodide is sodium iodide.

4. The preparation method according to claim 1 or 2, characterized in that: The cuprous halide is cuprous fluoride, cuprous chloride, cuprous bromide or cuprous iodide.

5. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the composite catalyst to the compound II is (0.1-0.5):

1.

6. The preparation method according to claim 2, characterized in that: The molar ratio of cuprous halide, proline and alkali metal halide in the composite catalyst is (1-3):(1-3):(0-3).

7. The preparation method according to claim 1 or 2, characterized in that: The alkaline agent is an alkali metal carbonate or an alkali metal phosphate.

8. The preparation method according to claim 1 or 2, characterized in that: The proline is L-proline, D-proline, or a mixture of L-proline and D-proline.

9. The preparation method according to claim 1 or 2, characterized in that: The preparation method of the 1-aryl-2-acetone compound is as follows: In the presence of an organic solvent, an alkaline reagent and a composite catalyst, 4-bromo-1,1'-biphenyl reacts with acetylacetone to prepare 1-(4-biphenyl)-2-propanone; 10. The preparation method according to claim 1 or 2, characterized in that: After the reaction is completed, the following post-treatment steps are also included: acidification, extraction, and recrystallization; Wherein, the reagent used for acidification is dilute hydrochloric acid; the solvent used for extraction is methyl tert-butyl ether; and the reagent used for recrystallization is a mixed solvent of methyl tert-butyl ether and n-heptane.

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