Preparation method of alpha-brominated aromatic ketone compound

Abstract

The invention discloses a preparation method of an alpha-brominated aromatic ketone compound, which is characterized in that under the bromination condition of an oxidizing agent potassium persulfate (K2S2O8) / a brominated source benzyl tributylammonium bromide, the alpha-brominated aromatic ketone compound is prepared by heating and reacting in an organic solvent benzotrifluoride. Under the bromination condition, alpha-position selective monobromination of aromatic ketone is realized, no dibrominated substance is generated, and the method has the advantages of high selectivity and high yield. Meanwhile, the method is wide in raw material source, economical, cheap, stable in property, easy to operate and free of environmental pollution and safety production hidden dangers, and the organic solvent can be recycled through simple distillation.

Description

Technical Field

[0001] The present application belongs to the technical field of fine chemical intermediate synthesis, and specifically relates to a method for preparing α-brominated aromatic ketone compounds. Background Art

[0002] α-brominated aromatic ketone compounds are important fine chemical intermediates, widely used in the synthesis of medicines, dyes, pesticides and material compounds. For example, α-brominated p-chloroacetophenone is a key intermediate in the synthesis of the weight loss drug rimonabant, α-brominated m-chloroacetophenone is used to synthesize the antidepressant bupropion hydrochloride; α-brominated p-methoxyacetophenone is used to synthesize the estrogen drug raloxifene; α-brominated acetophenone is used to synthesize the aromatic ethanolamine receptor agonist mirabegron, etc.

[0003] Bromination of aromatic ketones is the primary route for the synthesis of α-brominated aromatic ketones. Widely used bromination reagents include liquid bromine (Br2), Jacques reagent, CuBr2, CuBr, CBr4, NBS, HBr / H2O2, dibromohydantoin, tetrabutylammonium bromide, etc. (see CN116082133A, CN108276264A, US2005176791A1, CN116262673A, CN102260154A, CN10 1531597A, CN101462935A; Research progress on the synthesis of α-brominated aromatic acetones, "Chemical Industry Times", Vol. 23, No. 5, pp. 67-69, 2009;), these bromination conditions often involve the expensive and poor stability of bromination reagents, complex operation, inconvenient storage and transportation, low product selectivity (dibrominated products), resulting in impurities that are difficult to remove, strong irritation, and the generation of acidic gas that corrodes equipment and seriously pollutes the environment, and are not suitable for industrial production and the concept of green chemical development. Therefore, the field is in urgent need of a green synthesis method for α-brominated aromatic ketone compounds. Summary of the invention

[0004] The object of the present invention is to provide an efficient green synthesis method of α-brominated aromatic ketone compounds, wherein the method is heated and reacted in an organic solvent trifluorotoluene under the bromination conditions of an oxidant potassium persulfate (K2S2O8) / bromine source benzyltributylammonium bromide to prepare α-brominated aromatic ketone compounds. Under the bromination conditions of the present invention, the aromatic ketone is selectively monobrominated at the α-position, and no dibrominated product is produced, and the method has the advantages of high selectivity and high yield. At the same time, the method of the present invention has a wide range of raw material sources, is economical and cheap, has stable properties and is easy to operate, does not cause environmental pollution and safety hazards in production, and the organic solvent can be recycled by simple distillation.

[0005] A method for preparing an α-brominated aromatic ketone compound provided by the present invention comprises the following steps:

[0006] The phenylpropiophenone derivative, potassium persulfate, benzyltributylammonium bromide and an organic solvent are sequentially added to the reactor, and then the reactor is heated and stirred under the protection of an inert atmosphere for reaction. After the reaction is completed, the α-brominated aromatic ketone compound shown in formula II is obtained by post-treatment; the reaction formula is as follows:

[0007]

[0008] Wherein, R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, -NO2, C 1-6 Haloalkyl, C 6-20 Aryl, C 1-6 Alkoxycarbonyl, C 1-6 Acyloxy, C 3-20 Heteroaryl, C 3-20 Cycloalkyl.

[0009] R2 is selected from C 1-20 Alkyl, C 1-20 Haloalkyl, halogen, C 6-20 Aryl, C 6-20 Aryl-C 1-6 alkyl.

[0010] Preferably, R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, -CN, -NO2, -CF3, tert-butoxycarbonyl, acetoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0011] R2 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, phenyl, fluorine, chlorine, and bromine.

[0012] Most preferably, R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl;

[0013] R2 is selected from methyl, ethyl, propyl, bromine, and phenyl.

[0014] In the present invention, in the alkyl group and / or alkyl moiety having the stated number of carbon atoms, the alkyl group is a linear or branched alkyl group.

[0015] According to the aforementioned preparation method of the present invention, the type of organic solvent selected has a significant effect on the yield of the target product, wherein the organic solvent is selected from any one or a mixture of trifluorotoluene, fluorobenzene, chlorobenzene, and toluene. Preferably, the organic solvent is trifluorotoluene. The amount of the organic solvent added is such that the concentration of the phenylacetone derivative described in formula I is 0.05 to 5 mol / L, preferably 0.5 mol / L.

[0016] According to the aforementioned preparation method of the present invention, the molar ratio of the phenylacetone derivative shown in formula I, potassium persulfate, and benzyltributylammonium bromide is 1:(1-3):(1-3); preferably, the molar ratio of the phenylacetone derivative shown in formula I, potassium persulfate, and benzyltributylammonium bromide is 1:2:2.

[0017] According to the aforementioned preparation method of the present invention, the reaction temperature of the heated stirring reaction is 60-120°C, preferably 80-100°C, and most preferably 90°C; the reaction time is 8-48h, preferably 12-36h, and more preferably 24h.

[0018] According to the aforementioned preparation method of the present invention, the inert atmosphere is an argon atmosphere or a nitrogen atmosphere.

[0019] According to the aforementioned preparation method of the present invention, the post-treatment operation is as follows: after the reaction is complete, the solvent is recovered by distillation under reduced pressure, water is added to the reaction solution, and ethyl acetate is extracted. The organic phase is dried and concentrated under reduced pressure to obtain a residue, and the residue is separated by silica gel column chromatography to obtain the α-bromoaromatic ketone compound shown in formula II.

[0020] Compared with the prior art, the method of the present invention has the following significant advantages:

[0021] 1) The bromination reagent of the present invention is cheap, stable in nature, easy to store and transport and feed, does not produce pungent odor, equipment corrosion, environmental pollution and hidden dangers in production safety, and is suitable for industrial production.

[0022] 2) The preparation method of the present invention selectively realizes α-monobromination, has high selectivity, broad substrate applicability and high yield, and is easy to separate and purify. DETAILED DESCRIPTION

[0023] The preparation method of the present invention is further described in detail below in conjunction with specific examples. In the following, unless otherwise specified, the methods used are all conventional methods in the art, and the raw materials and reagents used are all obtained through conventional commercial channels without further purification.

[0024] Example 1 α-bromopropiophenone Preparation

[0025]

[0026] In a 50mL Schlenk bottle, 0.5mmol of phenylacetone, 2 equivalents of potassium persulfate (272mg), 2 equivalents of benzyltributylammonium bromide (358mg) and 1.0mL of anhydrous trifluorotoluene solvent were added in sequence. Then the Schlenk bottle was evacuated and argon was introduced, and the operation was repeated three times. Finally, the mixture was heated to 90°C under an argon atmosphere for 24h to 48h. After the reaction was completed, 10mL of water was added to the reaction solution, and then extracted with ethyl acetate three times (40mL each time), the organic phases were combined and dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was column-coated with petroleum ether / ethyl acetate 150:1 to 80:1 to obtain 83mg of the target product α-bromophenylacetone shown in formula II-1, with a yield of 78%. 1 H NMR (500MHz, CDCl3) δ8.03-8.01(m,2H),7.61-7.59(m,1H),7.52-7.48(m,3H),5.26(q,J=6.7Hz,1H),1.75(d,J=6.7Hz,3H); 13 CNMR (125MHz, CDCl3) δ193.6,134.1,133.7,129.0,128.8,41.4,20.0.

[0027] Example 2-13 Preparation of α-bromopropiophenone under different experimental conditions

[0028] Using Example 1 as a template, the effects of different oxidants, bromine sources, solvent types and amounts, and different temperatures on the yield of the target product were investigated. The results are shown in Table 1:

[0029] Table 1:

[0030]

[0031]

[0032] Embodiment 14 Preparation

[0033]

[0034] In a 50mL Schlenk bottle, 0.5mmol of the phenylacetone compound shown in formula I-2, 2 equivalents of potassium persulfate (272mg), 2 equivalents of benzyltributylammonium bromide (358mg) and 1.0mL of anhydrous trifluorotoluene solvent were added in sequence. Then the Schlenk bottle was evacuated and argon was introduced, and the operation was repeated three times. Finally, the mixture was heated to 90°C under an argon atmosphere for 24h to 48h. After the reaction was completed, 10mL of water was added to the reaction solution, and then extracted with ethyl acetate three times (40mL each time), the organic phases were combined and dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through a column with petroleum ether / ethyl acetate 150:1 to 80:1 to obtain 76mg of the target product α-bromophenylacetone shown in formula II-2, with a yield of 67%. 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 8.3Hz, 2H), 7.29 (d, J = 7.9Hz, 2H), 5.28 (q, J = 6.7Hz, 1H), 2.43 (s, 3H), 1.89 (d, J = 6.6Hz, 3H). 13 C NMR (100MHz, CDCl3) δ193.0,144.7,131.5,129.4,129.0,41.5,21.7,20.2.

[0035] Embodiment 15 Preparation

[0036]

[0037] In a 50mL Schlenk bottle, 0.5mmol of the phenylacetone compound shown in formula I-3, 2 equivalents of potassium persulfate (272mg), 2 equivalents of benzyltributylammonium bromide (358mg) and 1.0mL of anhydrous trifluorotoluene solvent were added in sequence. Then the Schlenk bottle was evacuated and argon was introduced, and the operation was repeated three times. Finally, the mixture was heated to 90°C under an argon atmosphere for 24h to 48h. After the reaction was completed, 10mL of water was added to the reaction solution, and then extracted with ethyl acetate three times (40mL each time), the organic phases were combined and dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through a column with petroleum ether / ethyl acetate 150:1 to 80:1 to obtain 100mg of the target product α-bromophenylacetone shown in formula II-3, with a yield of 71%. 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.1Hz,2H),7.76(d,J=8.1Hz,2H),5.26(q,J=6.6Hz,1H),1.93(d,J=6.6Hz,3H); 13CNMR (100MHz, CDCl3) δ192.3, 134.9 (d, J = 33.0Hz), 129.3, 125.8 (dd, J = 7.0, 4.0Hz), 123.5 (d, J = 271.0Hz), 41.3, 19.9.

[0038] Example 16 Preparation

[0039]

[0040] In a 50mL Schlenk bottle, 0.5mmol of the phenylacetone compound shown in formula I-4, 2 equivalents of potassium persulfate (272mg), 2 equivalents of benzyltributylammonium bromide (358mg) and 1.0mL of anhydrous trifluorotoluene solvent were added in sequence. Then the Schlenk bottle was evacuated and argon was introduced, and the operation was repeated three times. Finally, the mixture was heated to 90°C under an argon atmosphere for 24h to 48h. After the reaction was completed, 10mL of water was added to the reaction solution, and then extracted with ethyl acetate three times (40mL each time), the organic phases were combined and dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through a column with petroleum ether / ethyl acetate 150:1 to 80:1 to obtain 105mg of the target product α-bromophenylacetone shown in formula II-4, with a yield of 87%. 1 H NMR (500MHz, CDCl3) δ8.03-8.01(m,2H),7.61-7.58(m,1H),7.51-7.47(m,2H),5.15(dd,J=7.9,6.4Hz,1H),2.22-2. 08(m,2H),1.57(dddd,J=12.9,9.5,7.4,5.4Hz,1H),1.45(dddd,J=13.3,9.8,7.4,6.0Hz,1H),0.99(t,J=7.4Hz,3H); 13 C NMR (125MHz, CDCl3) δ193.3,134.5,133.6,128.8,128.7,47.0,35.4,20.7,13.6.

[0041] Embodiment 17 Preparation

[0042]

[0043] In a 50mL Schlenk bottle, 0.5mmol of bromophenylpropiophenone shown in formula I-5, 2 equivalents of potassium persulfate (272mg), 2 equivalents of benzyltributylammonium bromide (358mg) and 1.0mL of anhydrous trifluorotoluene solvent were added in sequence. Then the Schlenk bottle was evacuated and argon was introduced, and the operation was repeated three times. Finally, the mixture was heated to 90°C under an argon atmosphere for 24h to 48h. After the reaction was completed, 10mL of water was added to the reaction solution, and then extracted with ethyl acetate three times (40mL each time), the organic phases were combined and dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through a column with petroleum ether / ethyl acetate 150:1 to 80:1 to obtain 115mg of the target product α-dibromophenylpropiophenone shown in formula II-5, with a yield of 83%. 1 H NMR (500MHz, CDCl3) δ8.10-8.08(m,2H),7.66-7.63(m,1H),7.53-7.50(m,2H),6.71(s,1H); 13 CNMR (125MHz, CDCl3) δ185.9,134.4,130.8,129.7,128.9,39.7.

[0044] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing α-brominated aromatic ketone compounds, characterized in that: The steps include: The phenylpropiophenone derivative, potassium persulfate, benzyltributylammonium bromide and an organic solvent are sequentially added to the reactor, and then the reactor is heated and stirred under the protection of an inert atmosphere for reaction. After the reaction is completed, the α-brominated aromatic ketone compound shown in formula II is obtained by post-treatment; the reaction formula is as follows: Wherein, R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, -NO2, C 1-6 Haloalkyl, C 6-20 Aryl, C 1-6 Alkoxycarbonyl, C 1-6 Acyloxy, C 3-20 Heteroaryl, C 3-20 Cycloalkyl; R2 is selected from C 1-20 Alkyl, C 1-20 Haloalkyl, halogen, C 6-20 Aryl, C 6-20 Aryl-C 1-6 alkyl; And wherein the organic solvent is selected from any one of trifluorotoluene, fluorobenzene, chlorobenzene, toluene or a mixture of several of them.

2. The preparation method according to claim 1, characterized in that: R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, -CN, -NO2, -CF3, tert-butoxycarbonyl, acetoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R2 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, phenyl, fluorine, chlorine, and bromine.

3. The preparation method according to claim 2, characterized in that: R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl; R2 is selected from methyl, ethyl, propyl, bromine, phenyl.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The organic solvent is selected from trifluorotoluene; the amount of the organic solvent added is such that the concentration of the phenylpropiophenone derivative described in formula I is 0.05-5 mol / L.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the phenylpropiophenone derivative, potassium persulfate and benzyltributylammonium bromide shown in formula I is 1:(1-3):(1-3).

6. The preparation method according to claim 5, characterized in that: The molar ratio of the phenylpropiotone derivative, potassium persulfate and benzyltributylammonium bromide shown in formula I is 1:2:

2.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction temperature of the heating and stirring reaction is 80-100° C. and the reaction time is 12-36 hours.

8. The preparation method according to claim 7, characterized in that: The reaction temperature of the heating and stirring reaction is 90° C. and the reaction time is 24 h.

9. The preparation method according to any one of claims 1 to 3, characterized in that: The inert atmosphere is an argon atmosphere or a nitrogen atmosphere.

10. The preparation method according to any one of claims 1 to 3, characterized in that: The post-treatment operation is as follows: after the reaction is complete, the solvent is recovered by distillation under reduced pressure, water is added to the reaction solution, and ethyl acetate is extracted. The organic phase is dried and concentrated under reduced pressure to obtain a residue, and the residue is separated by silica gel column chromatography to obtain the α-bromoaromatic ketone compound shown in formula II.

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