Preparation method of α-aminoketone compounds synthesized from fatty aldehydes and secondary amines

Abstract

The present invention discloses a preparation method for synthesizing α-amino ketone compounds from fatty aldehydes and secondary amines, belonging to the technical field of organic chemical synthesis. The fatty aldehyde, secondary amine, and sodium percarbonate are added to a reaction vessel for mixing, and the reaction is carried out at a temperature of 95 to 115 °C for 16 to 24 hours. After purifying the reaction mixture, α-amino ketone compounds are obtained. The fatty aldehydes and secondary amines used in the method of the present invention are commercially available raw materials or are prepared from commercially available primary alcohols and primary amines through simple oxidation or reduction; the substrate has a wide range of applicability and is applicable to the above-mentioned various fatty aldehydes and secondary amines. The method of the present invention can be prepared only by oxidizing and rearranging with cheap and easily available sodium percarbonate, without the need for additional catalysts and additives, and has the characteristics of high economy, wide commercial sources, and environmental friendliness; the method of the present invention has few reaction steps and has the characteristic of simple operation.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method for synthesizing α α-aminoketone compounds from aliphatic aldehydes and secondary amines. Background Art

[0002] α The α-aminoketone structural unit is an important molecular skeleton in natural products and bioactive molecules. Its structure contains both amino and carbonyl active sites, which can exhibit adjustable activities on important biological receptors, thus attracting increasing attention from scientific researchers. Additionally, α α-aminoketone derivatives show great application value in the fields of synthetic chemistry and medicinal chemistry. In particular, using α α-aminoketone as an intermediate to synthesize α α-amino alcohols and 1,2-diamine drug molecules through simple reduction or reductive amination has great practical value. Therefore, α the research on the synthesis methods of α-aminoketone compounds has correspondingly become one of the hotspots in organic synthesis research.

[0003] For their synthesis methods, two-step operations are usually used. Since it is necessary to pre-prepare α α-haloketone or silyl enol ether intermediates or further transform nitrogen functional groups, their wide application is inhibited. Recently, the oxidative α α-amination of ketones provides a direct route for the synthesis of α α-aminoketones. However, the poor regioselectivity of linear ketones remains a challenge to be solved. Other methods, such as metal-catalyzed carbene N-H insertion, functionalization of unsaturated hydrocarbons, α the Haynes rearrangement of α-hydroxy ketones, still have challenges such as the need for pre-functionalization of substrates, scarcity of electrophilic nitrogen sources, metal catalysis, additional functional group transformation, or harsh reaction conditions. From the environmental and economic perspectives, using cheap and readily available aliphatic aldehydes and secondary amines as reaction raw materials, and under the promotion of commercially available and clean oxidants, realizing the synthesis of α α-aminoketone compounds in one step is considered an energy-saving, efficient and green synthesis method. Summary of the Invention

[0004] The primary object of the present invention is to provide a preparation method for synthesizing α α-aminoketone compounds from aliphatic aldehydes and secondary amines, aiming to solve many defects existing in the existing synthesis methods, such as high raw material costs, cumbersome steps, harsh conditions, poor atom economy, etc.

[0005] Another object of the present invention is to provide α-aminoketone compounds with potential pharmaceutical activity and biological activity obtained by the above preparation method.

[0006] The present invention is implemented as follows. A method for preparing α -aminoketone compounds from fatty aldehydes and secondary amines includes the following steps:

[0007] Step 1: Add fatty aldehyde, secondary amine, and sodium percarbonate in a molar ratio of (0.75~1.5):(0.5~1.0):(0.5~1.0) to a reaction vessel for mixing, and react at a temperature of 95~115 °C for 16~24 hours to obtain a reaction mixture;

[0008] Step 2: After purifying the reaction mixture, obtain α -aminoketone compounds.

[0009] Preferably, in Step 1, the fatty aldehyde is selected from any one of caproaldehyde, nonanal, propionaldehyde, isovaleraldehyde, phenylpropionaldehyde, phenylacetaldehyde, 4-(pyridin-4-yl)butyraldehyde, methyl 6-oxohexanoate, 6-((tert-butyldiphenylsilyl)oxy)hexanal, 4-(1,3-dioxoisoindol-2-yl)butyraldehyde, oleic aldehyde, and (R)-4-(((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta a phenanthren-17-yl)pentanal.

[0010] Preferably, in Step 1, the secondary amine is selected from any one of dibenzylamine, bis(4-methoxybenzyl)amine, diallylamine, N -benzylethylamine, N -benzylpropan-2-amine, N -benzylcyclopropylamine, N -benzyl-1-(pyridin-4-yl)methanamine, (R)-N-benzyl-1-phenylethan-1-amine, (S)- N -benzyl-1-((tert-butyldiphenylsilyl)oxy)-3-phenylpropan-2-amine, N -benzyl-L-phenylalanine methyl ester, N -propyl-L-phenylalanine methyl ester, and methyl (1R,4R)-4-((benzylamino)methyl)cyclohexane-1-carboxylate.

[0011] Preferably, in Step 1, a solvent is further included, and the solvent includes chloroform and dichloromethane; wherein, fatty aldehyde, secondary amine, sodium percarbonate, chloroform, and dichloromethane are added to a reaction vessel for mixing in a molar volume ratio of (0.75~1.5) mmol:(0.5~1.0) mmol:(0.5~1.0) mmol:(1.5~3.0) mL:(0.5~1.0) mL.

[0012] Preferably, in step 2, the reaction mixture is purified by thin layer chromatography, the developing agent system is ethyl acetate / petroleum ether, and the volume ratio of the amounts of ethyl acetate and petroleum ether used is 1 / 100 to 1 / 10.

[0013] The present invention further discloses the α -aminoketone compound obtained by the above preparation method, and the chemical structural formula of the compound is shown as the following formula (I):

[0014] ;

[0015] In formula (I), R 1 is selected from at least one of methyl, n-butyl, n-heptyl, isopropyl, benzyl, phenyl, 2-(4-pyridyl)ethyl, methyl 4-butyrate, tert-butyldiphenylsilyl-4-butoxy, 2-(isoindoline-1,3-dione)ethyl, (Z)-hexadec-7-enyl, and (R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)isopropyl;

[0016] R 2 is selected from at least one of benzyl, 4-methoxybenzyl, and allyl;

[0017] R 3 is selected from at least one of benzyl, 4-methoxybenzyl, allyl, ethyl, isopropyl, cyclopropyl, 4-pyridylmethyl, (R)-1-phenylethyl, (S)-(1-tert-butyldiphenylsilyloxy)-3-phenyl-2-propyl, (S)-2-(3-phenyl)propionate methyl ester, and (1R,4R)-(4-cyclohexanecarboxylate methyl ester)-1-methyl.

[0018] Compared with the prior art, the beneficial effects of the present invention are:

[0019] (1) The fatty aldehydes and secondary amines used in the method of the present invention are commercially available raw materials or are prepared by simple oxidation or reduction of commercially available primary alcohols and primary amines; the substrate has a wide range of applicability and is applicable to the above-mentioned various fatty aldehydes and secondary amines, such as fatty aldehydes having double bonds, siloxane bonds, amide bonds, ester groups, heterocycles, and complex molecular structures, and secondary amines derived from benzyl, allyl, alkyl, amino acids, and complex molecules; this method can be prepared only by oxidizing and rearranging inexpensive and easily available sodium percarbonate, without the need for additional catalysts and additives, and has the characteristics of high economy, wide commercial sources, and environmental friendliness; this method has few reaction steps and has the characteristics of simple operation.

[0020] (2) The α-Aminoketone compounds are widely distributed among biologically and pharmaceutically active molecules and have broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the 1H NMR spectrum of 1-(dibenzylamino)-2-hexanone in Example 1 of the present invention;

[0022] Figure 2 is the 13C NMR spectrum of 1-(dibenzylamino)-2-hexanone in Example 1 of the present invention;

[0023] Figure 3 is the 1H NMR spectrum of 1-(dibenzylamino)-3-methyl-2-butanone in Example 2 of the present invention;

[0024] Figure 4 is the 13C NMR spectrum of 1-(dibenzylamino)-3-methyl-2-butanone in Example 2 of the present invention;

[0025] Figure 5 is the 1H NMR spectrum of 1-(dibenzylamino)-4-(pyridin-4-yl)butan-2-one in Example 3 of the present invention;

[0026] Figure 6 is the 13C NMR spectrum of 1-(dibenzylamino)-4-(pyridin-4-yl)butan-2-one in Example 3 of the present invention;

[0027] Figure 7 is the 1H NMR spectrum of (Z)-1-(dibenzylamino)octadec-2-en-1-one in Example 4 of the present invention;

[0028] Figure 8 is the 13C NMR spectrum of (Z)-1-(dibenzylamino)octadec-2-en-1-one in Example 4 of the present invention;

[0029] Figure 9 is the 1H NMR spectrum of 1-(benzyl(ethyl)amino)-2-hexanone in Example 5 of the present invention;

[0030] Figure 10 is the 13C NMR spectrum of 1-(benzyl(ethyl)amino)-2-hexanone in Example 5 of the present invention;

[0031] Figure 11 is the 1H NMR spectrum of 1-(benzyl(cyclopropyl)amino)-2-hexanone in Example 6 of the present invention;

[0032] Figure 12 is the 13C NMR spectrum of 1-(benzyl(cyclopropyl)amino)-2-hexanone in Example 6 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0033] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments. Example 1

[0034] An embodiment of the present invention provides a method for preparing α -aminoketone compounds from fatty aldehydes and secondary amines, which comprises the following steps:

[0035] Step 1: In a 10 mL sealed tube, 0.50 mmol of sodium percarbonate, 0.50 mmol of dibenzylamine, 1.0 mmol of n-hexanal, and 1.5 mL of solvent chloroform and 0.5 mL of dichloromethane were successively added, and the mixture was stirred and reacted at 105 °C for 24 hours. The reaction equation is:

[0036] 。

[0037] Step 2: After monitoring the completion of the reaction by TLC, the mixture was taken out with dichloromethane, and the product was separated by thin layer chromatography. The developing agent system was ethyl acetate: petroleum ether = 1:170. The product was a colorless oily compound 1 with a yield of 68%. The chemical structure and nuclear magnetic resonance spectrum of this colorless liquid are as Figures 1 to 2 shown. Example 2

[0038] An embodiment of the present invention provides a method for preparing α -aminoketone compounds from fatty aldehydes and secondary amines, which comprises the following steps:

[0039] Step 1: In a 10 mL sealed tube, 0.50 mmol of sodium percarbonate, 0.50 mmol of dibenzylamine, 1.0 mmol of isovaleraldehyde, and 1.5 mL of solvent chloroform and 0.5 mL of dichloromethane were successively added, and the mixture was stirred and reacted at 105 °C for 24 hours. The reaction equation is:

[0040] 。

[0041] Step 2: After monitoring the completion of the reaction by TLC, the mixture was taken out with dichloromethane, and the product was separated by thin layer chromatography. The developing agent system was ethyl acetate: petroleum ether = 1:190. The product was a colorless liquid compound 2 with a yield of 64%. The chemical structure and nuclear magnetic resonance spectrum of this colorless liquid are as Figures 3 to 4 shown. Example 3

[0042] An embodiment of the present invention provides a method for preparing α -aminoketone compounds from fatty aldehydes and secondary amines, which comprises the following steps:

[0043] Step 1: In a 10 mL sealed tube, add 0.50 mmol of sodium percarbonate, 0.50 mmol of dibenzylamine, 1.0 mmol of 4-(pyridin-4-yl)butyraldehyde, and solvents 1.5 mL of chloroform and 0.5 mL of dichloromethane successively. Stir and react at 105 °C for 24 hours. The reaction equation is:

[0044] .

[0045] Step 2: After monitoring the reaction to completion by TLC, take out the mixture with dichloromethane, separate the product by thin-layer chromatography. The developing agent system is ethyl acetate:petroleum ether = 1:3. The product is a yellow oily compound 3 with a yield of 56%. The chemical structure and nuclear magnetic resonance spectrum of this yellow liquid are as shown in Figures 5 to 6 shown. Example 4

[0046] An embodiment of the present invention provides a preparation method of α -aminoketone compounds from aliphatic aldehydes and secondary amines, which includes the following steps:

[0047] Step 1: In a 10 mL sealed tube, add 0.50 mmol of sodium percarbonate, 0.50 mmol of dibenzylamine, 1.0 mmol of oleic aldehyde, and solvents 1.5 mL of chloroform and 0.5 mL of dichloromethane successively. Stir and react at 105 °C for 24 hours. The reaction equation is:

[0048] .

[0049] Step 2: After monitoring the reaction to completion by TLC, take out the mixture with dichloromethane, separate the product by thin-layer chromatography. The developing agent system is ethyl acetate:petroleum ether = 1:200. The product is a yellow oily compound 4 with a yield of 90%. The chemical structure and nuclear magnetic resonance spectrum of this yellow liquid are as shown in Figures 7 to 8 shown. Example 5

[0050] An embodiment of the present invention provides a preparation method of α -aminoketone compounds from aliphatic aldehydes and secondary amines, which includes the following steps:

[0051] Step 1: In a 10 mL sealed tube, add 0.50 mmol of sodium percarbonate, N 0.50 mmol of N-ethylbenzylamine, 1.0 mmol of hexanal, and solvents 1.5 mL of chloroform and 0.5 mL of dichloromethane successively. Stir and react at 105 °C for 24 hours. The reaction equation is:

[0052] .

[0053] Step 2: After monitoring the reaction to completion by TLC, the mixture was taken out with dichloromethane, and the product was separated by thin-layer chromatography. The developing agent system was ethyl acetate: petroleum ether = 1:15. The product was a yellow oily compound 5 with a yield of 57%. The chemical structure and NMR spectrum of this yellow liquid are as shown in Figures 9 to 10 shown. Example 6

[0054] An embodiment of the present invention provides a preparation method of α -aminoketone compounds by synthesizing from fatty aldehydes and secondary amines, which comprises the following steps:

[0055] Step 1: In a 10 mL sealed tube, 0.50 mmol of sodium percarbonate, N 0.50 mmol of -cyclopropylbenzylamine, 1.0 mmol of n-hexanal, and 1.5 mL of solvent chloroform and 0.5 mL of dichloromethane were successively added, and the mixture was stirred and reacted at 105 °C for 24 hours. The reaction equation is:

[0056] .

[0057] Step 2: After monitoring the reaction to completion by TLC, the mixture was taken out with dichloromethane, and the product was separated by thin-layer chromatography. The developing agent system was ethyl acetate: petroleum ether = 1:100. The product was a colorless oily compound 6 with a yield of 54%. The chemical structure and NMR spectrum of this colorless liquid are as shown in Figures 11 to 12 shown.

[0058] Examples 7 - 23

[0059] Examples 7 - 23 of the present invention adopted the same preparation method as Example 1, with the only difference being the types of fatty aldehydes and secondary amines selected, and the differences are shown in Table 1:

[0060] Table 1 Comparison of differences

[0061]

[0062]

[0063]

[0064]

[0065] The present invention has been described in detail through the embodiments above. However, the above content is only an exemplary embodiment of the present invention and cannot be considered as defining the scope of implementation of the present invention. The protection scope of the present invention is defined by the claims. Any use of the technical solutions described in the present invention, or any similar technical solutions designed by those skilled in the art under the inspiration of the technical solutions of the present invention to achieve the above technical effects within the essence and protection scope of the present invention, or any equivalent changes and improvements made to the application scope, shall still fall within the scope of patent protection of the present invention.

Claims

1. A preparation method of α -aminoketone compounds by synthesizing from fatty aldehydes and secondary amines, characterized in that It includes the following steps: Step 1: Add fatty aldehyde, secondary amine, and sodium percarbonate into a reaction vessel for mixing according to the molar ratio of (0.75~1.5):(0.5~1.0):(0.5~1.0), and react at a temperature of 95~115 °C for 16~24 hours to obtain a reaction mixture; Step 2: After purifying the reaction mixture, obtain α -aminoketone compounds; α -The chemical structural formula of aminoketone compounds is shown in the following formula (I): ； In formula (I), R 1 is selected from at least one of methyl, n-butyl, n-heptyl, isopropyl, benzyl, phenyl, 2-(4-pyridyl)ethyl, methyl 4-butyrate, tert-butyldiphenylsilyl-4-butoxy, 2-(isoindoline-1,3-dione)ethyl, (Z)-hexadec-7-enyl, and (R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)isopropyl; R 2 selected from at least one of benzyl, 4-methoxybenzyl and allyl; R 3 selected from at least one of benzyl, 4-methoxybenzyl, allyl, ethyl, isopropyl, cyclopropyl, 4-pyridylmethyl, (R)-1-phenylethyl, (S)-(1-tert-butyldiphenylsilyloxy)-3-phenyl-2-propyl, (S)-methyl 2-(3-phenyl)propionate, and (1R,4R)-(methyl 4-cyclohexanecarboxylate)-1-methyl; In step 1, the fatty aldehyde is selected from any one of capraldehyde, nonanal, propionaldehyde, isovaleraldehyde, phenylpropionaldehyde, phenylacetaldehyde, 4-(pyridin-4-yl)butyraldehyde, methyl 6-oxohexanoate, 6-((tert-butyldiphenylsilyl)oxy)hexanal, 4-(1,3-dioxoisoindol-2-yl)butyraldehyde, oleic aldehyde, and (R)-4-(((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta a phenanthren-17-yl)pentanal; In step 1, the secondary amine is selected from dibenzylamine, bis(4-methoxybenzyl)amine, diallylamine, N -benzylethylamine, N -benzylpropan-2-amine, N -benzylcyclopropylamine, N -benzyl-1-(pyridin-4-yl)methanamine, (R)- N -benzyl-1-phenylethan-1-amine, (S)- N -benzyl-1-((tert-butyldiphenylsilyl)oxy)-3-phenylpropan-2-amine, N -benzyl-L-phenylalanine methyl ester, N -propyl-L-phenylalanine methyl ester, and any one of (1R,4R)-4-((benzylamino)methyl)cyclohexane-1-carboxylic acid methyl ester; In Step 1, a solvent is further included, and the solvent includes chloroform and dichloromethane.

2. The preparation method of α α -aminoketone compounds by synthesizing from fatty aldehyde and secondary amine, characterized in that, In Step 1, wherein, fatty aldehyde, secondary amine, sodium percarbonate, chloroform, and dichloromethane are added into a reaction vessel for mixing according to the molar volume ratio of (0.75~1.5) mmol:(0.5~1.0) mmol:(0.5~1.0) mmol:(1.5~3.0) mL:(0.5~1.0) mL.

3. The preparation method of α α -aminoketone compounds synthesized from fatty aldehydes and secondary amines according to claim 1, characterized in that, In Step 2, the reaction mixture is purified by thin layer chromatography, and the developing agent system is ethyl acetate / petroleum ether, and the volume ratio of the amounts of ethyl acetate and petroleum ether used is 1 / 100~1 / 10.

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