A method for preparing a ketone compound using an alkynyl amide

Abstract

The application discloses a preparation method of a ketone compound, which comprises the following steps: taking a carboxylic acid as a raw material, taking an alkyne amide compound as an activating reagent to react to obtain an alpha-acyloxy enamide compound, and then coupling the alpha-acyloxy enamide compound with a metal organic compound to obtain the target ketone compound. The ketone compound synthesis method provided by the application has wide application range, simple operation and fast reaction rate. It is worth noting that the reaction can also be used for C-terminal modification of an amino acid, and provides a new efficient method for synthesizing ketone compounds.

Description

Technical Field

[0001] The present invention relates to the preparation of ketone compounds, in particular to a method for preparing ketone compounds mediated by acetylene amide, and belongs to the technical field of organic synthesis. Background Art

[0002] Ketones are fundamental compounds in organic chemistry and play a crucial role in organic synthesis. They are not only widely present in natural products and pharmaceuticals, but also serve as raw materials and substrates for numerous chemical reactions. Therefore, the synthesis of ketones is of vital importance.

[0003] The construction of ketone compounds via carbon-carbon bonds has long been a hot topic in organic chemistry. With the recent development of synthetic organic chemistry, transition-metal-catalyzed cross-coupling reactions have made it possible to efficiently construct carbon-carbon bonds between electrophiles and nucleophiles, which traditionally would not react directly. While transition-metal-catalyzed carbon-carbon bond construction has performed well in the synthesis of aromatic ketones, this approach is less effective for the synthesis of aliphatic ketones, primarily due to the susceptibility of aliphatic compounds to free radical β-H elimination. Furthermore, relatively few methods exist for constructing carbon-carbon bonds for amino acid carboxyl modification to synthesize aminoketones. Therefore, developing a synthetic method for ketone compounds that is mild, selective, and amenable to amino acid and peptide C-terminal modification is of great significance. Summary of the Invention

[0004] In response to the shortcomings of the prior art, the present invention discloses a method for preparing ketone compounds mediated by alkyneamide. In the method described in the present invention, the synthetic reaction exhibits advantages in the construction of ketone carbonyl groups, such as mild conditions, tolerance of multiple functional groups, a wide range of substrate applicability, simple operation, and fast reaction speed. The raw materials are simple and readily available carboxylic acid substrates, making this strategy more practical and economical. Importantly, the α-chiral carboxylic acid maintains stereochemical integrity during the transformation process, thus also providing new ideas for C-terminal modification of peptides and proteins.

[0005] To achieve the above objectives, the technical solutions adopted by the present invention are specifically described as follows:

[0006] According to a first embodiment of the present invention, a method for preparing ketone compounds mediated by alkyne amide is provided.

[0007] A method for preparing an acetyleneamide-mediated ketone compound, wherein the ketone compound having the general structural formula (V) is prepared by reacting a carboxylic acid having the general structural formula (I) as a raw material with an acetyleneamide having the general structural formula (II) as an activating reagent to obtain an intermediate, and then reacting the intermediate with a metal organic reagent. The carboxylic acid having the general structural formula (I), the acetyleneamide having the general structural formula (II), and the ketone compound having the general structural formula (V) are as follows:

[0008]

[0009] In formula (I), formula (II), and formula (V), R 1 R is selected from alkyl, cycloalkyl, substituted aromatic ring, and heterocyclic aromatic group. 2 R is selected from hydrogen, alkyl, aryl, alkynyl, and alkenyl. 3 Selected from alkyl, aryl, and substituted aromatic ring groups.

[0010] Preferably, the method specifically comprises the following steps:

[0011] 1) First, a carboxylic acid having the general structural formula (I) and an alkynamide having the general structural formula (II) are reacted in a first solvent to obtain an α-acyloxy alkynamide compound having the general structural formula (III):

[0012]

[0013] 2) reacting an α-acyloxy enamide compound having the general structural formula (III) and a metal organic compound having the general structural formula (IV) in the presence of a base in a second solvent to obtain a ketone compound having the general structural formula (V):

[0014]

[0015] In formula (I) to formula (V), R 1 and R 4 Each is independently selected from alkyl, cycloalkyl, alkynyl, aryl, substituted aryl, substituted aromatic ring, and heterocyclic aromatic group. 2 R is selected from hydrogen, alkyl, aryl, alkynyl, and alkenyl. 3 is selected from alkyl, aryl, and substituted aromatic ring groups. M is a metal. EWG (electron withdrawing group) is selected from alkylsulfonyl, alkanoyl, arylsulfonyl, aroyl, nitrile, and nitro.

[0016] As a preference, R 1 Selected from methyl, butyl, isobutyl, cyclohexyl, adamantyl, n-octyl, propynyl, phenylethynyl, phenyl, substituted aryl, and heterocyclic aryl.

[0017] R 2Selected from hydrogen, phenyl, methyl, propyl, isobutyl, ethynyl, vinyl.

[0018] R 3 Selected from methyl, ethyl, phenyl, heterocyclic aromatic group, halogenated aromatic ring group.

[0019] R 4 Selected from methyl, ethyl, benzyl, naphthyl, aryl, and substituted aryl.

[0020] M is selected from magnesium, lithium, and zinc.

[0021] EWG (electron withdrawing group) is selected from methylsulfonyl, ethylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, nitrile, and nitro.

[0022] Preferably, the substituent of the substituted phenylsulfonyl group is selected from methyl, tert-butyl, methoxy, phenyl, F, Cl, Br, I, benzyloxy, benzyloxycarbonyl, and cyano, and the number of the substituent is 1 or 2.

[0023] Preferably, the substituents of the substituted aryl group are selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy, and cyano, and the number of the substituents is an integer of 1-3.

[0024] Preferably, the heteroatom of the heterocyclic aromatic group is O, N or S, and the number of heteroatoms is 1 or 2.

[0025] Preferably, the substituents of the substituted aromatic ring group are selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy, and cyano, and the number of the substituents is an integer of 1-3.

[0026] Preferably, the EWG is one of p-methoxybenzenesulfonyl (A), p-methylbenzenesulfonyl (B), p-fluorobenzenesulfonyl (C), p-chlorobenzenesulfonyl (D), m-iodobenzenesulfonyl (E), m-bromobenzenesulfonyl (F), p-cyanobenzenesulfonyl (G), 3,5-dimethylbenzenesulfonyl (H), p-bromobenzenesulfonyl (I), 2-methylpropanesulfonyl (J), ethylsulfonyl (K), methylsulfonyl (L), nitrile, and nitro groups:

[0027]

[0028] Preferably, in step 1), the first solvent is an organic solvent. Preferably, the first solvent is selected from one or more of dichloromethane (DCM), trichloroethane, dimethyl sulfoxide, methanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, n-pentane, diethyl ether, and petroleum ether.

[0029] Preferably, in step 2), the second solvent is an organic solvent. Preferably, the second solvent is selected from one or more of dichloromethane (DCM), trichloroethane, dimethyl sulfoxide, methanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, n-pentane, diethyl ether, and petroleum ether.

[0030] Preferably, in step 2), the base is one or more of NaH, NaOH, Na2CO3, Et3N, and EtONa.

[0031] Preferably, the first solvent and the second solvent are the same solvent. Preferably, the first solvent and the second solvent are both dichloromethane (DCM).

[0032] Preferably, in step 1), the molar ratio of the carboxylic acid having the general structural formula (I) to the alkynamide having the general structural formula (II) is 1:0.5-8, preferably 1:0.8-5, more preferably 1:1-3.

[0033] Preferably, in step 2), the molar ratio of the α-acyloxy ene amide compound having the general structural formula (III), the metal organic compound having the general structural formula (IV), and the added base is 1:1-8:1-8, preferably 1:1.5-5:1.5-5. More preferably, it is 1:2-3.5:2-3.5.

[0034] Preferably, step 1) is specifically as follows: dissolving a carboxylic acid having the general structural formula (I) and an alkynamide having the general structural formula (II) in a first solvent in proportion, stirring and mixing the mixture at room temperature, and after the reaction is completed, distilling under reduced pressure to obtain an α-acyloxy alkynamide compound having the general structural formula (III).

[0035] Preferably, step 2) is specifically as follows: under nitrogen atmosphere, first dissolving an α-acyloxy enamide compound having the general formula (III) and a base in a second solvent, then cooling the mixture in a low-temperature reactor at -50 to -90°C (preferably -60 to -80°C) for 1-30 minutes (preferably 5-15 minutes), then slowly adding a metal organic compound having the general formula (IV) to react, monitoring by TLC, and after the reaction is complete, quenching the reaction by adding a saturated ammonium chloride solution, and extracting the aqueous phase 1-3 times with the second solvent. The organic phases are combined, dried over anhydrous magnesium sulfate, and finally concentrated, and separated and purified by column chromatography to obtain a ketone compound having the general formula (V).

[0036] According to a second embodiment of the present invention, a ketone compound having the general structural formula (V) is provided.

[0037] A ketone compound having the general structural formula (V), wherein the ketone compound having the general structural formula (V) is prepared by the method described in the first embodiment of the present invention:

[0038]

[0039] In formula (V), R 1 is selected from alkyl, cycloalkyl, alkynyl, aryl, substituted aryl, substituted aromatic ring, and heterocyclic aromatic group. 1 R is selected from methyl, butyl, isobutyl, cyclohexyl, adamantyl, n-octyl, propynyl, phenylethynyl, phenyl, substituted aryl, and heterocyclic aryl. 4 is selected from hydrogen, alkyl, aryl, alkynyl, alkenyl, preferably R 2 Selected from hydrogen, phenyl, methyl, propyl, isobutyl, ethynyl, vinyl.

[0040] Preferably, the substituent of the substituted aryl group or substituted aromatic ring group is selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy, and cyano, and the number of substituents is an integer from 1 to 3. The heteroatom of the heterocyclic aryl group is O, N, or S, and the number of heteroatoms is 1 or 2.

[0041] In the present invention, the ketone compound having the general structural formula (V) of the present invention can be prepared by a "two-pot two-step" method (i.e., the method described in the first embodiment of the present invention) or a "one-pot two-step" method, i.e., a carboxylic acid having the general structural formula (I) and an alkynamide having the general structural formula (II) are reacted to prepare an α-acyloxy alkynamide compound having the general structural formula (III) (intermediate product), and then, without isolating the intermediate product, a base is directly added to react with an organometallic compound having the general structural formula (IV) to achieve the alkynamide-mediated ketone compound having the general structural formula (V). The reaction formula is as follows:

[0042]

[0043] In the above reaction formula, EWG, R 1 、R 2 、R 3 、R 4 The definition of is the same as in the first embodiment.

[0044] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0045] 1. The present invention is a novel method for synthesizing ketone compounds, which is prepared by using carboxylic acid compounds as raw materials, reacting with acetylene amides as activating reagents to obtain intermediates, and finally reacting with metal organic compounds. That is, the present invention is the first to use acetylene amide compounds to mediate the synthesis of ketone compounds, which has the advantages of mild reaction conditions, fast reaction speed, and high reaction efficiency.

[0046] 2. The reaction of synthesizing ketone compounds mediated by alkyne amide in the present invention can be carried out through a "one-pot two-step" method, which is simple to operate and has no other side reactions. In addition, the substrate of the present invention has a wide range of applications and can achieve efficient synthesis of aromatic, aliphatic and α-amino ketone compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The synthetic route diagram of the ketone compound having the general structural formula (V) of the present invention is shown.

[0048] Figure 2 The schematic diagram shows the synthesis of ketone compounds with the general structural formula (V) via the alkyneamide-mediated "one-pot two-step" method.

[0049] Figure 3 HPLC spectrum of the racemic mixture of compound 10a (L:D=1:1).

[0050] Figure 4 is the HPLC spectrum of compound 10a.

[0051] Figure 5 HPLC spectrum of the racemic mixture of compound 11a (L:D=1:1).

[0052] Figure 6 is the HPLC spectrum of compound 11a.

[0053] Figure 7 HPLC spectrum of the racemic mixture of compound 12a (L:D=1:1).

[0054] Figure 8 is the HPLC spectrum of compound 12a. DETAILED DESCRIPTION

[0055] The technical solutions of the present invention are illustrated below with examples, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0056] Example 1

[0057] Synthesis of compound 4-methylbenzophenone (1a)

[0058]

[0059] The crude product was dissolved in DCM (2.0 mL) under nitrogen atmosphere. It was cooled in a -78 °C cooling bath for 10 min and benzyl magnesium bromide (0.3 mmol) was added slowly. TLC was used to monitor the reaction. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted with DCM twice. The organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and the target product 2a was obtained as a white solid after column chromatography separation and purification with a yield of 63%. The following are the nuclear magnetic resonance experimental data of the product:

[0060] 1 H NMR (400 MHz, CDC13) δ 7.86 - 7.75 (m, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H);

[0061] 13 C NMR (100 MHz, CDC13) δ 196.50, 143.23, 137.97, 134.90, 132.15, 130.31, 129.93, 128.98, 128.21, 21.67.

[0062] Example 2

[0063] Synthesis of compound 4-methyl-2-phenylacetophenone (2a)

[0064]

[0065] The crude product was dissolved in DCM (2.0 mL) under nitrogen atmosphere. It was cooled in a -78 °C cooling bath for 10 min and benzyl magnesium bromide (0.3 mmol) was added slowly. TLC was used to monitor the reaction. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted with DCM twice. The organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and the target product 2a was obtained as a white solid after column chromatography separation and purification with a yield of 63%. The following are the nuclear magnetic resonance experimental data of the product:

[0066] 1 H NMR(400MHz, CDCl3)δ8.02(dd,J=8.2,1.3Hz,2H),7.49(d,J=6.2Hz,2H),7.43(t, J=6.5Hz,2H),7.40–7.36(m,1H),7.27(d,J=6.5Hz,2H),5.40(s,2H),2.44(s,3H);

[0067] 13 C NMR (100MHz, CDCl3) δ166.53,143.74,136.24,129.77,129.12,128.60,128.20,128.14,127.44,66.53,21.69.

[0068] Example 3

[0069] Synthesis of compound 4-methylacetophenone (3a)

[0070]

[0071] At room temperature, p-toluic acid (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) and stirred at room temperature. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a crude α-acyloxy enamide product. Under nitrogen protection, the crude product and sodium hydride (0.3 mmol) were dissolved in ultra-dry DCM (2.0 mL). The product was placed in a -78°C low-temperature reactor and cooled for ten minutes. Methylmagnesium bromide (0.3 mmol) was slowly added. TLC tracking was monitored. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to obtain the target product 3a as a white solid in a yield of 67%. The following is the nuclear magnetic resonance experimental data of the product:

[0072] 1 H NMR (400MHz, CDCl3) δ7.86 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 2.58 (d, J = 1.4 Hz, 3H), 2.41 (s, 3H);

[0073] 13 C NMR (100MHz, CDCl3) δ197.75,143.83,134.72,129.22,128.42,26.48,21.60.

[0074] Example 4

[0075] Synthesis of compound benzophenone (4a)

[0076]

[0077] Benzoic acid (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) at room temperature and stirred at room temperature. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a crude α-acyloxy enamide product. Under nitrogen protection, the crude product and sodium hydride (0.3 mmol) were dissolved in ultra-dry DCM (2.0 mL). The product was placed in a -78°C low-temperature reactor and cooled for ten minutes, and phenylmagnesium bromide (0.3 mmol) was slowly added. TLC tracking was monitored. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to obtain the target product 4a as a white solid with a yield of 75%. The following is the nuclear magnetic resonance experimental data of the product:

[0078] 1 H NMR (400MHz, CDCl3) δ7.86–7.80 (m, 4H), 7.60 (d, J = 7.4Hz, 2H), 7.50 (t, J = 7.6Hz, 4H);

[0079] 13 C NMR (100MHz, CDCl3) δ196.74,137.61,132.43,130.06,128.29.

[0080] Example 5

[0081] Synthesis of compound 4-trifluoromethylbenzophenone (5a)

[0082]

[0083] At room temperature, p-trifluoromethylbenzoic acid (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) and stirred at room temperature. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a crude α-acyloxy enamide product. Under nitrogen protection, the crude product and sodium hydride (0.3 mmol) were dissolved in ultra-dry DCM (2.0 mL). The product was placed in a -78°C low-temperature reactor and cooled for ten minutes. Phenylmagnesium bromide (0.3 mmol) was slowly added. TLC was monitored. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to obtain the target product 5a as a white solid in a 90% yield. The following is the nuclear magnetic resonance experimental data of the product:

[0084] 1 H NMR (400MHz, CDCl3) δ7.92(d,J=8.1Hz,2H),7.83(d,J=6.9Hz,2H),7.78(d,J=8.1Hz,2H),7.68–7.63(m,1H),7.53(t,J=7.8Hz,2H);

[0085] 13 C NMR (100MHz, CDCl3) δ195.53, 140.73, 136.73, 133.72 (q, J = 32.7Hz), 133.09, 130.14, 130.10, 128.53, 125.36 (q, J = 26.0Hz), 123.68 (q, J = 272.5Hz).

[0086] Example 6

[0087] Synthesis of compound 2-benzoylthiophene (6a)

[0088]

[0089] The crude product was dissolved in DCM (2.0 mL) with 2-thiophene carboxylic acid (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) at room temperature. After the reaction was completed, the crude product was distilled under reduced pressure to obtain the crude product of a-acyloxy enamide. The crude product was dissolved in super dry DCM (2.0 mL) with sodium hydride (0.3 mmol) under nitrogen protection. It was cooled in a low-temperature reaction kettle at -78 °C for ten minutes, and phenylmagnesium bromide (0.3 mmol) was slowly added. TLC tracking was used to monitor the reaction, and after the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the combined organic phase was dried over anhydrous magnesium sulfate. The organic phase was concentrated, and the target product 6a was obtained after column chromatography separation and purification, which was a white solid with a yield of 72%. The following are the nuclear magnetic resonance experimental data of the product:

[0090] 1 H NMR (400 MHz, CDCl3) δ 7.92-7.87 (m, 2H), 7.75 (dd, J = 4.9, 1.2 Hz, 1H), 7.68 (dd, J = 3.8, 1.1 Hz, 1H), 7.65-7.60 (m, 1H), 7.53 (dd, J = 8.3, 7.0 Hz, 2H), 7.19 (dd, J = 5.0, 3.8 Hz, 1H);

[0091] 13 C NMR (100 MHz, CDCl3) δ 188.25, 143.65, 138.16, 134.85, 134.21, 132.27, 129.18, 128.42, 127.95.

[0092] Example 7

[0093] Synthesis of compound phenylpropargyl ketone (7a)

[0094]

[0095] At room temperature, 2-butynoic acid (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) and stirred at room temperature. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a crude α-acyloxy enamide product. Under nitrogen protection, the crude product and sodium hydride (0.3 mmol) were dissolved in ultra-dry DCM (2.0 mL). The product was placed in a -78°C low-temperature reactor and cooled for ten minutes. Phenylmagnesium bromide (0.3 mmol) was slowly added. TLC was monitored. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to obtain the target product 7a as a colorless oily liquid with a yield of 79%. The following is the nuclear magnetic resonance experimental data of the product:

[0096] 1 H NMR (400MHz, CDCl3) δ8.14 (d, J = 7.0Hz, 2H), 7.62–7.57 (m, 1H), 7.51–7.43 (m, 2H), 2.15 (s, 3H);

[0097] 13 C NMR (100MHz, CDCl3) δ178.20,136.79,133.94,129.55,128.49,92.55,78.99,4.31.

[0098] Example 8

[0099] Synthesis of Cyclohexylphenyl Ketone (8a)

[0100]

[0101] At room temperature, cyclohexanecarboxylic acid (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) and stirred at room temperature. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a crude α-acyloxy enamide product. Under nitrogen protection, the crude product and sodium hydride (0.3 mmol) were dissolved in ultra-dry DCM (2.0 mL). The product was placed in a -78°C low-temperature reactor and cooled for ten minutes, and phenylmagnesium bromide (0.3 mmol) was slowly added. TLC tracking was monitored. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to obtain the target product 8a as a white solid in an 87% yield. The following is the nuclear magnetic resonance experimental data of the product:

[0102] 1H NMR (400MHz, CDCl3) δ7.97–7.92(d,2H),7.57–7.52(m,1H),7.46(dd,J=8.2,6.7 Hz,2H),3.26(t,1H),1.88(m,J=21.7,11.8,5.3,2.8Hz,4H),1.58–1.20(m,6H);

[0103] 13 C NMR (100MHz, CDCl3) δ203.86,136.39,132.70,128.57,128.25,45.65,29.43,25.98,25.87.

[0104] Example 9

[0105] Synthesis of Compound Cyclohexyl Ethyl Ketone (9a)

[0106]

[0107] At room temperature, cyclohexanecarboxylic acid (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) and stirred at room temperature. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a crude α-acyloxy enamide product. Under nitrogen protection, the crude product and sodium hydride (0.3 mmol) were dissolved in ultra-dry DCM (2.0 mL). The product was placed in a -78°C low-temperature reactor and cooled for ten minutes. Ethylmagnesium bromide (0.3 mmol) was slowly added. TLC tracking was monitored. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to obtain the target product 9a as a colorless oily liquid with a yield of 83%. The following is the nuclear magnetic resonance experimental data of the product:

[0108] 1 H NMR(400MHz, CDCl3) δ2.46(q,J=7.3Hz,2H),2.35(t,J=10.4Hz,1H),1.80(dd,J=19.5,10 .8Hz,4H),1.67(d,J=10.4Hz,4H),1.28(dt,J=19.2,10.6Hz,2H),1.03(t,J=7.3Hz,3H);

[0109] 13 C NMR (100MHz, CDCl3) δ214.64,50.54,33.61,28.58,25.85,25.68,7.73.

[0110] Example 10

[0111] Synthesis of compound S-(1 -benzoyl- 1 -tert-butyl) carbamic acid tert-butyl ester (10a)

[0112]

[0113] Boc-tert-leucine (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) at room temperature and stirred until the reaction was complete. The crude product was dissolved in super dry DCM (2.0 mL) with sodium hydride (0.3 mmol) under nitrogen protection. It was cooled in a -78 °C cooling bath for ten minutes and phenylmagnesium bromide (0.3 mmol) was added slowly. TLC was used to monitor the reaction and when it was complete, the reaction was quenched with saturated ammonium chloride solution. The aqueous phase was extracted twice with DCM and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and the product was purified by column chromatography to give the target product 10a as a white solid in 78% yield. The following are the nuclear magnetic resonance experimental data for the product:

[0114] 1 H NMR (400 MHz, CDC13) δ 8.01 (s, 2H), 7.58 (s, 1H), 7.49 (d, J = 5.6 Hz, 2H), 5.45 (s, 1H), 1.45 (s, 9H), 0.94 (s, 9H);

[0115] 13 C NMR (100 MHz, CDC13) δ 201.61, 155.71, 137.98, 133.38, 128.71, 128.57, 79.62, 60.41, 35.51, 28.36, 26.96.

[0116] Example 11

[0117] Synthesis of compound S-(1 -benzoyl- 1 -tert-butyl) carbamic acid tert-butyl ester (10a)

[0118]

[0119] At room temperature, Boc-valine (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) and stirred at room temperature. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a crude α-acyloxy enamide product. Under nitrogen protection, the crude product and sodium hydride (0.3 mmol) were dissolved in ultra-dry DCM (2.0 mL). The product was placed in a -78°C low-temperature reactor and cooled for ten minutes. Phenylmagnesium bromide (0.3 mmol) was slowly added. TLC was monitored. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phase was concentrated and purified by column chromatography to obtain the target product 11a as a white solid in a yield of 78%. The following is the nuclear magnetic resonance experimental data of the product:

[0120] 1 H NMR (400MHz, CDCl3) δ7.97(d,J=7.5Hz,2H),7.59(t,J=7.4Hz,1H),7.49(t,J=7.7Hz,2H),5.5 0–5.34(m,1H),5.31–5.15(m,1H),1.45(s,9H),1.04(d,J=6.8Hz,3H),0.76(d,J=6.8Hz,3H);

[0121] 13 C NMR (100MHz, CDCl3) δ199.87,133.57,128.81,128.58,59.59,31.63,28.35,20.03,16.43.

[0122] Example 12

[0123] Synthesis of Compound S-(1-acryloyl-1-tert-butyl)carbamate (12a)

[0124]

[0125] At room temperature, Boc-tert-leucine (0.1 mmol) and N-methyl-N-ethynyl-p-toluenesulfonamide (MYTsA, 0.1 mmol) were dissolved in DCM (2.0 mL) and stirred at room temperature. After the reaction was complete, the mixture was distilled under reduced pressure to obtain a crude α-acyloxy enamide product. Under nitrogen protection, the crude product and sodium hydride (0.3 mmol) were dissolved in ultra-dry DCM (2.0 mL). The product was placed in a -78°C low-temperature reactor and cooled for ten minutes. Isopropenyl magnesium bromide (0.3 mmol) was slowly added. TLC was monitored. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted twice with DCM, and the organic phases were combined and dried over anhydrous magnesium sulfate. The organic phases were concentrated and purified by column chromatography to obtain the target product 12a as a white solid in a 70% yield. The following is the NMR experimental data of the product:

[0126] 1 H NMR (400MHz, CDCl3) δ5.97 (s, 1H), 5.80 (s, 1H), 4.16 (d, J = 13.7Hz, 1H), 1.87 (s, 3H), 1.42 (s, 9H), 0.94 (s, 9H);

[0127] 13 C NMR (100MHz, CDCl3) δ197.61, 155.91, 144.98, 79.94, 79.62, 35.51, 28.36, 26.96, 17.71.

Claims

1. A method for preparing a ketone compound mediated by alkyne amide, characterized in that: The method specifically comprises the following steps: 1) First, a carboxylic acid having the general structural formula (I) and an alkynamide having the general structural formula (II) are reacted in a first solvent to obtain an α-acyloxy alkynamide compound having the general structural formula (III): 2) reacting an α-acyloxy enamide compound having the general structural formula (III) and a metal organic compound having the general structural formula (IV) in the presence of a base in a second solvent to obtain a ketone compound having the general structural formula (V): In formula (I), formula (II), formula (IV), and formula (V), R 1 is selected from alkyl, cycloalkyl, substituted aryl, alkynyl, aryl, heteroaryl, α-amino acid residue; R 2 is selected from hydrogen, alkyl, aryl, alkynyl, alkenyl; R 3 is selected from alkyl, aryl, and substituted aryl; R 4 M is selected from phenylmagnesium bromide, benzylmagnesium bromide, methylmagnesium bromide, ethylmagnesium bromide; when R 4 When M is phenylmagnesium bromide, R 4 is phenyl, when R 4 When M is benzylmagnesium bromide, R 4 is benzyl, when R 4 When M is methylmagnesium bromide, R 4 is methyl, when R 4 When M is ethylmagnesium bromide, R 4 is ethyl; EWG is selected from alkylsulfonyl, alkanoyl, arylsulfonyl, aroyl, substituted phenylsulfonyl, and the substituent of the substituted phenylsulfonyl is selected from methyl, tert-butyl, methoxy, phenyl, F, Cl, Br, I, benzyloxy, benzyloxycarbonyl, and cyano.

2. The method according to claim 1, wherein: R 1 One selected from the group consisting of methyl, butyl, isobutyl, cyclohexyl, adamantyl, n-octyl, propynyl, phenylethynyl, phenyl, substituted aryl, and α-amino acid residues; and / or R 2 One selected from hydrogen, phenyl, methyl, propyl, isobutyl, ethynyl, vinyl; and / or R 3 One selected from methyl, ethyl, phenyl, and substituted aryl; and / or EWG is selected from methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and substituted phenylsulfonyl.

3. The method according to claim 2, wherein: The number of substituents of the substituted phenylsulfonyl group is 1 or 2; and / or The substituents of the substituted aryl group are selected from alkyl, alkoxy, halogen, phenyl, benzyl, benzyloxy, and cyano, and the number of the substituents is an integer of 1-3.

4. The method according to claim 1, wherein: The heteroatom of the heterocyclic aromatic group is O, N or S, and the number of the heteroatoms is 1 or 2.

5. The method according to claim 1, wherein: The EWG is specifically one of p-methoxybenzenesulfonyl (A), p-methylbenzenesulfonyl (B), p-fluorobenzenesulfonyl (C), p-chlorobenzenesulfonyl (D), m-iodobenzenesulfonyl (E), m-bromobenzenesulfonyl (F), p-cyanobenzenesulfonyl (G), 3,5-dimethylbenzenesulfonyl (H), p-bromobenzenesulfonyl (I), 2-methylpropanesulfonyl (J), ethylsulfonyl (K), and methylsulfonyl (L):

6. The method according to any one of claims 1 to 5, characterized in that: In step 1), the first solvent is an organic solvent; and / or In step 2), the second solvent is an organic solvent; and / or In step 2), the base is one or more of NaH, NaOH, Na2CO3, Et3N, and EtONa.

7. The method according to claim 6, characterized in that: In step 1), the first solvent is selected from one or more of dichloromethane, trichloroethane, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, n-pentane, diethyl ether, and petroleum ether; and / or In step 2), the second solvent is selected from one or more of dichloromethane, trichloroethane, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, n-pentane, diethyl ether, and petroleum ether.

8. The method according to claim 7, wherein: The first solvent and the second solvent are the same solvent.

9. The method according to claim 8, characterized in that: The first solvent and the second solvent are both dichloromethane.

10. The method according to any one of claims 1 to 5, characterized in that: In step 1), the molar ratio of the carboxylic acid having the general structural formula (I) to the acetylene amide having the general structural formula (II) is 1:0.5-8; and / or In step 2), the molar ratio of the α-acyloxy ene amide compound having the general structural formula (III), the metal organic compound having the general structural formula (IV), and the added amount of the base is 1:1-8:1-8.

11. The method according to claim 10, characterized in that: In step 1), the molar ratio of the carboxylic acid having the general structural formula (I) to the alkynamide having the general structural formula (II) is 1:0.8-5; and / or In step 2), the molar ratio of the α-acyloxy ene amide compound having the general structural formula (III), the metal organic compound having the general structural formula (IV), and the added amount of the base is 1:1.5-5:1.5-5.

12. The method according to claim 11, wherein: In step 1), the molar ratio of the carboxylic acid having the general structural formula (I) to the acetylene amide having the general structural formula (II) is 1:1-3; and / or In step 2), the molar ratio of the α-acyloxy ene amide compound having the general structural formula (III), the metal organic compound having the general structural formula (IV), and the added amount of the base is 1:2-3.5:2-3.

5.

13. The method according to claim 10, wherein: Step 1) specifically comprises: dissolving a carboxylic acid having the general structural formula (I) and an alkynamide having the general structural formula (II) in a first solvent in proportion, stirring and mixing the mixture at room temperature, and after the reaction is completed, performing vacuum distillation to obtain an α-acyloxy alkynamide compound having the general structural formula (III).

14. The method according to claim 10, wherein: Step 2) is specifically as follows: under nitrogen atmosphere, first dissolving an α-acyloxy enamide compound having the general formula (III) and a base in a second solvent, then cooling the mixture in a low-temperature reactor at -90 to 50° C. for 1-30 min, then slowly adding a metal organic compound having the general formula (IV) to react, and monitoring by TLC. After the reaction is complete, saturated ammonium chloride solution is added to quench the reaction, and the aqueous phase is extracted 1-3 times with the second solvent; the organic phases are combined and dried over anhydrous magnesium sulfate, and finally the organic phases are concentrated and separated and purified by column chromatography to obtain a ketone compound having the general formula (V).

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