Process for preparation of novel alpha-carbonyl-alpha-amido-substituted methylphosphorus ylide

Abstract

The invention discloses a method for preparing novel alpha-carbonyl-alpha-acylamino substituted methyl phosphorus ylide, and relates to the technical field of organic synthesis. The novel alpha-carbonyl-alpha-acylamino substituted methyl phosphorus ylide derivative is synthesized in one step by taking alpha-carbonyl substituted methyl phosphorus ylide and N-pivaloyloxy benzamide derivatives as optimal substrates and cobalt salt as an optimal catalyst. The method has the advantages of mild reaction conditions, short reaction time, simplicity in operation, wide substrate applicability and the like. Meanwhile, the cheap cobalt salt is used as the catalyst in the method, so that the cost required by the reaction is greatly reduced. The alpha-carbonyl-alpha-acylamino substituted methyl phosphorus ylide obtained by the method disclosed by the invention can be used as an important intermediate in organic synthesis, is used for synthesizing a 1, 1-dicarbonyl substituted olefin structure, and provides more raw material choices for development of various bioactive molecules (such as steroids and sesquiterpenoids) and antitumor and antifungal drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly to a method for preparing novel α-carbonyl-α-amido-substituted methylphosphonium ylides. Background Art

[0002] α-Carbonyl-α-amido-substituted methylphosphonium ylide derivatives, as an important class of organic synthesis intermediates, have extensive application values in the fields of medicinal chemistry and natural product synthesis. The unique structural features of these compounds make them key precursors for constructing 1,1-dicarbonyl-substituted alkenes, which are important structural units for synthesizing various bioactive molecules (such as steroids, sesquiterpenoids) and anti-tumor and anti-fungal drugs.

[0003] However, the current synthesis methods for α-carbonyl-α-amido-substituted methylphosphonium ylide derivatives still have many limitations, such as cumbersome reaction steps, low yields, limited substrate applicability, etc., which severely restrict their further application in organic synthesis.

[0004] Based on this, the present invention has developed an efficient and convenient synthesis method, which not only significantly improves the yield and purity of the target product, but also expands the substrate applicability, providing a new solution for the synthesis of related drug molecules and natural products. The innovation of this method is mainly reflected in the following aspects: (1) adopting a novel catalyst system to achieve efficient conversion under mild conditions; (2) developing a unique reaction path to avoid the generation of by-products in traditional methods; (3) establishing a process route that can be scaled up for production. Therefore, the present invention has important theoretical significance and application value, and is worthy of further in-depth research and development. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for preparing novel α-carbonyl-α-amido-substituted methylphosphonium ylides. This method does not require photoinduction, uses inexpensive and abundant metal cobalt salts as catalysts, has low cost, and does not require the addition of extra photosensitizers or ligands. The reaction time is short, the reaction conditions are mild, and it has good substrate applicability, filling the blank of the method for preparing α-carbonyl-α-amido-substituted methylphosphonium ylides.

[0006] To achieve the above purpose, the technical solution of the present invention is as follows:

[0007] In the first aspect, the present invention provides a method for preparing novel α-carbonyl-α-amido-substituted methylphosphonium ylides, including the following steps;

[0008] At room temperature, the α-carbonyl-substituted methylphosphonium ylide and the N-acyloxybenzamide amide derivative are dissolved in an organic solvent, and then a metal catalyst is added. After mixing, the reaction is heated at 60 °C. The resulting reaction solution is filtered, and the obtained filtrate is separated by column chromatography. The resulting product is the α-carbonyl-α-amido-substituted methylphosphonium ylide;

[0009] The structure of the α-carbonyl-substituted methylphosphonium ylide is as follows:

[0010]

[0011] The structure of the N-acyloxybenzamide amide derivative is as follows:

[0012]

[0013] Among them, R is an aryl group, an alkoxy group or a cycloalkane, R 1 is an alkyl group or an aryl group, R 2 is hydrogen, a halogen or an alkoxy group;

[0014] The metal catalyst is a cobalt catalyst;

[0015] The organic solvent is dichloromethane.

[0016] Preferably, the α-carbonyl-substituted methylphosphonium ylide is selected from one of α-benzoylmethylphosphonium ylide, α-(4-methoxybenzoyl)methylphosphonium ylide, α-(4-iodobenzoyl)methylphosphonium ylide, α-(2-thiazolylcarbonyl)methylphosphonium ylide, α-cyclopropylmethylphosphonium ylide and α-esterylmethylphosphonium ylide.

[0017] Preferably, the α-carbonyl-substituted methylphosphonium ylide is α-benzoylmethylphosphonium ylide, and its structure is as follows:

[0018]

[0019] Preferably, the N-acyloxybenzamide amide derivative is selected from one of N-pivaloyloxybenzamide amide, N-pivaloyloxy-4-methoxybenzamide amide, N-pivaloyloxy-4-fluorobenzamide amide and N-pivaloyloxy-2-thiophenecarboxamide amide.

[0020] Preferably, the N-acyloxybenzamide amide derivative is the N-pivaloyloxybenzamide amide derivative, and the R 1 group in the structure of the N-pivaloyloxy-benzamide amide derivative is a tert-butyl group.

[0021] Preferably, the N-acyloxybenzamide amide derivative is the N-pivaloyloxybenzamide amide derivative, and its structure is as follows:

[0022]

[0023] Preferably, the molar ratio of the input amounts of the α-carbonyl substituted methyl phosphonium ylide, N-acetyloxybenzamide amide derivative, and catalyst is (10-20):10:1.

[0024] Preferably, the column chromatography separation is carried out by silica gel column chromatography, and the solvent used is a mixed solvent of ethyl acetate and petroleum ether, wherein petroleum ether:ethyl acetate = 1:5.

[0025] In a second aspect, the present invention provides a novel α-carbonyl-α-amido substituted methyl phosphonium ylide, which is prepared by the method according to any one of the above.

[0026] In a third aspect, the present invention provides the application of the above novel α-carbonyl-α-amido substituted methyl phosphonium ylide in the synthesis of 1,1-dicarbonyl olefin structures.

[0027] Compared with the prior art, the technical effects of the present invention are as follows:

[0028] The method for preparing the novel α-carbonyl-α-amido substituted methyl phosphonium ylide provided by the present invention uses α-carbonyl substituted methyl phosphonium ylide and N-pivaloyloxybenzamide amide derivative as the most suitable substrates, dissolves them in dichloromethane, uses cobalt salt as the best catalyst, and synthesizes the novel α-carbonyl-α-amido substituted methyl phosphonium ylide derivative in one step. It does not require photoinduction, nor does it require the addition of an additional photosensitizer or ligand. It has the advantages of mild reaction conditions, short reaction time, simple operation, wide substrate applicability, etc. At the same time, this method uses inexpensive metal cobalt salt as a catalyst, which greatly reduces the cost required for the reaction. The α-carbonyl-α-amido substituted methyl phosphonium ylide obtained by the method of the present invention can be used as an important intermediate in organic synthesis for the synthesis of 1,1-dicarbonyl substituted olefin structures, providing more raw material options for the development of various bioactive molecules (such as steroids, sesquiterpenoids) and anti-tumor and anti-fungal drugs. Description of the Drawings

[0029] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings required in the embodiments. Obviously, the drawings in the following description are only some embodiments recorded in the present invention. For those of ordinary skill in the art, other drawings can also be obtained based on these drawings.

[0030] Figure 1 For Embodiment 1 of the present invention 1 1H NMR spectrum.

[0031] Figure 2For Example 1 of the present invention 13 13C NMR spectrum. Detailed implementation mode

[0032] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be further described in detail below in conjunction with the drawings and embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of protection of the present invention.

[0033] The experimental methods in the following examples are all conventional methods unless otherwise specified.

[0034] The test materials used in the following examples are all obtained from conventional biochemical reagent stores unless otherwise specified.

[0035] The method for preparing a novel α-carbonyl-α-amido-substituted methylphosphonium ylide provided by the present invention includes the following steps;

[0036] At room temperature, dissolve the α-carbonyl-substituted methylphosphonium ylide and the N-acyl oxybenzamide amide derivative in an organic solvent, then add a metal catalyst and heat the mixture at 60 °C for reaction. Filter the obtained reaction solution, and separate the obtained filtrate by column chromatography. The obtained product is the α-carbonyl-α-amido-substituted methylphosphonium ylide; the molar ratio of the α-carbonyl-substituted methylphosphonium ylide, the N-acyl oxybenzamide amide derivative, and the catalyst is (10-20):10:1.

[0037] The structure of the α-carbonyl-substituted methylphosphonium ylide is as follows:

[0038]

[0039] The structure of the N-acyl oxybenzamide amide derivative is as follows:

[0040]

[0041] Among them, R is an aryl group, an alkoxy group or a cycloalkane, R 1 is an alkyl group or an aryl group, R 2 is hydrogen, a halogen or an alkoxy group;

[0042] The metal catalyst is a cobalt catalyst; preferably tetraphenylcobalt porphyrin;

[0043] The organic solvent is dichloromethane.

[0044] Preferably, the α-carbonyl substituted methylphosphonium ylide is selected from one of α-benzoylmethylphosphonium ylide, α-(4-methoxybenzoyl)methylphosphonium ylide, α-(4-iodobenzoyl)methylphosphonium ylide, α-(2-thiazolylcarbonyl)methylphosphonium ylide, α-cyclopropylmethylphosphonium ylide and α-esterylmethylphosphonium ylide.

[0045] Preferably, the α-carbonyl substituted methylphosphonium ylide is α-benzoylmethylphosphonium ylide, and its structure is as follows:

[0046]

[0047] Preferably, the N-acetyloxybenzamide amide derivative is selected from one of N-pivaloyloxybenzamide amide, N-pivaloyloxybenzamide amide, N-pivaloyloxy-4-methoxybenzamide amide, N-pivaloyloxy-4-fluorobenzamide amide and N-pivaloyloxy-2-thiophenecarboxamide amide.

[0048] Preferably, the N-acetyloxybenzamide amide derivative is N-pivaloyloxybenzamide amide derivative. In the structure of the N-pivaloyloxy-benzamide amide derivative, the 1 group is tert-butyl.

[0049] Preferably, the N-acetyloxybenzamide amide derivative is N-pivaloyloxybenzamide amide derivative, and its structure is as follows:

[0050]

[0051] Preferably, the column chromatography separation is carried out by silica gel column chromatography, and the solvent used is a mixed solvent of ethyl acetate and petroleum ether, wherein petroleum ether:ethyl acetate = 1:5

[0052] In order to verify the effectiveness of the present invention, the following experiments were carried out:

[0053] First, we screened the catalysts, and the results are as follows:

[0054] Number Cobalt catalyst Yield of target product 1 Tetraphenylcobalt porphyrin 70％ 2 Cobalt chloride 65％ 3 Cobalt oxide No reaction

[0055] Therefore, we selected tetraphenylcobalt porphyrin as the optimal catalyst.

[0056] Secondly, we screened the N-acetyloxybenzamide amide derivatives, and the results are as follows:

[0057] Number N - acyloxybenzamide amide derivative Yield of target product 1 N - pivaloyloxybenzamide 70％ 2 N - pivaloyloxy - 4 - fluorobenzamide 56％ 3 N - pivaloyloxy - 4 - methoxybenzamide 58％ 4 N - pivaloyloxy - 2 - thiophenecarboxamide 55％

[0058] Therefore, we selected N-pivaloyloxybenzamide as the optimal substrate.

[0059] Then, we screened α-carbonyl-substituted methyl phosphonium ylides, and the results are as follows:

[0060] Number α - substituted methyl phosphonium ylide Yield of target product 1 α - benzoyl methyl phosphonium ylide 70％ 2 α - ethoxycarbonyl methyl phosphonium ylide 52％ 3 Methyl phosphonium ylide No reaction

[0061] Therefore, we selected α-benzoylmethyl phosphonium ylide as the optimal substrate.

[0062] Finally, we screened the feeding ratios of the α-benzoylmethyl phosphonium ylide, N-pivaloyloxy-benzamide amide derivative, and tetraphenylcobalt porphyrin, and the results are as follows:

[0063]

[0064] Therefore, we selected the feeding molar ratios of the α-benzoylmethyl phosphonium ylide, N-pivaloyloxy-benzamide amide derivative, and tetraphenylcobalt porphyrin as:

[0065] (15 - 20):10:1, and the optimal feeding molar ratio is: 15:10:1.

[0066] Example 1

[0067] Into a 15 mL test tube, add α-benzoylmethyl phosphonium ylide (0.3 mmol), N-pivaloyloxybenzamide amide (0.2 mmol), tetraphenylcobalt porphyrin (0.02 mmol), and 2 mL of dichloromethane. Then, place the test tube in an oil bath at sixty degrees Celsius and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by a rotary evaporator, silica gel column chromatography is carried out for purification and separation to obtain the corresponding α-carbonyl-α-amido-substituted methyl phosphonium ylide, and its structural formula is:

[0068]

[0069] Purity 99%. Yield 70%. Through the 1 1H NMR spectrum of this compound and its 31 31P NMR spectrum shows. Its NMR data are 1 1H NMR (400 MHz, CDCl3) δ 12.06 (s, 1H), 7.56 - 7.53 (m, 6H), 7.47 - 7.45 (m, 2H), 7.37 - 7.34 (m, 3H), 7.28 - 7.24 (m, 6H), 7.14 - 7.10 (m, 2H), 6.91 - 6.85 (m, 7.6 Hz, 4H), 6.75 - 6.72 (m, 2H). 31 31P NMR (162 MHz, CDCl3) δ 18.47; 313C NMR (101 MHz, CDCl3) δ 192.9 (d, J = 18.4 Hz), 168.0 (d, J = 9.8 Hz), 144.0 (d, J = 0.8 Hz), 140.0 (d, J = 1.6 Hz), 133.4, 133.3, 131.8, 131.7 (d, J = 3.8 Hz), 128.7, 128.6, 128.6, 127.8, 127.2, 126.4, 125.5, 122.3, 119.9, 77.3, 76.7, 75.5.

[0070] Example 2

[0071] To a 15 mL test tube, add α-(4-methoxybenzoyl)methylphosphonium ylide compound (0.2 mmol), N-neopentyloxybenzamide amide (0.2 mmol), cobalt chloride (0.02 mmol), and 2 mL of dichloromethane. Then, place the test tube in an oil bath at sixty degrees Celsius and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by rotary evaporation, silica gel column chromatography is used for purification and separation to obtain the corresponding α-(4-methoxybenzoyl)-α-benzamido-substituted methylphosphonium ylide, and its structural formula is:

[0072]

[0073] Purity 99%. Yield 65%. Its NMR data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 7.60 - 7.56 (m, 6H), 7.47 - 7.46 (m, 2H), 7.37 - 7.34 (m, 3H), 7.29 7.24 (m, 6H), 7.13 - 7.09 (m, 2H), 6.86 - 6.84 (m, 3H), 6.26 - 6.23 (m, 2H), 3.56 (s, 3H). 31 31P NMR (162 MHz, CDCl3) δ 18.53; 13 13C NMR (101 MHz, CDCl3) δ 192.5 (d, J = 18.2 Hz), 168.1 (d, J = 10.2 Hz), 160.1, 140.0 (d, J = 1.6 Hz), 137.1 (d, J = 0.8 Hz), 133.4, 133.3, 131.7 (d, J = 2.8 Hz), 129.0, 128.7, 128.6 (d, J = 7.4 Hz), 125.7, 122.2, 119.8, 113.2, 77.3, 76.1, 74.9, 55.3.

[0074] The difference between this embodiment and Example 1 is that the substrate is α-(4-methoxybenzoyl)methylphosphonium ylide compound, and the catalyst is cobalt chloride.

[0075] The reason for the decrease in yield in this example compared to Example 1 is that cobalt chloride is used as the catalyst and its solubility is poor.

[0076] Example 3

[0077] Add α-(4-iodobenzoyl)methylphosphonium ylide compound (0.4 mmol), N-neopentyloxybenzamide (0.2 mmol), tetraphenylcobalt porphyrin (0.02 mmol), and 2 mL of dichloromethane into a 15 mL test tube. Then, place the test tube in an oil bath at 60 °C and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by a rotary evaporator, silica gel column chromatography is used for purification and separation to obtain the corresponding α-(4-iodobenzoyl)-α-benzamidomethylphosphonium ylide, and its structural formula is:

[0078]

[0079] Purity 99%. Yield 58%. Its NMR data are as follows: 1 H NMR(400MHz,CDCl3)δ12.04(s,1H),7.56 - 7.51(m,6H),7.47 - 7.39(m,5H),7.32 - 7.27(m,6H),7.15 - 7.11(m,2H),7.06 - 7.04(m,2H),6.89 - 6.85(m,1H),6.59 - 6.56(m,2H). 31 P NMR(162MHz,CDCl3)δ18.28. 13 C NMR(101MHz,CDCl3)δ191.5(d,J=18.4Hz),167.8(d,J=9.8Hz),143.5(d,J=1.4Hz),139.8(d,J=1.6Hz),136.8,133.4,133.3,131.9(d,J=3.0Hz),128.9,128.8,128.7(d,J=5.4Hz),126.3,125.3,122.4,119.9,94.9,77.3,77.2,76.0.

[0080] The difference between this embodiment and Example 1 is that the substrate is α-(4-iodobenzoyl)methylphosphonium ylide compound and its dosage is increased.

[0081] The reason for the decrease in yield in this example compared to Example 1 is that with the increase in the amount of ylide used, some by-products are produced.

[0082] Example 4

[0083] Into a 15 mL test tube, add α-(2-thiazolylcarbonyl)methylphosphonium ylide compound (0.3 mmol), N-pivaloyloxybenzamide (0.2 mmol), tetraphenylcobalt porphyrin (0.02 mmol), and 2 mL of chloroform. Then, place the test tube in an oil bath at sixty degrees Celsius and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by a rotary evaporator, silica gel column chromatography is carried out for purification and separation to obtain the corresponding α-(2-thiazolylcarbonyl)-α-benzamido-substituted methylphosphonium ylide, and its structural formula is:

[0084]

[0085] Purity 99%. Yield 54%. Its NMR data are as follows: 1 H NMR(400MHz,CDCl3)δ11.90(s,1H),7.80-7.75(m,6H),7.45-7.27(m,11H),7.14-7.10(m,2H),7.04-7.00(m,2H),6.88-6.84(m,1H). 31 P NMR(162MHz,CDCl3)δ20.08. 13 C NMR(101MHz,CDCl3)δ170.7,167.1(d,J=10.6Hz),141.9,139.7(d,J=1.6Hz),133.3,133.2,131.4(d,J=3.0Hz),128.6,128.5,128.4,127.4,126.5,123.0,122.5,120.0,77.3,75.6.

[0086] The difference between this embodiment and Example 3 is that the substrate is α-(2-thiazolylcarbonyl)methylphosphonium ylide compound, and its dosage is reduced.

[0087] The reason for the further decrease in the yield of this example compared to Example 3 is that the amount of ylide used is reduced, and part of the raw materials are not completely converted, and the conversion rate is not 100%.

[0088] Example 5

[0089] Into a 15 mL test tube, add α-cyclopropylmethylphosphonium ylide compound (0.3 mmol), N-pivaloyloxybenzamide amide (0.2 mmol), tetraphenylcobalt porphyrin (0.02 mmol), and 2 mL of dichloromethane. Then, place the test tube in an oil bath at sixty degrees Celsius and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by a rotary evaporator, silica gel column chromatography is used for purification and separation to obtain the corresponding α-cyclopropylformyl-α-benzamidomethylphosphonium ylide, and its structural formula is:

[0090]

[0091] The purity is 99%. The yield is 63%. Its NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 12.03 (s, 1H), 7.77 - 7.71 (m, 6H), 7.48 - 7.38 (m, 11H), 7.09 - 7.05 (m, 2H), 6.82 - 6.79 (m, 1H), 0.82 - 0.73 (m, 3H), 0.03 - 0.01 (m, 2H). 31 P NMR (162 MHz, CDCl3) δ 17.64. 13 C NMR (101 MHz, CDCl3) δ 193.57 (d, J = 18.2 Hz), 167.77 (d, J = 9.8 Hz), 140.0 (d, J = 1.6 Hz), 133.5, 133.4, 132.0 (d, J = 2.8 Hz), 129.0, 128.9, 128.5, 127.8, 126.9, 122.0, 119.8, 77.3, 75.9, 74.7, 20.9, 9.7.

[0092] The difference between this embodiment and Example 4 is that the substrate is replaced with α-cyclopropylmethylphosphonium ylide compound.

[0093] The reason for the increase in the yield of this example compared to Example 4 is that when using α-cyclopropylmethylphosphonium ylide, the reaction by-products increase.

[0094] Example 6

[0095] Into a 15 mL test tube, add α-esterylmethylphosphonium ylide compound (0.3 mmol), N-pivaloyloxybenzamide amide (0.2 mmol), tetraphenylcobalt porphyrin (0.02 mmol), and 2 mL of dichloromethane. Then, place the test tube in an oil bath at sixty degrees Celsius and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by a rotary evaporator, silica gel column chromatography is carried out for purification and separation to obtain the corresponding α-esteryl-α-benzamido-substituted methylphosphonium ylide, and its structural formula is:

[0096]

[0097] Purity 99%. Yield 52%. Its NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H), 7.67 - 7.62 (m, 6H), 7.45 - 7.37 (m, 11H), 7.12 - 7.08 (m, 2H), 6.84 - 6.81 (m, 1H), 3.65 - 3.60 (m, 2H), 0.47 - 0.44 (m, 3H). 31 P NMR (162 MHz, CDCl3) δ 18.48. 13 C NMR (101 MHz, CDCl3) δ 170.2 (d, J = 12.8 Hz), 168.2 (d, J = 9.4 Hz), 140.1, 133.4, 133.3, 131.6, 128.6, 128.5, 128.0, 127.0, 121.8, 119.4, 58.3, 57.5, 56.2, 13.7.

[0098] The main difference between this embodiment and Example 5 is that the substrate is replaced with an α-esterylmethylphosphonium ylide compound.

[0099] The reason for the decrease in yield in this example compared to Example 5 is that when using α-esterylmethylphosphonium ylide, the reaction by-products increase.

[0100] Example 7

[0101] Into a 15 mL test tube, add α-benzoylmethylphosphonium ylide compound (0.3 mmol), N-pivaloyloxy-4-methoxybenzamide amide (0.2 mmol), tetraphenylcobalt porphyrin (0.02 mmol), and 2 mL of dichloromethane. Then, place the test tube in an oil bath at forty degrees Celsius and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by a rotary evaporator, silica gel column chromatography is carried out for purification and separation to obtain the corresponding α-benzoyl-α-(4-methoxybenzamido)methylphosphonium ylide, and its structural formula is:

[0102]

[0103] The purity is 99%. The yield is 58%. Its NMR data are as follows: 1 H NMR(400MHz,CDCl3)δ11.96(s,1H),7.57-7.39(m,6H),7.36-7.26(m,5H),7.27-7.22(m,6H),6.88-6.85(m,3H),6.74-6.66(m,4H),3.63(s,3H). 31 P NMR(162MHz,CDCl3)δ18.36. 13 C NMR(101MHz,CDCl3)δ192.8(d,J=18.4Hz),167.8(d,J=9.8Hz),155.0,144.3(d,J=0.6Hz),133.4,133.3,131.7(d,J=2.8Hz),128.7,128.6,127.8,127.2,126.5,125.6,121.3,113.9,77.4,76.5,75.2,55.5.

[0104] The difference between this embodiment and Example 1 is that the substrate is replaced with N-pivaloyloxy-4-methoxybenzamide amide.

[0105] The reason for the lower yield of this example compared to Example 1 is the increase in by-products.

[0106] Example 8

[0107] To a 15 mL test tube, add α-benzoylmethylphosphonium ylide compound (0.3 mmol), N-pivaloyloxy-4-fluorobenzamide amide (0.2 mmol), tetraphenylcobalt porphyrin (0.02 mmol), and 2 mL of dichloromethane. Then, place the test tube in an oil bath at 40 °C and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by a rotary evaporator, silica gel column chromatography is carried out for purification and separation to obtain the corresponding α-benzoyl-α-(4-fluorobenzamido)methylphosphonium ylide, and its structural formula is:

[0108]

[0109] The purity is 99%. The yield is 56%. Its NMR data are as follows: 1 H NMR(400MHz,CDCl3)δ12.08(s,1H),7.59-7.54(m,6H),7.43-7.37(m,5H),7.30-7.26(m,6H),6.93-6.80(m,5H),6.77-6.73(m,2H).19 FNMR (376 MHz, CDCl3) δ 121.19. 31 P NMR (162 MHz, CDCl3) δ 18.50. 13 C NMR (101 MHz, CDCl3) δ 192.0 (d, J = 18.4 Hz), 166.9 (d, J = 10.0 Hz), 157.3 (d, J = 254.6 Hz), 143.1, 134.9, 132.4, 132.3, 130.7 (d, J = 2.8 Hz), 127.7, 127.6, 126.8, 126.1, 125.2, 124.3, 120.2 (d, J = 7.6 Hz), 114.1, 113.9, 76.2, 75.4, 74.2.

[0110] The difference between this embodiment and Example 1 is that the substrate is N-pivaloyloxy-4-fluorobenzamide amide.

[0111] The reason for the lower yield of this example compared to Example 1 is the increase in by-products.

[0112] Example 9

[0113] Into a 15 mL test tube, add α-benzoylmethylphosphonium ylide compound (0.3 mmol), N-pivaloyloxy-2-thiophenecarboxamide amide (0.2 mmol), tetraphenylcobalt porphyrin (0.02 mmol), and 2 mL of dichloromethane. Then, place the test tube in an oil bath at sixty degrees Celsius and stir for 12 h. After the reaction is complete, filter the resulting reaction solution. After the organic solvent is concentrated and dried by rotary evaporation, silica gel column chromatography is used for purification and separation to obtain the corresponding α-benzoyl-α-(2-fluorothiophenecarboxamido)methylphosphonium ylide, and its structural formula is:

[0114]

[0115] Purity 99%. Yield 55%. Its NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 12.78 (s, 1H), 7.56 - 7.37 (m, 6H), 7.35 - 7.28 (m, 3H), 7.27 - 7.35 (m, 6H), 6.90 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.2 Hz, 2H), 6.78–6.68 (m, 3H), 6.59 (d, J = 5.8 Hz, 2H). 31 P NMR (162 MHz, CDCl3) δ 18.32. 13CNMR (101 MHz, CDCl3) δ 193.0 (d, J = 17.8 Hz), 166.1 (d, J = 10.4 Hz), 144.1 (d, J = 1.0 Hz), 141.0 (d, J = 1.8 Hz), 133.5, 133.4, 131.9 (d, J = 2.8 Hz), 128.8, 128.7 (d, J = 3.2 Hz), 127.9, 127.1, 125.9, 124.9, 123.8, 115.8, 109.7, 77.3, 75.0, 73.8.

[0116] The difference between this embodiment and Example 1 is that the substrate is N-pivaloyloxy-2-thiophenecarboxamide amide.

[0117] The reason for the decrease in the yield of this example compared to Example 1 is the increase in by-products.

[0118] As can be seen from the above examples, the present invention provides an α-carbonyl-α-amido substituted methyl derivative and a preparation method thereof. The method of the present invention is inexpensive, has mild reaction conditions, and a short reaction time. The method of the present invention uses an α-carbonyl substituted methyl and an N-pivaloyloxyformamide amide derivative to synthesize an α-carbonyl-α-amido substituted methyl derivative in one step. This method is simple and has a wide substrate applicability.

[0119] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and without departing from the spirit or basic characteristics of the present invention, the present invention can be implemented in other specific forms. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the present invention. Any reference signs in the claims should not be regarded as limiting the claims involved.

[0120] In addition, it should be understood that although this specification is described according to embodiments, not every embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for preparing novel α-carbonyl-α-amido substituted methyl phosphonium ylides, characterized in that: The method comprises the following steps: Dissolving an α-carbonyl-substituted methyl phosphonium ylide and an N-acyloxybenzamide amide derivative in an organic solvent at room temperature, adding a metal catalyst, mixing, and heating at 60 degrees Celsius for reaction, filtering the obtained reaction solution, and separating the obtained filtrate by column chromatography to obtain a product, namely, an α-carbonyl-α-amide-substituted methyl phosphonium ylide; The structure of the α-carbonyl substituted methyl phosphonium ylide is as follows: The structure of the N-acyloxybenzamide derivative is as follows: Wherein, R is aryl, alkoxy or cycloalkane, R 1 is an alkyl or aryl group, R 2 is hydrogen, halogen or alkoxy; The metal catalyst is a cobalt catalyst; The organic solvent is dichloromethane.

2. The method for preparing novel α-carbonyl-α-amide substituted methyl phosphonium ylide according to claim 1, characterized in that: The α-carbonyl substituted methyl phosphonium ylide is selected from one of α-benzoylmethyl phosphonium ylide, α-(4-methoxybenzoyl)methyl phosphonium ylide, α-(4-iodobenzoyl)methyl phosphonium ylide, α-(2-thiazolecarbonyl)methyl phosphonium ylide, α-cyclopropylmethyl phosphonium ylide and α-ester methyl phosphonium ylide.

3. The method for preparing novel α-carbonyl-α-amide substituted methyl phosphonium ylide according to claim 1, characterized in that: The α-carbonyl-substituted methyl phosphonium ylide adopts α-benzoylmethyl phosphonium ylide, and its structure is as follows:

4. The method for preparing novel α-carbonyl-α-amide substituted methyl phosphonium ylide according to claim 1, characterized in that: The N-acyloxybenzamide derivative is selected from one of N-pivaloyloxybenzamide, N-pivaloyloxy-4-methoxybenzamide, N-pivaloyloxy-4-fluorobenzamide and N-pivaloyloxy-2-thiophenecarboxamide.

5. The method for preparing novel α-carbonyl-α-amide substituted methyl phosphonium ylide according to claim 1, characterized in that: The N-acyloxybenzamide amide derivative is an N-pivaloyloxybenzamide amide derivative. The structure of the N-pivaloyloxy-benzamide amide derivative is as follows: 1 The group is tert-butyl.

6. The method for preparing novel α-carbonyl-α-amide substituted methyl phosphonium ylide according to claim 1, characterized in that: The N-acyloxybenzamide amide derivative adopts an N-pivaloyloxybenzamide amide derivative, and its structure is as follows:

7. The method for preparing novel α-carbonyl-α-amide substituted methyl phosphonium ylide according to claim 1, characterized in that: The molar ratio of the α-carbonyl substituted methyl phosphonium ylide, the N-acyloxybenzamide amide derivative and the catalyst is (15-20):10:

1.

8. The method for preparing novel α-carbonyl-α-amide substituted methyl phosphonium ylide according to claim 1, characterized in that: The column chromatography separation adopts silica gel column chromatography separation, and the solvent used is a mixed solvent of ethyl acetate and petroleum ether, wherein the ratio of petroleum ether to ethyl acetate is 1:

5.

9. Novel α-carbonyl-α-amido substituted methyl phosphonium ylide, prepared according to the method according to any one of claims 1 to 8.

10. Use of the novel α-carbonyl-α-amide substituted methyl phosphonium ylide according to claim 9 in the synthesis of 1,1-biscarbonyl olefin structures.

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