Preparation method of ketene derivative and application of ketene derivative in synthesis of rosuvastatin calcium intermediate

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a ketene derivative as well as a preparation method and application thereof. A novel synthesis method is researched and developed, a strategy of catalytic reduction coupling reaction of cheap metal cobalt is adopted, cobalt bromide is used as a catalyst, terpyridyl is used as a ligand, zinc powder is used as a reducing agent, and dimethyl sulfoxide is used as a solvent to realize coupling addition. Aiming at the reaction conditions of the reaction, the four aspects of the catalyst, the reaction solvent, the ligand and the reaction temperature are confirmed and optimized. By researching and developing the novel synthesis method, the synthesis of the ketene derivative has wider universality, reaction conditions are milder, the reaction process is easier to operate and control, and the method is energy-saving, environment-friendly, economical and efficient. In addition, an intermediate of a medicine rosuvastatin calcium for treating cardiovascular diseases is synthesized by using the method, so that the intermediate has potential significance in industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to an enone derivative and a preparation method and application thereof. Background Art

[0002] Alkenyl derivatives, especially enone compounds, are widely present as key structural fragments in natural products. Enones are also often used as important templates for the rapid construction of complex synthetic target molecules through structural value-added.

[0003] Enone groups are widely present in natural products and bioactive molecules. Enones are also considered to be very important synthetic components, with extensive applications in various chemical transformations and pharmaceutical syntheses. For example, the representative cardiovascular disease drug rosuvastatin is easily obtained by direct conversion of the enone scaffold. However, the classical synthetic strategy has the following problems:

[0004] Traditional synthetic methods, such as aldol condensation, Novenagel reaction, and Wittig reaction, may be limited in the synthesis of complex functionalized molecules;

[0005] In the context of advancing synthetic methods, new synthetic methods have been developed. Although carbon monoxide is widely used as a raw material for C1 in various metal-catalyzed carbonylation reactions, its use is not convenient and has high environmental pollution.

[0006] Carboxylic acids are abundant, diverse, and stable, and have become an indispensable source of carbon groups in modern chemical synthesis. A relatively mature system has been established to enable the carbonylation of alkyl and aryl groups. However, there have been only sporadic reports on the reductive coupling carbonylation of alkenyl halides with carboxylic acids. In 2019, the Shu group reported a nickel-catalyzed reductive coupling of acyl fluorides with cyclic olefin sulfonates (Org. Lett. 2019, 21, 3701−3705), but it was limited to the synthesis of polysubstituted enones and could not produce linear monosubstituted enone compounds. The main reasons are that 1) in the second oxidative addition step, the activity of the monosubstituted olefin halide is much greater than that of the acyl donor, and the olefin-olefin self-coupling product is dominant; 2) the decarbonylation factor cannot be ignored, and 3) in addition, linear enones E / Z Controlling the configuration is key to this reaction. Cobalt, a cheap metal from the third period, also has high catalytic activity in reductive coupling reactions. Developing a method to obtain a broader spectrum of inexpensive enone compounds is of great significance.

[0007] Statins are a class of selective HMG-CoA reductase inhibitors. HMG-CoA reductase is a key rate-limiting enzyme in cholesterol synthesis. Rosuvastatin primarily acts in the liver, increasing the number of LDL (low-density lipoprotein) receptors on the surface of hepatocytes, promoting LDL absorption and metabolism, while inhibiting VLDL (very low-density lipoprotein) synthesis, thereby reducing VLDL and LDL levels in the blood. It is often used in combination with exercise, diet control, and weight loss to treat hypercholesterolemia and prevent cardiovascular disease. Among statins, rosuvastatin is known as a "super statin" for its specificity for hepatocytes, minimal drug interactions, and few adverse reactions. The key to the synthesis of rosuvastatin lies in the connection between the main ring and the side chain. However, existing strategies, which primarily rely on the Wittig reaction (Am. J. Transl. Res. 2021, 13, 9444-9450), require the pre-preparation of ylide reagents, resulting in harsh reaction conditions, high energy consumption, and complex reaction steps, leading to low yields. Therefore, there is an urgent need to develop a new synthetic route that is both highly efficient and economically safe.

[0008] Summary of the Invention

[0009] In order to overcome the shortcomings and deficiencies in the prior art, the primary purpose of the present invention is to provide an enone derivative.

[0010] Another object of the present invention is to provide a method for preparing the above-mentioned enone derivative; the preparation method is based on a reductive coupling strategy and is carried out at room temperature using cobalt catalysis.

[0011] Another object of the present invention is to provide an application of the above-mentioned enone derivative.

[0012] The purpose of the present invention is achieved through the following technical solutions:

[0013] An enone derivative, the structural formula of the enone derivative is shown in formula (I):

[0014] An enone derivative, characterized in that the structural formula of the enone derivative is as shown in formula (I):

[0015]

[0016] Wherein, R¹ and R² are respectively C1-C20 1°, 2° and 3° hydrocarbon groups, C5-C30 aryl or heteroaryl groups; C1-C20 hydrocarbon groups, C5-C30 ester groups, methoxy groups, halogen-substituted aryl or heteroaryl groups.

[0017] The preparation method of the above-mentioned enone derivative comprises the following steps: The compound represented by formula (II) and the compound represented by formula (III) are dissolved in an inert solvent, and reacted in the presence of a reducing agent, a metal catalyst and a ligand to obtain an enone derivative;

[0018] Wherein, R¹ and R² are respectively C1-C20 1°, 2° and 3° hydrocarbon groups, C5-C30 aryl or heteroaryl groups; C1-C20 hydrocarbon groups, C5-C30 ester groups, methoxy groups, halogen-substituted aryl or heteroaryl groups.

[0019] The metal catalysts are cobalt bromide, cobalt chloride, cobalt iodide, nickel iodide, nickel bromide, nickel chloride, nickel acetylacetonate, dichlorobis-(triphenylphosphine) nickel, nickel bromide (ethylene glycol dimethyl ether), nickel chloride (ethylene glycol dimethyl ether), cuprous iodide, and ferrous acetylacetonate.

[0020] The reaction temperature is 0°C to 60°C; the reaction time is 4 h to 12 h.

[0021] The ligand is a substituted bipyridine, a substituted 1,10-phenanthroline or a substituted terpyridine.

[0022] The reducing agents are zinc powder, manganese powder and magnesium powder.

[0023] The inert solvent is tetrahydrofuran, 1,4-dioxane, N , N '-dimethylformamide, N , N' - one or more of dimethylacetamide, dimethyl sulfoxide, and acetonitrile.

[0024] The molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1 to 1:2.

[0025] The amount of the metal catalyst used is 1 mol% to 20 mol% of the amount of the compound represented by formula (II).

[0026] The amount of the ligand used is 1.2 mol% to 24 mol% of the amount of the compound represented by formula (II).

[0027] The amount of the reducing agent used is 200 mol% to 300 mol% of the amount of the compound represented by formula (II).

[0028] The concentration of the compound represented by formula (II) in the inert solvent is 0.05 mol / L to 0.2 mol / L.

[0029] Preferably, the molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1.5.

[0030] Preferably, the amount of the metal catalyst used is 10 mol% of the amount of the compound represented by formula (II).

[0031] Preferably, the amount of the ligand used is 12 mol% of the amount of the compound represented by formula (II).

[0032] Preferably, the amount of the reducing agent is 300 mol% of the amount of the compound represented by formula (II).

[0033] Preferably, the concentration of the compound represented by formula (II) in the inert solvent is 0.1 mol / L.

[0034] The above-mentioned enone derivatives are used as precursors for synthesizing heterocyclic compounds, in the later modification of drug molecules or in the synthesis of rosuvastatin calcium intermediates.

[0035] The heterocyclic compound is furan, pyridine or pyrimidine; the drug molecule is ibuprofen, probenecid or gemfibrozil.

[0036] The above-mentioned derivatives can be applied to the later modification of drug molecules such as ibuprofen, probenecid, gemfibrozil, etc., as well as the simple synthesis of rosuvastatin calcium intermediates. Considering the rich reactivity of enone, the invention of this application is expected to further realize the rapid establishment of the molecular library of the above-mentioned materials with potential biological activity and high performance through the rapid conversion of products into heterocyclic molecules, and is expected to provide new ideas for the development of new drugs and the discovery of new material molecules.

[0037] In the present invention, the preparation method preferably comprises the following steps (General Scheme 1): zinc powder (32.0 mg, 0.5 mmol, 2.5 equiv), terpyridine (2.8 mg, 6 mol%), and cobalt dibromide (2.2 mg, 5 mol%) are added to an oven-dried Schleck tube equipped with magnetic stirring. The Schleck tube is placed under vacuum and backfilled with nitrogen three times. 2 mL of DMSO is added. The mixture is stirred for 30 minutes to reduce the precatalyst. Subsequently, thiopyridyl ester (II) (0.2 mmol, 1.0 equiv) and alkenyl halide (III) (0.3 mmol, 1.5 equiv) are added under a gentle nitrogen countercurrent. The resulting mixture is stirred at room temperature for 4-12 hours. The reaction mixture is treated with ethyl acetate (5 mL), washed with water (2 × 20 mL), extracted with ethyl acetate (3 × 15 mL), and the combined organic phases are washed with brine (30 mL). The mixture is then dried over Na2SO4. The crude product was concentrated by rotary evaporation and purified by silica gel column chromatography using an eluent (petroleum ether / ethyl ether or ethyl acetate) to obtain a pure enone compound.

[0038] Principle of the present invention:

[0039] Carboxylic acids can be activated in a variety of ways, and the reductive coupling of their derived activated amides or esters with various electrophiles is a well-established system (CCS Chem. 2022, 4, 9-30). However, this approach is primarily focused on nickel catalysis, while cobalt catalysis, which has similar properties, has been less reported (J. Org. Chem. 2004, 69, 936-942). Compared to nickel catalysts, cobalt is more readily involved in the oxidative addition step, making it more advantageous for C(sp2)-C(sp2) reductive coupling reactions. We envisioned addressing the issue of olefin self-coupling in linear enone synthesis by replacing the metal catalyst, thereby obtaining monosubstituted enones with a single configuration.

[0040] In the present invention, we have developed a universal synthetic method for obtaining enones under mild conditions by reacting carboxylic acid derivative thioesters with alkenylating agents in the presence of cobalt catalysts, terpyridine ligands, and zinc powder as a reducing agent.

[0041] The preparation method of the present invention utilizes a carboxylic acid thioester compound represented by formula (II) and an alkenylating agent represented by formula (III), utilizing a cobalt-catalyzed reductive coupling strategy. Specifically, the 2-thiopyridine-activated carboxylic acid compound not only acts as a carbonyl derivative with a certain degree of oxidizing activity, but its 2-thiopyridine substituent also exhibits a certain degree of coordination with the metal catalyst. Furthermore, 2-thiopyridine also functions as a leaving group, accelerating the oxidative addition step. Furthermore, alkenyl halides are effective reagents for selectively introducing alkenyl fragments into molecules. During the reaction, it was found that the stereoselectivity of the product configuration is independent of the configuration of the initial raw material. This facilitates the acquisition of a wide range of raw materials, which helps broaden the scope of the reaction.

[0042] The basic process of this type of cobalt-catalyzed reductive coupling is generally believed to be that the cobalt catalyst is reduced or disproportionated by the substrate to generate an active monovalent cobalt species, which then undergoes oxidative addition to the pyridine-substituted thioester to produce a divalent cobalt species. This divalent cobalt intermediate is then reduced and further oxidized by an alkenyl halide to a trivalent cobalt intermediate, which undergoes reductive elimination to yield the target enone compound and monovalent cobalt. Zinc powder serves as the key reducing agent in this step. This strategy also enables the efficient and universal synthesis of enone derivatives.

[0043] In general, the present invention achieves a simple and efficient synthesis of enone compounds under mild conditions through the design and synthesis of substrates, and provides an important alternative to traditional enone synthesis methods.

[0044] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0045] 1) This invention enables the construction of enone compounds under mild conditions catalyzed by inexpensive metal cobalt, without the need for complex ligands and additional additives. It also provides a strategy that complements traditional conditions using expensive metals (such as palladium and gold catalysis) and harsh conditions (involving stoichiometric organometallics such as butyllithium or stoichiometric non-environmentally friendly oxidants).

[0046] 2) Through ingenious substrate design, the present invention utilizes very simple and readily available carboxylic acid derivatives, activated to pyridine thioesters as substrates. As leaving groups with certain directing abilities, pyridine thioesters can better promote this transformation. Furthermore, the chemical reaction of the present invention is compatible with enone compounds derived from substituted carboxylic acids of aliphatic, alkenyl, and (hetero)aromatic groups, as well as some commonly used drugs such as propanesulfonic acid and ibuprofen, thus broadening the substrate limitations of previous methods for constructing enone compounds.

[0047] 3) The enone compound obtained by the present invention can not only be used as a practical synthon, but also as a precursor of heterocyclic compounds such as furan, pyridine, pyrimidine, and some drugs such as rosuvastatin calcium; this transformation also realizes the later derivatization reaction of drugs such as ibuprofen and propanesulfonic acid.

[0048] Application of the present invention in the synthesis of rosuvastatin calcium intermediate:

[0049]

[0050] Rosuvastatin calcium intermediate formula (V) N -5-2-bromovinyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)- N The synthesis of -methylmethanesulfonamide starts from a commercially available aldehyde through a Horner-Wadsworth-Emmons olefination reaction to obtain an alkenyl methyl ester, which is then hydrolyzed to form an alkenyl carboxylic acid. Finally, it undergoes a bromination reaction with NBS catalyzed by manganese acetate tetrahydrate to obtain the alkenyl bromide starting material (Formula V) in a three-step yield of 85% overall.

[0051] The present invention can be applied to the rosuvastatin calcium intermediate formula (IV) ( R , E )-3-((tert-butyldiphenylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-( N The synthesis of methyl 5-oxohept-6-enoate (5-(methylsulfonylamino)pyrimidin-5-yl)-5-oxohept-6-enoate is carried out under milder conditions than the traditional synthesis method, and the overall yield is increased by 30%.

[0052] DETAILED DESCRIPTION

[0053] The present invention will be further described below with reference to specific examples, but the embodiments of the present invention are not limited thereto.

[0054] The present invention provides a method for preparing enone, which is used to provide a new strategy based on cobalt-catalyzed reductive coupling, selectively obtain enone compounds through the reductive coupling of carboxylic acid thioesters and alkenyl halides, and broaden the types of enone derivatives.

[0055] Example 1

[0056] This embodiment performs methyl ( E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-phenyl-6-enoic acid methyl ester (1a), the reaction formula is as follows:

[0057]

[0058] 1a was synthesized according to General Scheme 1, and silica gel flash chromatography (petroleum ether / ethyl acetate from 30:1 to 20:1, v / v) provided the title compound as a colorless oil (92.5 mg, 95%).

[0059] p-methyl E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-phenyl-6-enoic acid methyl ester was detected by nuclear magnetic resonance, see Figures 1 to 2 , the result is: 1 H NMR (400 MHz, CDCl3) δ7.70 - 7.68 (m,4H), 7.46 - 7.32 (m, 12H), 6.50 (d, J = 16.0 Hz, 1H), 4.69 (p, J = 6.0 Hz, 1H), 3.60 (s, 3H), 2.91 (qd, J = 15.2, 6.4 Hz, 2H), 2.64 - 2.53 (m, 2H), 1.02 (s,9H); 13 C NMR(151 MHz, CDCl3) δ 197.8, 171.4, 143.0, 135.9, 135.9, 134.4,133.6, 133.5, 130.5, 129.8, 128.9, 128.3, 127.7, 126.3, 67.3, 51.5, 47.8, 41.7, 26.8, 19.2.

[0060] In this embodiment, commercially available alkenyl bromides can be used as a catalyst to obtain statin side chain-substituted enones through the use of inexpensive metal cobalt. Impurities can be removed by column chromatography to obtain enone compounds.

[0061] Example 2

[0062] This embodiment performs methyl ( E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-(2-(methoxy)phenyl)hept-6-enoate (1b), the reaction formula is as follows:

[0063]

[0064] 1b was synthesized according to General Scheme 1. Silica gel flash chromatography (petroleum ether / ethyl acetate from 10:1 to 8:1, v / v) afforded the title compound as a colorless oil (99.2 mg, 96%).

[0065] p-methyl E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-(2-(methoxy)phenyl)hept-6-enoate (3b) was subjected to NMR examination. Figures 3 and 4 , the result is: 1 H NMR (400 MHz, CDCl3) δ7.77 (d, J = 16.4 Hz, 1H), 7.69 (d, J = 7.2 Hz, 4H), 7.44 - 7.34 (m, 8H), 6.97 -6.89 (m, 2H), 6.58 (d, J = 16.4 Hz, 1H), 4.70 (p, J = 6.2 Hz, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 3.00 - 2.87 (m, 2H), 2.64 - 2.52 (m, 2H), 1.02 (s, 9H); 13 C NMR(101 MHz, CDCl3) δ 198.3, 171.5, 158.5, 138.3, 135.9, 135.9, 133.7, 133.6,131.8, 129.8, 129.8, 128.6, 127.6, 127.0, 123.4, 120.7, 111.1, 67.4, 55.5,51.4, 47.5, 41.8, 26.9, 19.3.

[0066] This embodiment uses a group with a methoxy group to verify the effect of electron donation on the reaction, and this embodiment verifies the effect of the steric hindrance of the ortho position of the phenyl group on the reaction.

[0067] Example 3

[0068] This embodiment performs methyl ( E )-4-(5-(tert-butyldiphenylsilyl)oxy)-7-methoxy-3,7-dioxohept-1-en-1-yl)benzoate (1c), the reaction formula is as follows:

[0069]

[0070] 1c was synthesized according to General Scheme 1. Silica gel flash chromatography (petroleum ether / diethyl ether from 8:1 to 6:1, v / v) afforded the title compound as a colorless oil (68.6 mg, 63%).

[0071] p-methyl E )-4-(5-(tert-butyldiphenylsilyl)oxy)-7-methoxy-3,7-dioxohept-1-en-1-yl)benzoate was detected by nuclear magnetic resonance. Figures 5 and 6 , the result is: 1 H NMR (400 MHz, CDCl3) δ8.04 (d, J = 8.0 Hz, 2H), 7.70 - 7.67 (m, 4H), 7.50 - 7.32 (m, 9H), 6.54 (d, J =16.0 Hz, 1H), 4.69 (p, J = 6.0 Hz, 1H), 3.94 (s, 3H), 3.60 (s, 3H), 3.03 -2.82 (m, 2H), 2.69 - 2.51 (m, 2H), 1.02 (s, 9H); 13 C NMR(101 MHz, CDCl3) δ197.6, 171.5, 166.5, 141.4, 138.7, 135.9, 135.9, 133.5, 133.4, 131.5, 130.1,129.9, 128.2, 128.2, 127.7, 67.2, 52.4, 51.6, 48.0, 41.7, 26.8, 19.3.

[0072] In this embodiment, an ester-substituted enone compound is obtained. As an extremely commonly used group, the ester group has potential application value in the fields of materials and medicine.

[0073] Example 4

[0074] This embodiment performs methyl ( E )-3-((tert-butyldiphenylsilyl)oxy)-7-(4-fluorophenyl)-5-oxoheptyl-6-enoic acid methyl ester (1d), the structural formula of which is shown below:

[0075]

[0076] 1d was synthesized according to general scheme 1. Flash chromatography on silica gel (petroleum ether / diethyl ether from 10:1 to 8:1, v / v) afforded the title compound as a colorless oil (82.7 mg, 82%).

[0077] p-methyl E )-3-((tert-butyldiphenylsilyl)oxy)-7-(4-fluorophenyl)-5-oxoheptyl-6-enoic acid methyl ester was detected by nuclear magnetic resonance. Figures 7 to 9 , the result is: 1 H NMR (400 MHz, CDCl3) δ7.70 -7.68 (m, 4H), 7.46 - 7.40 (m, 8H), 7.31 (d, J = 16.2 Hz, 1H), 7.09 - 7.04 (m,2H), 6.41 (d, J = 16.2 Hz, 1H), 4.68 (p, J = 5.8 Hz, 1H), 3.60 (s, 3H), 2.97 -2.83 (m, 2H), 2.65 - 2.48 (m, 2H), 1.02 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ197.6, 171.4, 164.0 (d, J = 251.6 Hz), 141.6, 135.9, 135.9, 133.5, 133.4, 130.6(d, J = 3.2 Hz), 130.2 (d, J = 8.4 Hz), 129.8 (d, J = 2.0 Hz), 127.6, 126.0 (d, J =2.4 Hz), 116.0 (d, J = 22.0 Hz), 67.3, 51.5, 47.8, 41.6, 26.8, 19.2; 19F NMR (377MHz, CDCl3) δ -109.1 (s, 1F).

[0078] The fluorine-substituted enone compound obtained in this embodiment is expected to have certain applications in the field of fluorine-related life chemistry.

[0079] Example 5

[0080] Example 5 This example carries out methyl ( E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-(thiophen-3-yl)hept-6-enoate (1e), the reaction formula is as follows:

[0081]

[0082] 1e was synthesized according to General Scheme 1. Silica gel flash chromatography (petroleum ether / diethyl ether from 10:1 to 8:1, v / v) afforded the title compound as a colorless oil (96.5 mg, 98%).

[0083] p-methyl E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-(thien-3-yl)hept-6-enoate was detected by NMR, see Figures 10 and 11 , the result is: 1 H NMR (400 MHz, CDCl3) δ 7.71 -7.68 (m, 4H), 7.45 - 7.29 (m, 9H), 7.21 - 7.20 (m, 1H), 6.32 (d, J = 16.0 Hz,1H), 4.67 (p, J = 5.6 Hz, 1H), 3.59 (s, 3H), 2.94 - 2.81 (m, 2H), 2.63 - 2.51(m, 2H), 1.02 (s, 9H); 13 C NMR(101 MHz, CDCl3) δ 198.0, 171.4, 137.6, 136.4,135.9, 135.9, 133.6, 133.5, 129.8, 129.8, 128.8, 127.6, 126.9, 126.2, 125.2, 67.3, 51.5, 47.6, 41.7, 26.8, 19.2.

[0084] In this example, a 3-thiophene-substituted enone compound is obtained, which is expected to be further transformed into a polysubstituted heterocyclic compound.

[0085] Example 6

[0086] This example performs methyl ( E )-3-[(tert-butyldiphenylsilyl)oxy]-7-(6-methoxypyridin-3-yl)-5-oxohept-6-enoate (1f), the structural formula of which is shown below:

[0087]

[0088] 1f was synthesized according to General Scheme 1. Flash chromatography on silica gel (petroleum ether / diethyl ether from 10:1 to 8:1, v / v) afforded the title compound as a colorless oil (98.4 mg, 95%).

[0089] p-methyl E )-3-[(tert-Butyldiphenylsilyl)oxy]-7-(6-methoxypyridin-3-yl)-5-oxohept-6-enoate (1f) was subjected to NMR detection. Figures 12 to 13 , the result is: 1 H NMR (400 MHz, CDCl3) δ7.61 (d, J = 16.0 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.35 - 7.32 (m, 3H), 7.19 -7.17 (m, 2H), 7.12 - 7.10 (m, 2H), 6.71 (d, J = 16.0 Hz, 1H), 3.99 (q, J = 6.8Hz, 1H), 2.45 (d, J = 7.2 Hz, 2H), 1.90 - 1.80 (m, 1H), 1.48 (d, J = 6.8 Hz, 3H),0.89 (d, J = 6.8 Hz, 6H); 13 C NMR(101 MHz, CDCl3) δ 199.7, 142.4, 140.5, 137.7,134.6, 130.2, 129.7, 128.8, 128.3, 127.7, 124.6, 51.5, 45.0, 30.1, 22.4,17.8.

[0090] This example obtains an enone compound of 2-methoxypyridine, which proves that the poisoning effect of nitrogen atoms on the catalyst is limited and is expected to adapt to more nitrogen heteroaromatic substrates.

[0091] Experimental Example 7

[0092] This embodiment performs methyl ( E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-9-phenyl-6-enoate (1 g), the structural formula of which is shown below:

[0093]

[0094] 1 g was synthesized according to General Scheme 1. Silica gel flash chromatography (petroleum ether / diethyl ether from 10:1 to 8:1, v / v) afforded the title compound as a colorless oil (65.9 mg, 64%).

[0095] p-methyl E )-3-((tert-Butyldiphenylsilyl)oxy)-5-oxo-9-phenyl-6-enoate (1 g) was subjected to NMR analysis. Figures 14 to 15 , the result is: 1 H NMR (400 MHz, CDCl3)δ 7.69 - 7.66 (m,4H), 7.45 - 7.36 (m, 6H), 7.30 - 7.27 (m, 2H), 7.22 - 7.13 (m, 3H), 6.55 (dt, J = 16.0, 6.8 Hz, 1H), 5.87 (d, J = 16.0 Hz, 1H), 4.60 (p, J = 6.0 Hz, 1H), 3.58(s, 3H), 2.81 - 2.72 (m, 2H), 2.70 - 2.67 (m, 2H), 2.58 - 2.47 (m, 2H), 2.44- 2.38 (m, 2H), 1.01 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 198.0, 171.5, 146.8,140.7, 135.9, 135.9, 133.6, 133.5, 131.0, 129.8, 129.8, 128.5, 128.3, 127.7,126.2, 67.3, 51.5, 47.0, 41.7, 34.3, 34.2, 26.8, 19.3.

[0096] This experimental example constructs the structure of alkyl-substituted alkenes, which further illustrates the universality of the conditions.

[0097] Example 8

[0098] This embodiment is carried out ( E)-4-(4-isobutylphenyl)-1-phenylpent-1-en-3-one (1h), the structural formula of which is shown below:

[0099]

[0100] 1h was synthesized according to General Scheme 1. Flash chromatography on silica gel (petroleum ether / diethyl ether from 10:1 to 8:1, v / v) afforded the title compound as a colorless oil (39.1 mg, 67%).

[0101] right （E） -4-(4-Isobutylphenyl)-1-phenylpent-1-en-3-one (1h) was subjected to NMR detection, see Figures 16 and 17 , the result is: 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 16.0 Hz, 1H), 7.48 -7.44 (m, 2H), 7.35 - 7.32 (m, 3H), 7.19 - 7.17 (m, 2H), 7.12 - 7.10 (m, 2H), 6.71 (d, J = 16.0 Hz, 1H), 3.99 (q, J = 6.8 Hz, 1H), 2.45 (d, J = 7.2 Hz, 2H), 1.90- 1.80 (m, 1H), 1.48 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H); 13 C NMR(101MHz, CDCl3) δ 199.7, 142.4, 140.5, 137.7, 134.6, 130.2, 129.7, 128.8, 128.3,127.7, 124.6, 51.5, 45.0, 30.1, 22.4, 17.8.

[0102] This embodiment achieves a late-stage modification of the drug molecule ibuprofen, providing new opportunities for developing its more potential practical value.

[0103] Example 9

[0104] This embodiment is carried out ( E )-7-(2,5-dimethylphenoxy)-4,4-dimethyl-1-phenylhept-1-en-3-one (1i), the structural formula of which is shown below:

[0105]

[0106] Synthesis of 1i according to general procedure 1 Flash chromatography on silica gel (petroleum ether / diethyl ether from 20:1 to 15:1, v / v) provided the title compound as a colorless oil (63.9 mg, 95%).

[0107] right( E )-7-(2,5-dimethylphenoxy)-4,4-dimethyl-1-phenylhept-1-en-3-one was examined by nuclear magnetic resonance, see Figures 18 and 19 , the result is: 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 15.6 Hz,1H), 7.58 - 7.53 (m, 2H), 7.39 - 7.35 (m, 3H), 7.14 (d, J = 15.6 Hz, 1H), 6.96(d, J = 7.2 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 3.90 (t, J = 6.0 Hz,2H), 2.27 (s, 3H), 2.13 (s, 3H), 1.85 - 1.67 (m, 4H), 1.25 (s, 6H); 13 C NMR(101 MHz, CDCl3) δ 203.8, 156.9, 143.1, 136.5, 134.9, 130.3, 128.9, 128.4,123.5, 120.7, 120.7, 111.9, 67.8, 46.5, 36.4, 25.0, 24.3, 21.4, 15.8.

[0108] This example performs a late-stage modification of the drug molecule gemfibrozil, which not only illustrates the compatibility of the reaction with ether compounds, but also is expected to provide a new idea and theoretical basis for the development of treatments for hyperlipidemia using gemfibrozil as an active ingredient.

[0109] Example 10

[0110] In this example, 4-(3,4-dihydronaphthalene-1-carbonyl)- N , N - Preparation of dipropylbenzenesulfonamide (1j), the structural formula of which is shown below:

[0111]

[0112] 1j was synthesized according to general procedure 1. Flash chromatography on silica gel (petroleum ether / diethyl ether from 10:1 to 8:1, v / v) afforded the title compound as a colorless oil (56.5 mg, 71%).

[0113] p-4-(3,4-dihydronaphthalene-1-carbonyl)- N , N -Dipropylbenzenesulfonamide (1j) was subjected to NMR detection, see Figures 20 to 21 , the result is: 1 H NMR (400 MHz, CDCl3) δ 7.95 - 7.93 (m, 2H), 7.88 - 7.86(m, 2H), 7.29 - 7.27 (m, 1H), 7.25 - 7.21 (m, 2H), 7.20 - 7.14 (m, 1H), 6.55(t, J = 4.8 Hz, 1H), 3.13 - 3.09 (m, 4H), 2.89 (t, J = 8.0 Hz, 2H), 2.55 - 2.50(m, 2H), 1.61 - 1.51 (m, 4H), 0.87 (t, J = 7.2 Hz, 6H); 13 C NMR (101 MHz, CDCl3)δ 195.6, 143.8, 141.1, 138.8, 138.4, 135.8, 131.4, 130.3, 128.2, 128.0,127.0, 126.7, 125.8, 50.0, 27.4, 23.5, 22.0, 11.2.

[0114] This example presents a late-stage modification of the drug molecule probenecid, which is expected to provide a new approach and theoretical basis for the development of drugs for the treatment of hyperuricemia using probenecid as the active ingredient. This will further facilitate the research and development of such drugs and promote the transformation of innovative achievements.

[0115] Example 11

[0116] This embodiment is carried out ( R , E )-3-((tert-butyldiphenylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-( N Preparation of methyl-5-(methylsulfonyl)pyrimidin-5-yl)-5-oxohept-6-enoate (IV), the structural formula of which is shown below:

[0117]

[0118] Formula (IV) was synthesized according to General Scheme 1. Flash chromatography on silica gel (petroleum ether / diethyl ether from 10:1 to 8:1, v / v) afforded the title compound as a colorless oil (124.3 mg, 85%).

[0119] right( R , E )-3-((tert-butyldiphenylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-( N -methylmethanesulfonamido)pyrimidin-5-yl)-5-oxohept-6-enoic acid methyl ester (IV) was subjected to NMR detection, see Figures 22 to 24 , the result is: 1 H NMR (400 MHz, Chloroform- d ) δ 7.66 – 7.62 (m, 4H), 7.59 –7.49 (m, 2H), 7.47 – 7.29 (m, 7H), 7.07 (t, J = 8.6 Hz, 2H), 5.95 (d, J = 16.4Hz, 1H), 4.59 (dt, J = 11.1, 5.6 Hz, 1H), 3.59 (d, J = 1.4 Hz, 7H), 3.52 (s, 3H), 3.25 (p, J = 6.6 Hz, 1H), 2.89 – 2.65 (m, 2H), 2.63 – 2.41 (m, 2H), 1.26 (t, J =6.9 Hz, 6H), 1.00 (s, 9H); 13 C NMR (101 MHz, Chloroform- d ) δ 196.7, 175.3,171.3, 164.3, 163.7 (d, J = 250.0 Hz), 158.0, 137.5, 133.7 (d, J = 3.1 Hz),133.6, 133.5, 133.3, 132.1 (d, J = 8.5 Hz), 129.9, 127.7, 127.7, 119.0, 115.5(d, J= 21.8 Hz), 67.0, 51.5, 47.9, 42.5, 41.5, 33.1, 32.3, 26.8, 21.9, 21.8,19.2; 19 F NMR (377 MHz, Chloroform- d )δ -110.0.

[0120] In this example, a rosuvastatin calcium intermediate was synthesized, and the chiral side chain was connected to the parent core by catalysis of inexpensive metal cobalt, replacing the traditional Wittig reaction, which is expected to be applied in industrial synthesis.

[0121] Synthesis of raw material formula (V):

[0122]

[0123] Formula (V) was synthesized according to existing literature (WO 2008 / 053334 A2; US 2010 / 0029940 A1; JACS, 145, 6270-6279).

[0124] right N -5-2-bromovinyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)- N -Methylmethanesulfonamide formula (V) was subjected to NMR detection, see Figures 25 to 27 , the result is: 1 H NMR (400 MHz, Chloroform- d ) δ 7.75– 7.58 (m, 2H), 7.20 – 7.10 (m, 2H), 7.06 (d, J = 14.2 Hz, 1H), 6.14 (d, J = 14.2Hz, 1H), 3.58 (s, 3H), 3.52 (s, 3H), 3.32 (p, J = 6.7 Hz, 1H), 1.28 (d, J = 6.7Hz, 6H); 13 C NMR (101 MHz, Chloroform- d ) δ 174.9, 163.5 (d, J = 251.5 Hz), 163.5,157.8, 133.8(d, J = 3.4 Hz), 132.1(d, J = 8.3 Hz), 130.9, 119.9, 115.4 (d,J = 21.8Hz), 112.2, 42.4, 33.1, 32.4, 21.7; 19 F NMR (377 MHz, Chloroform- d )δ -110.7.

[0125] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 The methyl group obtained in Example 1 of the present invention ( E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-phenyl-6-enoic acid methyl ester (1a) H NMR spectrum. Figure 2 The methyl group obtained in Example 1 of the present invention ( E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-phenyl-6-enoic acid methyl ester (1a). Figure 3 The methyl obtained in Example 2 of the present invention ( E ¹H NMR spectrum of 3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-(4-(trifluoromethyl)phenyl)hept-6-enoate (1b). Figure 4 The methyl obtained in Example 2 of the present invention ( E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-(4-(trifluoromethyl)phenyl)hept-6-enoate (1b). Figure 5 The methyl group obtained in Example 3 of the present invention ( E ¹H NMR spectrum of 4-(5-(tert-butyldiphenylsilyl)oxy)-7-methoxy-3,7-dioxohept-1-en-1-yl)benzoate (1c). Figure 6 The methyl group obtained in Example 3 of the present invention ( E NMR of 4-(5-(tert-butyldiphenylsilyl)oxy)-7-methoxy-3,7-dioxohept-1-en-1-yl)benzoate (1c) 13 C spectrum. Figure 7 The methyl obtained in Example 4 of the present invention (E )-3-((tert-butyldiphenylsilyl)oxy)-7-(4-fluorophenyl)-5-oxoheptyl-6-enoic acid methyl ester (1d). Figure 8 The methyl obtained in Example 4 of the present invention ( E NMR of methyl 3-((tert-butyldiphenylsilyl)oxy)-7-(4-fluorophenyl)-5-oxoheptyl-6-enoate (1d) 13 C spectrum. Figure 9 The methyl obtained in Example 4 of the present invention ( E NMR of methyl 3-((tert-butyldiphenylsilyl)oxy)-7-(4-fluorophenyl)-5-oxoheptyl-6-enoate (1d) 19 F spectrum. Figure 10 The methyl obtained in Example 5 of the present invention ( E )-3-((tert-butyldiphenylsilyl)oxy)-5-oxo-7-(thiophen-3-yl)hept-6-enoate (1e). Figure 11 The methyl obtained in Example 5 of the present invention ( E )-3-((tert-Butyldiphenylsilyl)oxy)-5-oxo-7-(thiophen-3-yl)hept-6-enoate (1e). Figure 12 The methyl group ( E )-3-[(tert-Butyldiphenylsilyl)oxy]-7-(6-methoxypyridin-3-yl)-5-oxohept-6-enoate (1f). ¹H NMR spectrum. Figure 13 The methyl group ( E )-3-[(tert-Butyldiphenylsilyl)oxy]-7-(6-methoxypyridin-3-yl)-5-oxohept-6-enoate (1f). Figure 14 The methyl group obtained in Example 7 of the present invention ( E )-3-((tert-Butyldiphenylsilyl)oxy)-5-oxo-9-phenyl-6-enoate (1g). ¹H NMR spectrum. Figure 15 The methyl group obtained in Example 7 of the present invention ( E )-3-((tert-Butyldiphenylsilyl)oxy)-5-oxo-9-phenyl-6-enoate (1g). Figure 16 The prepared product of Example 8 of the present invention ( E )-4-(4-isobutylphenyl)-1-phenylpent-1-en-3-one (1h) ¹H NMR spectrum. Figure 17 The prepared product of Example 8 of the present invention ( E )-4-(4-isobutylphenyl)-1-phenylpent-1-en-3-one (1h). Figure 18 The ( E ¹H NMR spectrum of 7-(2,5-dimethylphenoxy)-4,4-dimethyl-1-phenylhept-1-en-3-one (1i). Figure 19 The ( E )-7-(2,5-dimethylphenoxy)-4,4-dimethyl-1-phenylhept-1-en-3-one (1i). Figure 20 4-(3,4-dihydronaphthalene-1-carbonyl)- N , N -H NMR spectrum of dipropylbenzenesulfonamide (1j). Figure 21 4-(3,4-dihydronaphthalene-1-carbonyl)- N , N -NMR¹³C spectrum of dipropylbenzenesulfonamide (1j). Figure 22 The ( R , E )-3-((tert-butyldiphenylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-( N 1H NMR spectrum of methyl 5-(2-methylmethanesulfonyl)pyrimidin-5-yl)-5-oxohept-6-enoate (IV). Figure 23 The ( R , E )-3-((tert-butyldiphenylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-( N 13C NMR spectrum of methyl (5-(2-methylmethanesulfonyl)pyrimidin-5-yl)-5-oxohept-6-enoate (IV). Figure 24 The ( R , E)-3-((tert-butyldiphenylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-( N NMR of methyl (5-(methylsulfonylamino)pyrimidin-5-yl)-5-oxohept-6-enoate of formula (IV)¹ 9 F spectrum. Figure 25 The present invention implements the raw material formula (V) synthesized ( N -5-2-bromovinyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)- N -NMR¹H spectrum of methylmethanesulfonamide (V). Figure 26 The present invention is prepared by synthesizing the raw material formula (V) N -5-2-bromovinyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)- N -NMR¹³C spectrum of methylmethanesulfonamide (V). Figure 27 The raw material formula (V) prepared in the present invention is N -5-2-bromovinyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)- N -NMR of methylmethanesulfonamide Formula (V)¹ 9 F spectrum.

Claims

1. An enone derivative, characterized in that: The structural formula of the enone derivative is shown in formula (I):

2. Wherein, R¹ and R² are respectively C1-C20 1°, 2° and 3° hydrocarbon groups, C5-C30 aryl or heteroaryl groups; C1-C20 hydrocarbon groups, C5-C30 ester groups, methoxy groups, halogen-substituted aryl or heteroaryl groups.

3. The method for preparing an ketene derivative according to claim 1, wherein The following steps are involved: The compound represented by formula (II) and the compound represented by formula (III) are dissolved in an inert solvent, and reacted in the presence of a reducing agent, a metal catalyst and a ligand to obtain an enone derivative; 4. Among them, R 1 and R 2 are respectively a C1-C20 hydrocarbon group, a C5-C30 aryl group or a C5-C30 aromatic heterocyclic group; The metal catalysts are cobalt bromide, cobalt chloride, cobalt iodide, nickel iodide, nickel bromide, nickel chloride, nickel acetylacetonate, dichlorobis-(triphenylphosphine) nickel, nickel bromide (ethylene glycol dimethyl ether), nickel chloride (ethylene glycol dimethyl ether), cuprous iodide, and ferrous acetylacetonate.

5. The preparation method according to claim 2, wherein: The reaction temperature is 0°C to 60°C; the reaction time is 4h to 24h.

6. The preparation method according to claim 2, wherein: The ligands are bipyridine and substituted bipyridine, terpyridine and substituted terpyridine, phenanthroline and substituted 1,10-phenanthroline.

7. The preparation method according to claim 2, characterized in that: The reducing agent is magnesium powder, zinc powder, and manganese powder.

8. The preparation method according to claim 2, wherein: The inert solvent is tetrahydrofuran, N , N '-dimethylformamide, N , N' - one or more of dimethylacetamide, dimethyl sulfoxide, and acetonitrile.

9. The preparation method according to claim 2, wherein: The molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1 to 1:2; The amount of the metal catalyst used is 1 mol% to 20 mol% of the amount of the compound represented by formula (II); The amount of the ligand used is 1.2 mol% to 24 mol% of the compound represented by formula (II); The amount of the reducing agent is 200 mol% to 300 mol% of the amount of the compound represented by formula (II); The concentration of the compound represented by formula (II) in the inert solvent is 0.05 mol / L to 0.2 mol / L.

10. The preparation method according to claim 7, characterized in that: The molar ratio of the compound represented by formula (II) to the compound represented by formula (III) is 1:1.5; The amount of the metal catalyst used is 10 mol% of the amount of the compound represented by formula (II); The amount of the ligand used is 12 mol% of the amount of the compound represented by formula (II); The amount of the reducing agent is 300 mol% of the amount of the compound represented by formula (II); The concentration of the compound represented by formula (II) in the inert solvent is 0.1 mol / L.

11. Use of the enone derivative according to claim 1 as a precursor for synthesizing heterocyclic compounds or in the later stage modification of drug molecules.

12. The use according to claim 9, characterized in that: The heterocyclic compound is furan, pyridine or pyrimidine; the drug molecule is ibuprofen, probenecid or gemfibrozil.

13. The use according to claim 9, characterized in that: The drug is an intermediate of rosuvastatin calcium.

Images