Synthesis process of beta, gamma-unsaturated ketone compound

Abstract

The invention discloses a synthesis process of beta, gamma-unsaturated ketone compounds, and belongs to the technical field of compound synthesis. The beta, gamma-unsaturated ketone compound is obtained through a one-step reaction under irradiation of 450-455 nm blue light in a composite catalyst system by taking allyl-containing olefin as an initial raw material, carboxylic acid as an acylating agent and dimethyl dicarbonate (DMDC) as a dehydrating agent. The composite catalyst system is a compound of a photocatalyst, NiBr2. DME, 4, 4 '-di-tert-butyl-2, 2'-dipyridyl and ammonium chloride; the photocatalyst is Ir [dF (CF3) ppy] 2 (dtbbpy) PF6, fusion of HAT and a coupling function is realized by reconstructing a catalytic system structure and utilizing a nickel-bromine synergistic free radical mechanism, the structural defects in the prior art are fundamentally overcome, and a universal platform is provided for constructing a C-C bond by directly utilizing free carboxylic acid and olefin.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and in particular relates to a synthesis process for β,γ-unsaturated ketone compounds. Background Technology

[0002] β,γ-unsaturated ketones play a prominent role as multifunctional building blocks in natural products, bioactive molecules, and synthetic chemistry. Therefore, developing efficient and selective synthesis methods is a major challenge in modern synthetic chemistry. Traditional synthetic methods for β,γ-unsaturated ketones mainly rely on prefunctionalized reagents (such as acyl halides and organometallic reagents). These methods are cumbersome, have low atom economy, require exogenous oxidants or directing groups, and exhibit poor functional group tolerance. Selective construction of β,γ-unsaturated ketones is difficult (especially through reverse synthesis to break the C(α)-C(O) bond).

[0003] While the carboxylic acid / olefin coupling method reported by Wang et al. (Wang, X. et al. Direct allylic acylation via cross-coupling involving cooperative N-heterocyclic carbene, hydrogen atom transfer, and photoredox catalysis. Nat. Commun. 14, 2951 (2023)) provides an alternative for the synthesis of β,γ-unsaturated ketones, it also has the following drawbacks:

[0004] I. The substrate scope is severely limited (only aromatic carboxylic acids). When N-heterocyclic carbene (NHC) catalysts activate carboxylic acids via nucleophilic addition, the key intermediate (Breslow intermediate) relies on the conjugation effect of the aryl group to stabilize it. Aliphatic carboxylic acids lack a conjugated system, making it difficult to form stable intermediates, leading to reaction failure. The pre-activation step also has side effects: the preparation of acyl fluorides requires highly reactive reagents (such as Deoxo-Fluor), which are inefficient for aliphatic carboxylic acids and prone to decarboxylation side reactions.

[0005] Second, the catalytic system relies on exogenous hydrogen atom transfer (HAT) reagents and lacks built-in HAT functionality: thiols (such as PhSH) must be added as HAT reagents, leading to an increase in byproducts (such as thioether compounds) and increased purification difficulty. Reagent compatibility is poor (thiols may poison metal catalysts or react with sensitive functional groups).

[0006] Third, the synthetic steps are uneconomical. Carboxylic acids must be pre-converted to acyl fluorides, adding at least one synthetic step, such as the prefunctionalization step of aromatic acids. Multi-catalyst synergy is costly: NHC, photocatalyst, and HAT reagent require precise proportions, making the operation complex and catalyst recovery difficult.

[0007] Fourth, insufficient functional group tolerance: Acyl fluorides readily undergo side reactions with nucleophilic groups such as amines and hydroxyl groups, limiting the later-stage modification of complex molecules (such as drugs). Poor selectivity of HAT reagents: Exogenous thiols may non-selectively seize other CH bonds (such as benzylic or α-carbonyl positions), reducing reaction efficiency. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention proposes a synthetic process for β,γ-unsaturated ketones. By reconstructing the catalytic system structure and utilizing a nickel-bromine synergistic radical mechanism to integrate HAT (Hydrogen-Acting-Active) and coupling functions, the structural defects of existing technologies are fundamentally resolved, providing a universal platform for directly constructing C-C bonds from free carboxylic acids and alkenes.

[0009] To achieve the above objectives, the present invention provides the following technical solution:

[0010] This invention provides a synthetic process for β,γ-unsaturated ketone compounds, using allyl-containing olefins as starting materials, carboxylic acids as acylating agents, and dimethyl dicarbonate (DMDC) as dehydrating agents. The β,γ-unsaturated ketone compounds are obtained in a one-step reaction under 450-455 nm blue light irradiation in a composite catalyst system. The composite catalyst system is a complex of a photocatalyst, NiBr2·DME (ethylene glycol dimethyl ether nickel bromide), and 4,4'-di-tert-butyl-2,2'-bipyridine and ammonium chloride. The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6, with the following structural formula:

[0011] The structural formula of 4,4'-di-tert-butyl-2,2'-bipyridine is:

[0012] The reaction mechanism of this invention is as follows:

[0013] 1. Activation of carboxylic acid: Ni(0) reacts with carboxylic acid through a dehydrating agent to form an acyl electrophilic reagent, which is then oxidized and added to obtain Ni(II)-acyl intermediate (II).

[0014] 2. Cleavage of the allyl CH bond: Br - It is photo-oxidized to generate bromine radicals. Bromine radicals selectively abstract the allyl H of the alkene (preferably a less sterically hindered / high substitution site) to generate allyl radicals.

[0015] 3. Free radical capture and coupling: Ni(II)-acyl(II) captures allyl radicals to form Ni(III) intermediate (III). Reductive elimination produces β,γ-unsaturated ketones and Ni(I) intermediate (IV).

[0016] 4. Catalytic cycle closed loop: The photocatalyst reduces Ni(I) to Ni(0) to complete the cycle.

[0017] As a preferred embodiment of the present invention, the amount of NiBr2·DME added is 20 mol%.

[0018] As a preferred embodiment of the present invention, the amount of 4,4'-di-tert-butyl-2,2'-bipyridine added is 26 mol%.

[0019] As a preferred embodiment of the present invention, the amount of photocatalyst added is 1 mol%.

[0020] As an optional embodiment of the present invention, the carboxylic acid is selected from aliphatic acids, aromatic acids, heterocyclic acids, amino acids, or natural carboxylic acids.

[0021] As an optional embodiment of the present invention, the allyl-containing olefin is selected from cyclic olefins, acyclic olefins, tri / tetrasubstituted olefins, β-citronellol, or α-pinene.

[0022] It is evident that the synthesis process of this invention has the advantage of substrate universality.

[0023] As a preferred embodiment of the present invention, the solvent for the reaction is 0.05M isopropyl acetate; the reaction is carried out in an alkaline environment, wherein the alkaline environment is 1.5 equivalents of disodium hydrogen phosphate (Na2HPO4), and disodium hydrogen phosphate can optimize the reaction efficiency.

[0024] As a preferred embodiment of the present invention, the reaction time is 12 hours.

[0025] As a preferred embodiment of the present invention, the amount of dimethyl dicarbonate (DMDC) added is 1.5 equivalents, and the acid anhydride reacts rapidly with Ni(O) to generate Ni(II)-acyl species, thereby improving the reaction efficiency.

[0026] Compared with the prior art, the present invention has the following advantages and technical effects:

[0027] This invention, through nickel / photo-redox synergistic catalysis, achieves for the first time the p-allyl C(sp) group of carboxylic acids. 3 Direct acylation of the -H bond. The core breakthrough lies in: utilizing bromine radical-mediated HAT to achieve selective cleavage of the allylic CH bond; the dual role of the nickel catalyst: activating the carboxylic acid and capturing free radicals to complete C / C coupling; and establishing a modular synthetic platform, free of toxic reagents, providing an efficient and green synthetic route for complex molecules (such as diketone scaffolds). Future potential directions include the development of enantioselective versions and applications in polymer chemistry.

[0028] The synthetic process of this invention can be extended for various applications. For example, it can be extended to a diacylation strategy: a one-step synthesis of bis(β,γ-unsaturated ketones) from dicarboxylic acids and olefins (yield 50-67%); it can also be extended to a cascade reaction: the β,γ-unsaturated ketone product, as an olefin component, is acylated with a second carboxylic acid to construct complex molecules. Furthermore, it can be used for bioactive molecule modification: late-stage functionalization of artesunate (an antimalarial drug), oxaprazin (NSAID), etc. (yield 40-60%). Detailed Implementation

[0029] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0030] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0031] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0032] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0033] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0034] This invention provides a synthetic process for β,γ-unsaturated ketone compounds. Starting with an allyl-containing olefin, using a carboxylic acid as an acylating agent, and dimethyl dicarbonate (DMDC) as a dehydrating agent, the β,γ-unsaturated ketone compounds are obtained in a one-step reaction under 450-455 nm blue light irradiation in a composite catalyst system. The composite catalyst system is a complex of a photocatalyst, NiBr2·DME, and 4,4'-di-tert-butyl-2,2'-bipyridine and ammonium chloride. The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0035] With products For example, route A is used for preparation:

[0036]

[0037] Note: The amounts of raw materials added in Route A are calculated based on the starting compound 1a. For example, 1 mol% PC-1 means that the amount of PC-1 added is 1% of the amount of 1a; isopropyl acetate (0.05M) means that the amount of isopropyl acetate solvent added is based on making the molar concentration of 1a 0.05M; 1.5 equiv. disodium hydrogen phosphate means that the amount of disodium hydrogen phosphate added is 1.5 times the amount of 1a.

[0038] To discuss the feasibility of this synthetic route, comparative experiments were conducted in this embodiment of the invention. The experimental conditions and synthesis results are shown in Table 1.

[0039] Table 1

[0040]

[0041] Note: The structural formulas for PC-1 to PC-3 and L1 to L3 are as follows:

[0042]

[0043] Table 1 shows that using 20 mol% NiBr2·DME, 26 mol% 4,4'-di-tert-butyl-2,2-bipyridine (L1), and 1 mol% Ir[dF(CF3)ppy]z(tbbpy)PF6 (PC-1) under blue LED irradiation, with the addition of 1.5 equivalents of DMDC, 1.0 equivalents of NNaCl, and 1.5 equivalents of Na2HPO4 in the solvent iProAc, a 62% yield of the target product can be obtained. Among the several photocatalysts, only PC-1 and PC-3 can effectively catalyze the reaction, while the yields of other photocatalysts are negligible (numbers 1-4). The alkalis potassium carbonate, cesium carbonate, and 2,6-lutidine (numbers 5-7) significantly reduce or render the product undetectable, confirming that Na2HPO4 is the optimal choice. Evaluation of various solvents indicates that iPrOAc is superior to other solvents, possibly due to its better compatibility with the reaction system (numbers 8-10). Replacing L1 or NiBr-DME with other ligands / nickel sources significantly reduces the yield of the target compound, highlighting the crucial role of the catalyst (items 11-14). The omission of ammonium chloride leads to a decrease in yield, indicating that its addition can improve reaction efficiency. The reaction fails in the absence of a photocatalyst, nickel catalyst, or light (items 16-18), confirming the critical role of these factors.

[0044] Therefore, in the following examples, all products are prepared according to route A.

[0045] All raw materials used in this invention were purchased through conventional channels.

[0046] Example 1: Synthesis method of compound 4

[0047]

[0048] The raw materials used included PC-1 (3.6 mg, 0.003 mmol), L1 (20.9 mg, 0.078 mmol), Na2HPO4 (63.9 mg, 0.45 mmol), NH4Cl (16 mg, 0.3 mmol), NiBr2·DME (18.5 mg, 0.06 mmol), 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol), DMDC (48 μL, 0.45 mmol), a Teflon stir bar, cyclohexene (60.7 μL, 0.6 mmol), and isopropyl acetate (i-PrOAc) (6 mL). After reacting for 12 hours under blue light irradiation at 450-455 nm, the mixture was purified by silica gel short column chromatography using a 1:5 mixture of ethyl acetate and n-hexane as the eluent (25 mL). After concentration, the mixture was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 10:1) to finally obtain a colorless liquid product, namely compound 4 (43.9 mg, 0.18 mmol, yield 60%).

[0049] 1 H NMR (300MHz, CDCl3) δ7.22–7.16(m,1H),6.78–6.72(m,3H),5.89–5.83(m,1H),5.74–5.68(m,1H),3.79(s,3H),3 .11–3.05(m,1H),2.90–2.85(m,2H),2.81–2.76(m,2H),2.05–1.94(m,2H),1.85–1.66(m,3H),1.58–1.49(m,1H).

[0050] 13 C NMR (126MHz, CDCl3) δ211.1,159.8,143.1,130.4,129.6,124.1,120.9,114.3,111.5,55.3,49.2,42.3,30.0,24.9,24.8,20.9.

[0051] HRMS(ESI)calcd for C 16 H 21 O2 + [(M+H) + ]:calculated 245.1536,found245.1534.

[0052] Example 2: Synthesis method of compound 5

[0053]

[0054] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-(2-methylphenyl)propionic acid (49.2 mg, 0.3 mmol).

[0055] The final colorless liquid product was compound 5 (39.7 mg, 0.174 mmol, yield 58%).

[0056] 1 H NMR(300MHz, CDCl3)δ7.13(d,J=2.4Hz,4H),5.99–5.81(m,1H),5.78–5.68(m,1H),3.16–3.04(m,1H),2.9 2–2.85(m,2H),2.79–2.71(m,2H),2.31(s,3H),2.05–1.98(m,2H),1.85–1.68(m,3H),1.61–1.51(m,1H).

[0057] 13 C NMR (126MHz, CDCl3) δ211.3,139.5,136.1,130.4,130.4,128.8,126.4,126.2,124.1,49.2,41.0,27.3,24.9,24.8,20.9,19.4.

[0058] HRMS(ESI)calcd for C 16 H 21 O + [(M+H) + ]: calculated 229.1587, found 229.1581.

[0059] Example 3: Synthesis method of compound 6

[0060]

[0061] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-(4-methylphenyl)propionic acid (49.2 mg, 0.3 mmol).

[0062] The final colorless liquid product was compound 6 (43.8 mg, 0.192 mmol, yield 64%).

[0063] 1H NMR(300MHz, CDCl3)δ7.09(d,J=3.3Hz,4H),6.02–5.77(m,1H),5.76–5.66(m,1H),3.11–3.03(m,1H),2.8 9–2.83(m,2H),2.81–2.70(m,2H),2.31(s,3H),2.04–1.97(m,2H),1.83–1.68(m,3H),1.60–1.49(m,1H).

[0064] 13 C NMR (126MHz, CDCl3) δ211.2,138.3,135.6,130.2,129.2,128.4,128.3,124.1,49.2,42.6,29.6,24.9,24.8,21.1,20.9.

[0065] HRMS(ESI)calcd for C 16 H 20 ONa + [(M+Na) + ]:calculated 251.1406,found251.1388.

[0066] Example 4: Synthesis method of compound 7

[0067]

[0068] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-(3-methylphenyl)propionic acid (49.2 mg, 0.3 mmol).

[0069] The final product was a colorless liquid, product 7 (36.3 mg, 0.159 mmol, yield 53%).

[0070] 1 H NMR (300MHz, CDCl3) δ7.20–7.14(m,1H),7.03–6.96(m,3H),5.90–5.83(m,1H),5.74–5.69(m,1H),3.12–3.04(m, 1H),2.89–2.83(m,2H),2.81–2.75(m,2H),2.32(s,3H),2.05–1.97(m,2H),1.82–1.66(m,3H),1.59–1.50(m,1H).

[0071] 13C NMR (126MHz, CDCl3) δ211.2,141.4,138.2,130.3,129.3,128.5,126.9,125.4,124.2,49.2,42.47,29.9,24.9,24.8,21.5,20.9.

[0072] HRMS(ESI)calcd for C 16 H 21 O + [(M+H) + ]: calculated 229.1587, found 229.1582.

[0073] Example 5: Synthesis method of compound 8

[0074]

[0075] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-(3,4-dimethylphenyl)propionic acid (53.4 mg, 0.3 mmol).

[0076] The final product was a colorless liquid, product 8 (43.5 mg, 0.18 mmol, yield 60%).

[0077] 1 H NMR (300MHz, CDCl3) δ7.04 (d, J = 7.6Hz, 1H), 6.97–6.89 (m, 2H), 5.92–5.81 (m, 1H), 5.74–5.69 (m, 1H), 3.1–3. 05(m,1H),2.85–2.73(m,4H),2.23(d,J=2.9Hz,6H),2.04–1.97(m,2H),1.85–1.68(m,3H),1.63–1.58(m,1H).

[0078] 13 C NMR (126MHz, CDCl3) δ211.3,138.8,136.7,134.3,130.3,129.9,129.8,125.8,124.2,49.2,42.7,29.6,24.9,24.9,20.9,19.8,19.4.

[0079] HRMS(ESI)calcd for C 17 H 22 ONa + [(M+Na) +]:calculated 265.1563,found265.1557.

[0080] Example 6: Synthesis method of compound 9

[0081]

[0082] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3,4-dimethoxyhydrocinnamic acid (63.1 mg, 0.3 mmol).

[0083] The final product was a colorless liquid, product 9 (50.1 mg, 0.183 mmol, yield 61%).

[0084] 1 H NMR (300MHz, CDCl3) δ6.78(d,J=8.7Hz,1H),6.71(dd,J=5.5,2.0Hz,2H),6.06–5.79(m,1H),5.76–5.64(m,1H),3.85(d,J=4. 2Hz,6H),3.11–3.03(m,1H),2.87–2.81(m,2H),2.81–2.70(m,2H),2.05–1.95(m,2H),1.80–1.68(m,3H),1.59–1.48(m,1H).

[0085] 13 C NMR (126MHz, CDCl3) δ211.3,148.9,147.4,134.1,130.3,124.1,120.3,111.9,111.5,56.1,55.9,49.2,42.6,29.6,24.8,24.8,20.9.

[0086] HRMS(ESI)calcd for C 17 H 22 O3Na + [(M+Na) + ]:calculated 297.1461,found297.1451.

[0087] Example 7 Synthesis of Compound 10

[0088]

[0089] Based on Example 1, the starting material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the starting material 3-(3,5-dimethylphenyl)propionic acid (53.4 mg, 0.3 mmol), and finally a colorless liquid product 10 (40.7 mg, 0.168 mmol, yield 56%) was obtained.

[0090] 1 H NMR(300MHz, CDCl3)δ6.82(d,J=9.4Hz,3H),5.99–5.80(m,1H),5.75–5.69(m,1H),3.12–3.04(m ,1H),2.85–2.73(m,4H),2.28(s,6H),2.04–1.97(m,2H),1.83–1.67(m,3H),1.60–1.54(m,1H).

[0091] 13 C NMR (126MHz, CDCl3) δ211.3,141.4,138.1,130.3,127.8,126.3,124.2,49.2,44.8,42.6,29.9,24.9,24.9,21.4,20.9.

[0092] HRMS(ESI)calcd for C 17 H 23 O + [(M+H) + ]: calculated 243.1743, found 243.1739.

[0093] Example 8 Synthesis of Compound 11

[0094]

[0095] Based on Example 1, the starting material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the starting material 3-phenylpropionic acid (45.1 mg, 0.3 mmol), and finally a colorless liquid product 11 (34.6 mg, 0.162 mmol, yield 54%) was obtained.

[0096] 1H NMR(300MHz, CDCl3)δ7.29(d,J=7.5Hz,2H),7.23–7.14(m,3H),5.94–5.80(m,1H),5.77–5.63(m,1H),3.13– 3.03(m,1H),2.94–2.86(m,2H),2.85–2.71(m,2H),2.06–1.95(m,2H),1.83–1.66(m,3H),1.57–1.49(m,1H).

[0097] 13 C NMR (126MHz, CDCl3) δ211.1,141.5,130.4,128.6,128.5,126.2,124.1,49.2,42.4,29.9,24.9,24.8,20.9.

[0098] HRMS(ESI)calcd for C 15 H 19 O + [(M+H) + ]: calculated 215.1430, found 215.1426.

[0099] Example 9 Synthesis of Compound 12

[0100]

[0101] Based on Example 1, the starting material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the starting material 3-(4-ethylphenyl)propionic acid (53.4 mg, 0.3 mmol), and finally a colorless liquid product 12 (42.8 mg, 0.177 mmol, yield 59%) was obtained.

[0102] 1 H NMR(300MHz, CDCl3) δ7.11(d,J=3.8Hz,4H),5.99–5.80(m,1H),5.78–5.61(m,1H),3.16–3.02(m,1H),2.91–2.7 4(m,4H),2.61(d,J=7.7Hz,2H),2.07–1.93(m,2H),1.82–1.67(m,3H),1.57–1.46(m,1H),1.22(t,J=7.8Hz,3H).

[0103] 13C NMR (126MHz, CDCl3) δ211.1,141.9,138.3,130.1,128.2,127.8,123.9,48.9,42.3,29.3,28.3,24.7,24.6,20.7,15.5.

[0104] HRMS(ESI)calcd for C 17 H 23 O + [(M+H) + ]: calculated 243.1743, found 243.1726.

[0105] Example 10 Synthesis of Compound 13

[0106]

[0107] Based on Example 1, the starting material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the starting material 3-(4-tert-butylphenyl)propionic acid (61.8 mg, 0.3 mmol). The final product was a colorless liquid, product 13 (54.3 mg, 0.20 mmol, yield 67%).

[0108] 1 H NMR (300MHz, CDCl3) δ7.30(d,J=8.3Hz,2H),7.12(d,J=8.4Hz,2H),5.93–5.80(m,1H),5.78–5.64(m,1H),3.15–3.04(m,1H ),2.87(dd,J=10.4,6.7Hz,2H),2.83–2.72(m,2H),2.05–1.97(m,2H),1.84–1.66(m,3H),1.58–1.51(m,1H),1.30(s,9H).

[0109] 13 C NMR (126MHz, CDCl3) δ211.3,149.0,138.3,130.3,128.1,125.5,124.2,49.2,42.4,34.5,31.5,29.4,24.9,24.9,20.9.

[0110] HRMS(ESI)calcd for C 19 H 26 O + [(M+H) + ]: calculated 271.2056, found 271.2051.

[0111] Example 11 Synthesis of Compound 14

[0112]

[0113] Based on Example 1, the starting material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the starting material 4-(4-biphenyl)butyric acid (72.1 mg, 0.3 mmol). The final product was a colorless liquid, product 14 (63.8 mg, 0.21 mmol, yield 70%).

[0114] 1 H NMR (300MHz, CDCl3) δ7.58(d,J=7.0Hz,2H),7.52(d,J=8.2Hz,2H),7.43(t, J=7.4Hz,2H),7.32(t,J=7.3Hz,1H),7.23(d,J=7.8Hz,2H),5.94–5.80(m,1H ),5.72(dd,J=10.3Hz,1H),3.12–3.06(m,1H),2.66(t,J=7.6Hz,2H),2.53(t ,J=7.3Hz,2H),2.08–1.89(m,4H),1.85–1.68(m,3H),1.61(d,J=6.4Hz,1H).

[0115] 13 C NMR (126MHz, CDCl3) δ211.9,141.2,140.9,139.0,130.3,129.0,128.9,127.3,127.2,127.1,124.3,49.1,39.9,34.9,25.3,24.9,24.9,21.0.

[0116] HRMS(ESI)calcd for C 24 H 24 ONa + [(M+Na) + ]:calculated 327.1719,found327.1713.

[0117] Example 12 Synthesis of Compound 15

[0118]

[0119] Based on Example 1, the starting material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the starting material 3-(3-chlorophenyl)propionic acid. The final product was a colorless liquid, product 15 (52.1 mg, 0.21 mmol, yield 70%).

[0120] 1 H NMR (300MHz, CDCl3) δ7.19–7.16(m,3H),7.09–7.05(m,1H),5.93–5.81(m,1H),5.77–5.64(m,1H),3.10–3. 04(m,1H),2.90–2.83(m,2H),2.83–2.70(m,2H),2.04–1.97(m,2H),1.83–1.68(m,3H),1.59–1.51(m,1H).

[0121] 13 C NMR (126MHz, CDCl3) δ210.7,143.5,134.3,130.5,129.9,128.6,126.8,126.4,124.0,49.2,42.0,29.6,24.9,24.8,20.9.

[0122] HRMS(ESI)calcd for C 15 H 18 ClO + [(M+H) + ]:calculated 249.1041,found249.1037.

[0123] Example 13 Synthesis of Compound 16

[0124]

[0125] Based on Example 1, the starting material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the starting material 4-chlorophenylpropionic acid. The final product was a colorless liquid product 16 (52.1 mg, 0.21 mmol, yield 55%).

[0126] 1 H NMR (300MHz, CDCl3) δ7.23(d,J=8.4Hz,2H),7.11(d,J=8.3Hz,2H),5.96–5.80(m,1H),5.74–5.65(m,1H),3.12– 3.01(m,1H),2.92–2.84(m,2H),2.79–2.74(m,2H),2.00(d,J=3.2Hz,2H),1.79–1.66(m,3H),1.59–1.50(m,1H).

[0127] 13C NMR (126MHz, CDCl3) δ210.8,139.9,132.0,130.5,129.9,128.7,124.0,49.2,42.1,29.2,24.9,24.8,20.9.

[0128] HRMS(ESI)calcd for C 15 H 18 ClO + [(M+H) + ]:calculated 249.1041,found249.1031.

[0129] Example 14 Compound 17

[0130]

[0131] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 4-fluorophenylpropionic acid (50.4 mg, 0.3 mmol).

[0132] After concentration, the mixture was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 15 / 1) to finally obtain colorless liquid product 17 (49.4 mg, 0.21 mmol, yield 71%).

[0133] 1 H NMR (300MHz, CDCl3) δ7.19–7.13(m,2H),7.01–6.94(m,2H),5.90–5.83(m,1H),5.72–5.66(m,1H),3.11–3. 02(m,1H),2.90-2.85(m,2H),2.80–2.74(m,2H),2.03–1.97(m,2H),1.81–1.65(m,3H),1.58–1.50(m,1H).

[0134] 13 C NMR (126MHz, CDCl3) δ210.9,162.5,137.1,137.1,130.4,130.0,129.9,124.0,115.4,115.3,49.2,42.4,29.1,24.9,24.8,20.9.

[0135] 19 F NMR (471MHz, CDCl3) δ-117.38.

[0136] HRMS(ESI)calcd for C15 H 17 FO + [(M+H) + ]:calculated 233.1336,found233.1354.

[0137] Example 15 Compound 18

[0138]

[0139] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material m-fluorophenylpropionic acid (50.4 mg, 0.3 mmol).

[0140] After concentrating the mixture, the residue was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 15 / 1) to finally obtain colorless liquid product 18 (44.6 mg, 0.192 mmol, yield 64%).

[0141] 1 H NMR (300MHz, CDCl3) δ7.25–7.16(m,1H),6.99–6.83(m,3H),5.90–5.83(m,1H),5.73–5.68(m,1H),3.11–3. 04(m,1H),2.94–2.86(m,2H),2.82–2.76(m,2H),2.04–1.97(m,2H),1.84–1.65(m,3H),1.63–1.57(m,1H).

[0142] 13 C NMR (126MHz, CDCl3) δ210.7,164.0,162.1,144.0,130.5,130.1,130.0,124.2,12 4.2,124.0,115.5,115.3,113.2,113.0,49.2,42.0,29.6,29.6,24.9,24.8,20.9.

[0143] 19 F NMR (471MHz, CDCl3) δ-113.6.

[0144] HRMS(ESI)calcd for C 15 H 17 FONa + [(M+Na) + ]:calculated 255.1156,found255.1148.

[0145] Example 16 Compound 19

[0146]

[0147] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-(4-(methoxycarbonyl)phenyl)propionic acid (62.4 mg, 0.3 mmol).

[0148] After concentration, the mixture was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 8:1) to finally obtain colorless liquid product 19 (54.1 mg, 0.189 mmol, yield 63%).

[0149] 1 H NMR (300MHz, CDCl3) δ7.94(d,J=8.3Hz,2H),7.25(d,J=7.7Hz,2H),5.99–5.78(m,1H),5.77–5.59(m,1H),3.90(s,3H ),3.11–3.03(m,1H),2.99–2.91(m,2H),2.87–2.74(m,2H),2.05–1.95(m,2H),1.82–1.66(m,3H),1.59–1.49(m,1H).

[0150] 13 C NMR (126MHz, CDCl3) δ210.6,167.2,147.0,130.5,130.0,129.9,128.6,128.6,128.2,123.9,52.2,49.2,41.8,29.9,24.9,24.8,20.9.

[0151] HRMS(ESI)calcd for C 18 H 23 O3 + [(M+H) + ]:calculated 287.1642,found287.1648.

[0152] Example 17 Compound 20

[0153]

[0154] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 5-oxo-5-phenylpentanoic acid (57.6 mg, 0.3 mmol).

[0155] After concentrating the mixture, the residue was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 5:1) to finally obtain colorless liquid product 20 (46.1 mg, 0.18 mmol, yield 60%).

[0156] 1 H NMR (300MHz, CDCl3) δ7.98–7.94(m,2H),7.59–7.53(m,1H),7.45(t,J=7.4Hz,2H),5.98–5.81(m,1H),5.75–5.71(m,1H), 3.16–3.06(m,1H),3.01(t,J=7.0Hz,2H),2.62(t,J=6.9Hz,2H),2.07–1.97(m,4H),1.86–1.69(m,3H),1.61–1.53(m,1H).

[0157] 13 C NMR (126MHz, CDCl3) δ211.8,200.1,137.0,133.2,130.3,128.7,128.2,124.2,49.1,39.6,37.7,25.0,24.9,21.0,18.5.

[0158] HRMS(ESI)calcd for C 17 H 20 O2Na + [(M+Na) + ]: calculated 293.1512, found293.1519.

[0159] Example 18 Synthesis of Compound 21

[0160]

[0161] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-(2-naphthyl)propionic acid (60.3 mg, 0.3 mmol).

[0162] After concentrating the product, the residue was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 10:1) to finally obtain product 21 (49.1 mg, 0.186 mmol, yield 62%), which was a colorless liquid.

[0163] 1H NMR (300MHz, CDCl3) δ8.00(d,J=8.1Hz,1H),7.86(d,J=7.4Hz,1H),7.72(d,J=8.0Hz,1H),7.58–7.44(m,2H),7.43–7.30(m,2H),5.97–5.79(m,1H), 5.76–5.60(m,1H),3.44–3.30(t,J=6.6Hz,2H),3.12–3.06(m,1H),2.92( t,J=8.1Hz,2H),2.08–1.91(m,2H),1.84–1.65(m,3H),1.56–1.49(m,1H).

[0164] 13 C NMR (126MHz, CDCl3) δ211.2,137.5,134.1,131.8,130.4,129.0,127.1,126 .2,126.2,125.8,125.7,124.1,123.6,49.3,41.7,27.1,24.9,24.9,20.9.

[0165] HRMS(ESI)calcd for C 19 H 20 ONa + [(M+Na) + ]: calculated 287.1406, found287.1403.

[0166] Example 19 Synthesis of Compound 22

[0167]

[0168] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-(2-furanyl)propionic acid (42.0 mg, 0.3 mmol).

[0169] The final product was a colorless liquid, 22 (37.9 mg, 0.186 mmol, yield 62%).

[0170] 1H NMR(300MHz, CDCl3)δ7.28(d,J=2.8Hz,1H),6.27–6.25(m,1H),6.01–5.97(m,1H),5.95–5.85(m,1H),5.80–5.70(m,1H) ,3.17–3.09(m,1H),2.94–2.89(m,2H),2.89–2.75(m,2H),2.05(d,J=8.7Hz,2H),1.88–1.69(m,3H),1.59–1.51(m,1H).

[0171] 13 C NMR (126MHz, CDCl3) δ210.6,154.9,141.2,130.4,124.0,110.3,105.3,49.1,38.9,24.9,24.9,22.4,20.9.

[0172] HRMS(ESI)calcd for C 13 H 16 O2Na + [(M+Na) + ]:calculated 241.1199,found241.1196.

[0173] Example 20 Synthesis of Compound 23

[0174]

[0175] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 4-(2-thienyl)butyric acid (51.0 mg, 0.3 mmol).

[0176] The final product was a colorless liquid, 23 (34.2 mg, 0.201 mmol, yield 67%).

[0177] 1 H NMR (300MHz, CDCl3) δ7.13–7.11(m,1H),6.93–6.90(m,1H),6.79–6.77(m,1H),5.90–5.83(m,1H),5.74–5.68(m,1H),3. 12–3.06(m,1H),2.85(t,J=7.4Hz,2H),2.53(t,J=7.2Hz,2H),2.05–1.93(m,4H),1.82–1.69(m,3H),1.62–1.54(m,1H).

[0178] 13C NMR (126MHz, CDCl3) δ211.6,144.6,130.3,126.9,124.6,124.2,123.3,49.1,39.5,29.3,25.7,25.0,24.9,21.0.

[0179] HRMS(ESI)calcd for C 14 H 18 OSNa + [(M+Na) + ]:calculated 234.1078,found234.1081.

[0180] Example 21 Synthesis of Compound 24

[0181]

[0182] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-{1-[(tert-butoxy)carbonyl]-1H-indole-3-yl}propionic acid (86.7 mg, 0.3 mmol).

[0183] After concentration, the resulting mixture was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 5:1) to finally obtain colorless liquid product 24 (70.9 mg, 0.201 mmol, yield 67%).

[0184] 1 H NMR(500MHz, CDCl3)δ8.12(s,1H),7.52(d,J=7.7Hz,1H),7.35(s,1H),7.31(t,J=7.1Hz,1H),7.26–7.21(m,1H),5.99–5.81(m,1H),5.78–5 .69(m,1H),3.15–3.08(m,1H),3.00–2.95(m,2H),2.92–2.83(m,2H), 2.04–1.98(m,2H),1.84–1.70(m,3H),1.66(s,9H),1.60–1.54(m,1H).

[0185] 13 C NMR (126MHz, CDCl3) δ211.1,149.9,135.7,130.5,130.4,124.5,124.1,122.6 ,122.5,120.13,119.0,115.4,83.6,49.2,40.2,28.4,24.9,24.9,20.9,19.1.

[0186] HRMS(ESI)calcd for C 22 H 27 NO3Na + [(M+Na) + ]:calculated 376.1883,found376.1875.

[0187] Example 22 Synthesis of Compound 25

[0188]

[0189] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3,3-diphenylpropionic acid (67.8 mg, 0.3 mmol).

[0190] The final product was a colorless liquid, 25 (34.8 mg, 0.12 mmol, yield 40%).

[0191] 1 H NMR (300MHz, CDCl3) δ7.29–7.16(m,10H),5.95–5.76(m,1H),5.71–5.56(m,1H),4.65(t,J=7.4Hz,1 H),3.32–3.14(m,2H),3.05–2.95(m,1H),2.02–1.92(m,2H),1.76–1.59(m,3H),1.55–1.46(m,1H).

[0192] 13 C NMR (126MHz, CDCl3) δ209.8,144.2,130.4,128.7,128.0,127.9,126.5,123.9,49.5,46.9,45.9,24.9,24.6,20.9.

[0193] HRMS(ESI)calcd for C 21 H 22 ONa + [(M+Na) + ]:calculated 313.1563,found313.1558.

[0194] Example 23 Synthesis of Compound 26

[0195]

[0196] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 4-(Boc-amino)cyclohexaneacetic acid (77.2 mg, 0.3 mmol).

[0197] The final product was a colorless liquid, 26 (38.5 mg, 0.12 mmol, yield 40%).

[0198] 1 H NMR (300MHz, CDCl3) δ5.99–5.80(m,1H),5.75–5.54(m,1H),4.60(s,1H),3.71(s,1H),3.17–2.94(m,1H),2.4 0(d,J=6.8Hz,2H),2.04–1.99(m,2H),1.82–1.72(m,2H),1.71–1.49(m,9H),1.44(s,9H),1.25–1.15(m,2H).

[0199] 13 C NMR (126MHz, CDCl3) δ211.4,130.4,124.1,60.6,58.6,49.6,29.8,28.6,24.9,24.9,21.2,21.0,18.6,14.3.

[0200] HRMS(ESI)calcd for C 19 H 31 NO3Na + [(M+Na) + ]:calculated 344.2196,found344.2192.

[0201] Example 24 Synthesis of Compound 27

[0202]

[0203] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material Boc-7-aminoheptanoic acid (73.6 mg, 0.3 mmol).

[0204] The final product was a colorless liquid, 27 (32.4 mg, 0.105 mmol, yield 35%).

[0205] 1H NMR (300MHz, CDCl3) δ5.88–5.82(m,1H),5.74–5.67(m,1H),4.53(s,1H),3.11–3.04(m,3H),2.45(t,J =7.3Hz,2H),2.03–1.96(m,2H),1.92–1.63(m,4H),1.63–1.47(m,4H),1.42(s,9H),1.32–1.25(m,4H).

[0206] 13 C NMR (126MHz, CDCl3) δ212.2,156.1,130.1,124.3,79.1,49.0,40.6,40.5,30.0,29.0,28.5,26.7,24.9,24.9,23.7,20.9.

[0207] HRMS(ESI)calcd for C 18 H 31 NO3Na + [(M+Na) + ]:calculated 332.2196,found332.2191.

[0208] Example 25 Synthesis of Compound 28

[0209]

[0210] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material monoethyl adipate (53 μL, 0.3 mmol).

[0211] After concentration, the product was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 15 / 1) to finally obtain colorless liquid product 28 (30.7 mg, 0.129 mmol, yield 43%).

[0212] 1 H NMR (300MHz, CDCl3) δ5.91–5.84(m,1H),5.75–5.69(m,1H),4.12(q,J=7.1Hz,2H),3.14–3.05(m,1H),2.52–2. 47(m,2H),2.33–2.28(m,2H),2.08–1.93(m,2H),1.87–1.67(m,3H),1.66–1.58(m,5H),1.25(t,J=7.1Hz,3H).

[0213] 13 C NMR (126MHz, CDCl3) δ211.7,173.6,130.3,124.2,60.4,49.1,40.2,34.3,24.9,24.9,24.7,23.4,21.0,14.4.

[0214] HRMS(ESI)calcd for C 14 H 23 O3 + [(M+H) + ]:calculated 239.1642,found245.1649.

[0215] Example 26 Synthesis of Compound 29

[0216]

[0217] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material monotert-butyl succinate.

[0218] The final product was a colorless liquid, 29 (42.8 mg, 0.18 mmol, yield 60%).

[0219] 1 H NMR (300MHz, CDCl3) δ6.02–5.81(m,1H),5.79–5.73(m,1H),3.18–3.10(m,1H),2.80–2.69(m, 2H),2.53–2.46(m,2H),2.05–1.97(m,2H),1.88–1.69(m,3H),1.60–1.52(m,1H),1.43(s,9H).

[0220] 13 C NMR (126MHz, CDCl3) δ210.3,172.3,130.3,124.2,48.9,35.4,29.4,28.2,25.0,24.9,21.0.

[0221] HRMS(ESI)calcd for C 14 H 22 O3Na + [(M+Na) + ]:calculated 261.1461,found261.1458.

[0222] Example 27 Synthesis of Compound 30

[0223]

[0224] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 3-cyclopentylpropionic acid (43 μL, 0.3 mmol).

[0225] After concentrating the product, the residue was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 30 / 1) to finally obtain colorless liquid product 30 (37.1 mg, 0.18 mmol, yield 60%).

[0226] 1 H NMR (300MHz, CDCl3) δ5.90–5.83(m,1H),5.75–5.70(m,1H),3.15–3.05(m,1H),2.50(d,J=7.6Hz,2H) ,2.30–2.17(m,2H),2.00(d,J=6.6Hz,2H),1.87–1.74(m,6H),1.65–1.57(m,5H),1.08–1.03(m,2H).

[0227] 13 C NMR (126MHz, CDCl3) δ212.2,130.1,124.4,49.5,49.2,47.0,35.7,35.6,32.8,25.1,25.0,21.0.

[0228] HRMS(ESI)calcd for C 14 H 23 O + [(M+H) + ]: calculated 207.1743, found 207.1750.

[0229] Example 28 Synthesis of Compound 31

[0230]

[0231] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 6-chlorohexanoic acid (45.1 mg, 0.3 mmol).

[0232] The final product was a colorless liquid, product 31 (39.1 mg, 0.183 mmol, yield 61%).

[0233] 1H NMR (300MHz, CDCl3) δ5.91–5.84(m,1H),5.75–5.70(m,1H),3.53(t,J=6.7Hz,2H),3.13–3.06(m,1H) ,2.50(t,J=7.2Hz,2H),2.05–1.98(m,2H),1.85–1.71(m,5H),1.58–1.55(m,3H),1.47–1.39(m,2H).

[0234] 13 C NMR (126MHz, CDCl3) δ211.8,130.2,124.1,49.0,44.9,40.3,32.4,26.5,24.8,24.8,23.0,20.9.

[0235] HRMS(ESI)calcd for C 12 H 19 ClO2Na + [(M+Na) + ]: calculated 237.1017, found 237.1011. Example 29 Synthesis of compound 32

[0236]

[0237] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material oleic acid (95 μL, 0.3 mmol).

[0238] The final product was 32 (41.5 mg, 0.12 mmol, yield 40%), a colorless liquid.

[0239] 1 H NMR (300MHz, CDCl3) δ5.93–5.81(m,1H),5.77–5.69(m,1H),5.39–5.33(m,2H),3.15–3.05(m,1H),2.46(t ,J=7.4Hz,2H),2.02–1.93(m,6H),1.84–1.69(m,3H),1.63–1.55(m,3H),1.31–1.25(m,20H),0.87(m,3H).

[0240] 13C NMR (126MHz, CDCl3) δ212.3,130.6,130.4,130.1,124.4,49.1,40.7,32.7,32.7,32. 0,29.9,29.8,29.7,29.6,29.5,29.4,29.3,29.1,27.4,25.0,24.0,22.8,21.0,14.2.

[0241] HRMS(ESI)calcd for C 24 H 42 ONa + [(M+Na) + ]:calculated 369.3128,found369.3119.

[0242] Example 30 Synthesis of Compound 33

[0243]

[0244] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material stearic acid (85.3 mg, 0.3 mmol).

[0245] After concentrating the mixture, the residue was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (PE / EA=20 / 1) to finally obtain colorless liquid product 33 (59.5 mg, 0.171 mmol, yield 57%).

[0246] 1 H NMR (300MHz, CDCl3) δ5.91–5.83(m,1H),5.77–5.69(m,1H),3.15–3.05(m,1H),2.46(t,J=7.4 Hz,2H),2.05–1.98(m,2H),1.84–1.69(m,3H),1.64–1.55(m,3H),1.25(m,28H),0.88(s,3H).

[0247] 13 C NMR (126MHz, CDCl3) δ212.4,130.1,124.4,49.1,40.8,32.1,29.8,29.8,29.8,29.8,29.6,29.6,29.5,29.5,25.0,24.9,24.0,22.8,21.0,14.3.

[0248] HRMS(ESI)calcd for C 24 H 45O + [(M+H) + ]: calculated 349.3465, found 349.3457.

[0249] Example 31 Synthesis of Compound 34

[0250]

[0251] Based on Example 1, the raw material 3-(3-methoxyphenyl)propionic acid (54 mg, 0.3 mmol) was replaced with the raw material 4-(4-methoxyphenyl)butyric acid (58.2 mg, 0.3 mmol); and the raw material cyclohexene (61 μL, 0.6 mmol) was replaced with cyclopentene (53.0 μL, 0.6 mmol).

[0252] The final product was a colorless liquid, 34 (49.8 mg, 0.204 mmol, yield 68%).

[0253] 1 H NMR(300MHz, CDCl3)δ7.08(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),6.00–5.84(m,1H),5.75–5.63(m,1H),3 .79(s,3H),3.61–3.54(m,1H),2.59–2.53(m,2H),2.49–2.31(m,4H),2.10–2.00(m,2H),1.93–1.83(m,2H).

[0254] 13 C NMR (126MHz, CDCl3) δ211.6,158.0,134.4,133.9,129.5,128.6,113.9,58.9,55.4,40.1,34.3,32.4,25.63,25.5.

[0255] HRMS(ESI)calcd for C 16 H 21 O2 + [(M+H) + ]:calculated 245.1536,found245.1531.

[0256] Example 32 Synthesis of Compound 35

[0257]

[0258] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material 4-methyl-1-cyclohexene (73 μL, 0.6 mmol).

[0259] The final product was a colorless liquid, 35 (50.6 mg, 0.186 mmol, yield 62%).

[0260] 1 H NMR(300MHz, CDCl3)δ7.09(d,J=8.3Hz,2H),6.82(d,J=8.6Hz,2H),5.87–5.61(m,1H),5.77–5.60(m,1H),3.79(s,3H),3.12–2.95(m,1 H),2.56(t,J=7.6Hz,2H),2.48(m,2H),2.22–2.06(m,1H),1.94–1.80(m,3H),1.75–1.59(m,2H),1.35–1.24(m,1H),1.00–0.91(m,3H).

[0261] 13 C NMR(126MHz,Chloroform-d)δ212.35,211.35,157.84,133.80,129.93,129.79,129.36,129.35,123.51,123.37,113.78,57. 79,55.27,50.74,48.09,40.16,40.10,34.26,34.23,33.24,31.68,29.67,28.98,25.52,25.47,25.36,24.38,21.42,20.30.

[0262] HRMS(ESI)calcd for C 18 H 25 O2 + [(M+H) + ]: calculated 273.1849, found273.1844.

[0263] Example 33 Synthesis of Compound 36

[0264]

[0265] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material cycloheptene (70.0 μL, 0.6 mmol).

[0266] The final product was a colorless liquid, 36 (35.1 mg, 0.129 mmol, yield 43%).

[0267] 1 H NMR(300MHz, CDCl3)δ7.09(d,J=8.6Hz,2H),6.82(d,J=8.7Hz,2H),6.05–5.84(m,1H),5.83–5.74(m,1H),3.79(s,3H),3.33–3.20(m,1H),2.59 –2.53(m,2H),2.50–2.44(m,2H),2.23–2.07(m,2H),2.04–1.96(m,1H) ,1.88(s,2H),1.83–1.74(m,1H),1.72–1.60(m,2H),1.55–1.33(m,2H).

[0268] 13 C NMR (126MHz, CDCl3) δ212.1,158.0,133.9,133.8,130.1,129.5,113.9,55.4,53.4,40.2,34.4,30.5,29.6,28.7,26.6,25.7.

[0269] HRMS(ESI)calcd for C 18 H 25 O2 + [(M+H) + ]:calculated 273.1849,found273.1839.

[0270] Example 34 Synthesis of Compound 37

[0271]

[0272] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material cyclooctene (78 μL, 0.6 mmol).

[0273] The final product was a colorless liquid, 37 (46.3 mg, 0.162 mmol, yield 54%).

[0274] 1H NMR(300MHz, CDCl3)δ7.09(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),5.89–5.69(m,1H),5.63–5.46(m,1H),3.79(s,3H),3.52–3.44(m,1H),2 .55(t,J=7.6Hz,2H),2.47(t,J=7.3Hz,2H),2.24–2.06(m,2H),1.92–1.82(m,2H),1.74–1.69(m,2H),1.59–1.51(m,2H),1.46–1.24(m,4H).

[0275] 13 C NMR (126MHz, CDCl3) δ212.7,158.0,133.9,131.9,129.5,127.8,113.9,55.4,49.9,41.0,34.4,32.1,29.4,26.8,26.6,25.6,25.4.

[0276] HRMS(ESI)calcd for C 19 H 27 O2Na + [(M+Na) + ]:calculated 309.1819,found309.1825.

[0277] Example 35 Synthesis of Compound 38

[0278]

[0279] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material cyclohexene (78 μL, 66.1 mg, 0.6 mmol).

[0280] The final product was a colorless liquid, 38 (42.6 mg, 0.15 mmol, yield 50%).

[0281] 1 H NMR (300MHz, CDCl3) δ7.09(d,J=8.5Hz,2H),6.83(d,J=8.6Hz,2H),5.75–5.67(m,1H),5.59–5.41(m,3H),3.79(s,3H ),3.68–3.60(m,1H),2.73–2.62(m,1H),2.59–2.47(m,5H),2.44–2.38(m,1H),2.36–2.25(m,3H),1.93–1.84(m,2H).

[0282] 13 C NMR (126MHz, CDCl3) δ210.9,1580,133.8,131.4,129.5,129.5,127.0,126.4,113.9,55.4,52.7,40.8,34.3,29.9,28.0,27.6,25.6.

[0283] HRMS(ESI)calcd for C 19 H 24 O2Na + [(M+Na) + ]:calculated 307.1669, found307.1661.

[0284] Example 36 Synthesis of Compound 39

[0285]

[0286] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material 1-cyclodocosahexene (115 μL, 0.6 mmol).

[0287] The final product was a colorless liquid, 39 (41.0 mg, 0.12 mmol, yield 40%).

[0288] 1 H NMR (300MHz, CDCl3) δ7.07(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),5.59–5.47(m,1H),5.35–5.26(m,1H),3.78(s,3H),3.06–2. 98(m,1H),2.55–2.50(m,2H),2.47–2.39(m,2H),2.26–2.16(m,1H),1.92–1.79(m,3H),1.51–1.43(m,3H),1.36–1.19(m,13H).

[0289] 13 C NMR (126MHz, CDCl3) δ212.0,157.9,135.2,133.9,129.5,128.7,113.8,56.9, 55.3,40.4,34.3,32.5,28.6,26.3,26.0,25.5,25.0,24.8,24.7,24.6,24.2.

[0290] HRMS(ESI)calcd for C23 H 34 O2 + [(M+H) + ]:calculated 343.2632,found343.2625.

[0291] Example 37 Synthesis of Compound 40

[0292]

[0293] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material trans-2-pentene (65 μL, 0.6 mmol).

[0294] The final product was a colorless liquid, 40 (44.3 mg, 0.18 mmol, yield 60%).

[0295] 1 H NMR(500MHz, CDCl3)δ7.07(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),5.60–5.52(m,1H),5.39–5.34(m,1H),3.78(s,3H),3.14–3.08 (m,1H),2.56–2.51(m,2H),2.50–2.45(m,1H),2.43–2.36(m,1H),1.85(q,J=7.4Hz,2H),1.68–1.65(m,3H),1.12(d,J=6.9Hz,3H).

[0296] 13 C NMR (126MHz, Chloroform-d) δ212.07,157.83,133.84,130.38,129.36,127.73,113.76,55.24,50.38,39.73,34.18,25.41,18.02,16.23.

[0297] HRMS(ESI)calcd for C 16 H 23 O2 + [(M+H) + ]:calculated 247.1693,found274.1682.

[0298] Example 38 Synthesis of Compound 41

[0299]

[0300] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material trans-4-methyl-2-pentene (74 μL, 0.6 mmol).

[0301] The final product was a colorless liquid, 41 (39.0 mg, 0.15 mmol, yield (total yield of both isomers) 50%).

[0302] 1 H NMR (300MHz, CDCl3) δ7.08(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),5.53–5.44(m,1.7H),5.40–5.38(m,0.3H),3.79(s,3H),3.13(d,J=5.6Hz ,0.3H),3.05(d,J=5.6Hz,1.7H),2.55(t,J=7.6Hz,2H),2.42(t,J=7.3Hz,2H),2.33–2.22(m,1H),1.90–1.80(m,2H),0.97(d,J=6.7Hz,6H).

[0303] 13 C NMR (126MHz, CDCl3) δ209.6,158.0,142.3,133.9,129.5,119.1,113.9,55.4,47.0,41.3,34.3,31.2,25.5,22.5.

[0304] HRMS(ESI)calcd for C 17 H 25 O2 + [(M+H) + ]: calculated 261.1849, found261.1844.

[0305] Example 39 Synthesis of Compound 42

[0306]

[0307] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material trans-β-methylstyrene (78 μL, 0.6 mmol).

[0308] The final product was a colorless liquid, 42 (47.6 mg, 0.162 mmol, yield 54%).

[0309] 1H NMR (300MHz, CDCl3) δ7.37–7.30(m,4H),7.24–7.19(m,1H),7.07(d,J=8.6Hz,2H),6.81(d,J=8.6Hz,2H),6.45(d,J=15.9Hz,1H ), 6.33–6.25(m,1H),3.78(s,3H),3.28(dd,J=7.0,1.3Hz,2H),2.58(d,J=7.5Hz,2H),2.49(t,J=7.3Hz,2H),1.93–1.87(m,2H).

[0310] 13 C NMR (126MHz, CDCl3) δ208.7,158.0,137.1,133.8,133.7,129.5,128.7,127.7,126.4,122.2,114.0,55.4,47.2,41.6,34.2,29.9,25.5.

[0311] HRMS(ESI)calcd for C 20 H 22 O2 + [(M+H) + ]:calculated 295.1693,found295.1683.

[0312] Example 40 Synthesis of Compound 43

[0313]

[0314] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material 2,2,4-trimethyl-3-pentene (94 μL, 0.6 mmol).

[0315] After concentrating the mixture, the residue was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 15:1) to finally obtain colorless liquid product 43 (56.2 mg, 0.195 mmol, yield 65%).

[0316] 1H NMR (300MHz, CDCl3) δ7.08(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),5.27(q,J=1.3Hz,1H),3.78(s,3H),2.94(d,J =1.1Hz,2H),2.54(t,J=7.5Hz,2H),2.42(t,J=7.3Hz,2H),1.89–1.80(m,2H),1.70(d,J=1.4Hz,3H),1.10(s,9H).

[0317] 13 C NMR (126MHz, CDCl3) δ210.3,158.2,140.7,134.1,129.7,128.4,114.2,56.5,55.6,40.7,34.6,32.8,31.7,31.2,25.8,17.9.

[0318] HRMS(ESI)calcd for C 19 H 28 O2Na + [(M+Na) + ]: calculated 311.1982, found311.1975.

[0319] Example 41 Synthesis of Compound 44

[0320]

[0321] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material 2,3-dimethyl-2-butene (71 μL, 0.6 mmol).

[0322] After concentration, the mixture was first purified by silica gel rapid column chromatography, and then purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 15:1) to finally obtain colorless liquid product 44 (47.6 mg, 0.183 mmol, yield 61%).

[0323] 1 H NMR (300MHz, CDCl3) δ7.07(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),3.78(s,3H),3.10(s,2H) ,2.54(t,J=7.6Hz,2H),2.39(t,J=7.3Hz,2H),1.90–1.80(m,2H),1.70(s,3H),1.64(s,6H).

[0324] 13C NMR (126MHz, CDCl3) δ209.6,158.0,133.9,129.5,128.6,121.4,113.9,55.4,49.3,41.0,34.3,25.7,20.9,20.8,19.4.

[0325] HRMS(ESI)calcd for C 17 H 25 O2 + [(M+H) + ]:calculated 261.1849,found261.1845.

[0326] Example 42 Synthesis of Compound 45

[0327]

[0328] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material toluene (63 μL, 0.6 mmol).

[0329] The final product was a colorless liquid, 45 (45.8 mg, 0.171 mmol, yield 57%).

[0330] 1 H NMR (500MHz, CDCl3) δ7.35–7.30(m,2H),7.28–7.26(m,1H),7.21–7.15(m,2H),7.03–6.99(m,2H),6.82– 6.78(m,2H),3.78(s,3H),3.65(s,2H),2.50(t,J=7.6Hz,2H),2.45(t,J=7.2Hz,2H),1.87–1.82(m,2H).

[0331] 13 C NMR (126MHz, CDCl3) δ208.3,158.0,134.4,133.8,129.6,129.5,128.9,127.1,113.9,55.4,50.3,41.2,34.2,25.5.

[0332] HRMS(ESI)calcd for C 18 H 21 O2 + [(M+H) + ]:calculated 269.1536,found269.1545.

[0333] Example 43 Synthesis of Compound 46

[0334]

[0335] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material ethyl 3-hexenoate (95 μL, 0.6 mmol).

[0336] The final product was a yellow liquid, 46 (60.1 mg, 0.189 mmol, yield (total yield of both isomers) 63%).

[0337] 1 H NMR(300MHz, CDCl3) δ7.08(d,J=8.5Hz,2H),6.81(d,J=8.6Hz,2H),5.71–5.57(m,1 H),5.36–5.17(m,1H),4.09(dd,J=7.1,2.8Hz,2H),3.94–3.86(m,0.18H),3.78(s, 3H),3.56–3.48(m,0.82H),2.85(dd,J=16.7,9.2Hz,1H),2.58–2.47(m,4H),2.38– 2.31(m,1H),1.90–1.80(m,2H),1.67(dd,J=6.5,1.7Hz,3H),1.22(t,J=7.1Hz,4H).

[0338] 13 C NMR (126MHz, CDCl3) δ210.0,172.3,158.0,134.0,130.3,129.5,127.4,113.9,60.7,55.4,51.9,40.6,35.8,34.3,25.4,18.2,14.3.

[0339] HRMS(ESI)calcd for C 20 H 29 O4 + [(M+H) + ]:calculated 333.2060,found333.2051.

[0340] Example 44 Synthesis of Compound 47

[0341]

[0342] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material 8-methoxy-2,6-dimethyloct-2-ene (102.1 mg, 0.6 mmol).

[0343] The final product was a colorless liquid, 47 (57.1 mg, 0.165 mmol, yield (total yield of both isomers) 55%).

[0344] 1 H NMR (300MHz, CDCl3) δ7.07(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),5.33(t,J=7.1Hz,0.37 H),5.24–5.19(m,0.63H),3.78(s,3H),3.43–3.36(m,2H),3.32(s,3H),3.08(s,0.6H),3.0 4(d,J=22.7Hz,2H),2.59–2.49(m,2H),2.42(t,J=7.3Hz,2H),2.14–1.88(m,2H),1.89–1. 79(m,2H),1.68–1.66(m,1H),1.61(d,J=5.7Hz,3H),1.44–1.15(m,4H),0.93–0.85(m,3H).

[0345] 13 C NMR (126MHz, CDCl3) δ209.8,208.8,158.0,133.9,133.8,130.2,129.5,129.3,128.9,113.9,113.9,113.9,71.2, 71.2,58.7,55.4,54.2,46.7,41.2,40.9,37.2,37.0,36.7,34.3,29.7,29.7,26.0,25.7,25.6,24.3,19.6,16.5.

[0346] HRMS(ESI)calcd for C 22 H 34 O3Na + [(M+Na) + ]:calculated 369.2400,found369.2395.

[0347] Example 45 Synthesis of Compound 48

[0348]

[0349] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material α-pinene (95 μL, 0.6 mmol).

[0350] The final product was a colorless liquid, 48 (54.3 mg, 0.174 mmol, yield (total yield of both isomers) 58%).

[0351] 1 H NMR(300MHz, CDCl3) δ7.08(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),5.36–5.31(m ,1H),3.79(s,3H),3.13(d,J=2.4Hz,0.24H),3.09–2.96(m,1.76H),3.11–2.87(m ,2H),2.54(t,J=7.6Hz,2H),2.50–2.33(m,3H),2.34–2.20(m,2H),2.16–2.04(m ,1H),2.00(m,1H),1.85(m,2H),1.25(s,3H),1.16(d,J=8.6Hz,1H),0.81(s,3H).

[0352] 13 C NMR (126MHz, CDCl3) δ209.2,158.0,141.9,133.9,129.5,121.3,113.9,55.4,51.7,46.0,41.3,40.6,38.1,34.3,31.9,31.7,26.3,25.5,21.1.

[0353] HRMS(ESI)calcd for C 21 H 28 O2Na + [(M+Na) + ]: calculated 335.1982, found335.1974.

[0354] Example 46 Synthesis of Compound 49

[0355]

[0356] Based on Example 31, the raw material cyclopentene (53.0 μL, 0.6 mmol) was replaced with the raw material 4-isopropyl-4-methoxy-1-methylcyclohex-1-ene (100.8 mg, 0.6 mmol).

[0357] The final product was a colorless liquid, 49 (61.9 mg, 0.18 mmol, yield (total yield of both isomers) 60%).

[0358] 1 H NMR (300MHz, CDCl3) δ7.07 (dd, J = 8.6, 3.5Hz, 2H), 6.84–6.78 (m, 2H), 5.42 (s, 1H), 3.78 (s, 3H), 3.12 (s, 2.32H), 3.09 (s, 0.68H), 3.01 (s, 1.56H) ,2.68–2.62(m,0.44H),2.54(t,J=7.6Hz,2H),2.44(t,J=7.3Hz,2H),2.2 1–1.91(m,4H),1.88–1.79(m,3H),1.76–1.59(m,2H),0.95–0.82(m,6H).

[0359] 13 C NMR (126MHz, CDCl3) δ158.0,131.7,129.5,123.4,113.9,55.4,52.1,48.2,40.9,34.3,31.5,30.1,26.8,25.9,25.6,17.7,16.6.

[0360] HRMS(ESI)calcd for C 22 H 32 O3Na + [(M+Na) + ]:calculated 367.2244,found367.2235.

[0361] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A synthetic process for β,γ-unsaturated ketone compounds, characterized in that, Using allyl-containing olefins as starting materials, carboxylic acids as acylating agents, and dimethyl dicarbonate as dehydrating agents, the β,γ-unsaturated ketone compounds were obtained in a one-step reaction under 450-455nm blue light irradiation in a composite catalyst system. The composite catalyst system is a complex of a photocatalyst, NiBr2·DME, 4,4'-di-tert-butyl-2,2'-bipyridine, and ammonium chloride; the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

2. The synthesis process of β,γ-unsaturated ketone compounds according to claim 1, characterized in that, The amount of NiBr2·DME added was 20 mol%.

3. The synthesis process of β,γ-unsaturated ketone compounds according to claim 1, characterized in that, The amount of 4,4'-di-tert-butyl-2,2'-bipyridine added was 26 mol%.

4. The synthesis process of β,γ-unsaturated ketone compounds according to claim 1, characterized in that, The amount of the photocatalyst added is 1 mol%.

5. The synthesis process of β,γ-unsaturated ketone compounds according to claim 1, characterized in that, The carboxylic acid is selected from aliphatic acids, aromatic acids, heterocyclic acids, amino acids, or natural carboxylic acids.

6. The synthesis process of β,γ-unsaturated ketone compounds according to claim 1, characterized in that, The allyl-containing olefin is selected from cyclic olefins, acyclic olefins, tri / tetrasubstituted olefins, β-citronellol, or α-pinene.

7. The synthesis process of β,γ-unsaturated ketone compounds according to claim 1, characterized in that, The solvent for the reaction is 0.05M isopropyl acetate; the reaction is carried out in an alkaline environment, which is 1.5 equivalents of disodium hydrogen phosphate.

8. The synthesis process of β,γ-unsaturated ketone compounds according to claim 1, characterized in that, The reaction time was 12 hours.

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