Synthesis method of furan derivative containing exocyclic double bonds

Abstract

The invention provides a synthesis method of furan derivatives containing exocyclic double bonds, on the basis of existing literature reports, synthesis of complex raw materials is avoided, a reaction system is simplified, a 1, 3-dicarbonyl compound and a beta, gamma-alkynyl-alpha-imine derivative are used as raw materials, cheap and easily available anhydrous ketone acetate and triphenylphosphine are used as catalysts, and the furan derivatives containing exocyclic double bonds are synthesized through a one-pot method. A series of furan derivatives containing exocyclic double bonds are successfully synthesized in a [3 + 2] cycloaddition mode, an efficient, reliable and economical preparation method is provided for synthesis of furan skeleton compounds containing exocyclic double bonds, and the method has good development potential and application background in the field of biological medicine.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a furan derivative containing an exocyclic double bond. Background Art

[0002] As an important nitrogen-containing heterocyclic compound, furan compounds are widely present in many clinical drugs with good efficacy. The molecular structures of drugs such as the diuretic furosemide, the β-lactam antibiotic cefuroxime, and neo-tanshinlactone used to treat breast cancer all contain this skeleton. Among them, furan skeletons containing exocyclic double bonds exist in many biologically active compounds, such as bisabolangelone, an effective ingredient of anti-inflammatory drugs, (-)-amphidinolide K with antitumor activity, arglabin, an antitumor clinical drug, tetrodecamycin, a key ingredient for inhibiting Gram-positive bacteria and Staphylococcus aureus, and inotilone, an effective ingredient of antifungal drugs. It is worth noting that furan compounds containing exocyclic double bonds can be converted into non-furan heterocyclic drug molecules with pharmaceutical activity, such as PDE10A inhibitors. Although there have been some reports on the synthesis strategies of furan, the potential application of furan containing exocyclic double bonds in medicine has important research value.

[0003] As an active compound with multiple reaction sites, 1,3-dicarbonyl compounds have a very high degree of participation in many developed heterocyclic compound synthesis strategies. For example, in 2019, Mohanty et al. reported a synthetic method for generating furan compounds by coupling 1,3-dicarbonyl compounds with alkynes. 1,3-dicarbonyl compounds are affected by the electron-withdrawing inductive effect of the two carbonyl groups, and the methylene group between the carbonyl groups has strong acidity, which makes such compounds have high reactivity and can be converted into enolate intermediates with strong nucleophilicity to participate in the synthesis of heterocyclic compounds. At the same time, they are also cheap and readily available.

[0004] β,γ-alkynyl-α-imine derivatives are a class of highly stable and easy-to-synthesize ketoamine compounds. In recent years, β,γ-alkynyl-α-imine derivatives with multiple reaction sites have attracted widespread attention from scientists as a synthetic building block.

[0005] Furan containing an exocyclic double bond has important application potential in medicine, but there are currently very few synthetic strategies for this structure. Therefore, developing efficient synthetic methods to obtain furan skeletons containing an exocyclic double bond has important research value. Summary of the invention

[0006] The purpose of the present invention is to provide a method for synthesizing furan derivatives containing an exocyclic double bond. On the basis of existing literature reports, a series of furan derivatives containing an exocyclic double bond are successfully synthesized by using 1,3-dicarbonyl compounds and β,γ-alkynyl-α-imine derivatives as raw materials, and inexpensive and easily available anhydrous acetic acid ketone and triphenylphosphine as catalysts through a [3+2] cycloaddition method, thereby providing an efficient, reliable and economical preparation method for synthesizing furan skeleton compounds containing an exocyclic double bond, and having good development potential and application background in the field of biomedicine.

[0007] The present invention is achieved through the following technical solutions:

[0008] The present invention provides a furan derivative I containing an exocyclic double bond, wherein Pg represents an amino protecting group, such as -Cbz, -Boc, R 1 , R 2 , R 3 , R 4 It represents hydrogen, C1-C12 straight chain alkyl, C1-C12 branched chain alkyl, aryl and alkyl containing different active functional groups.

[0009] The method for preparing a furan derivative containing an exocyclic double bond and its analogues according to the present invention is characterized in that the synthesis route is as shown in Formula 1: DETAILED DESCRIPTION

[0010] In order to facilitate a better understanding of the present invention, the following examples are used to illustrate the present invention. These examples belong to the protection scope of the present invention, but do not limit the protection scope of the present invention.

[0011] Example 1

[0012]

[0013] 0.2 mmol of alkynyl imine compound 1 and 0.24 mol of 1,3-dicarbonyl compound 2 were dissolved in 2 ml of solvent, and reacted completely at room temperature under the catalysis of 0.02 mmol of anhydrous copper acetate, and then the solvent was removed under reduced pressure by extraction. The residue was separated and purified by column chromatography to obtain the target compound 3, which was a white solid with a melting point of 90-91°C. 1 H NMR (400MHz, CDCl3) 68.04 (t, J=14.8Hz, 2H), 7.63 (t, J=10.4Hz, 2H), 7.52 (s, 3H), 7.35 (d, J=7.2H z, 2H), 7.23 (s, 1H), 6.32 (s, 1H), 5.75 (s, 1H), 4.43-4.00 (m, 4H), 1.37 (s, 9H), 1.22-1.10 (m, 6H).13 C NMR (100MHz, CDCl3) δ169.4, 165.2, 162.6, 153.9, 153.1, 152.6, 134.0, 131.7, 129.9 , 128.8, 128.7, 128.1, 127.2, 103.8, 80.9, 70.3, 70.2, 63.2, 60.6, 28.3, 14.2, 14.0.

[0014] Embodiment 2:

[0015]

[0016] 0.2 mmol of alkynyl imine compound 4 and 0.24 mmol of 1,3-dicarbonyl compound 5 were dissolved in 2 ml of solvent, and reacted completely at room temperature under the catalysis of 0.02 mmol of anhydrous copper acetate, and then the solvent was removed under reduced pressure by extraction. The residue was separated and purified by column chromatography to obtain the target compound 6, which was a white solid with a melting point of 95-96°C. 1 H NMR (400MHz, CDCl3) δ8.15-8.02 (m, 2H), 7.53 (t, J=9.0Hz, 5H), 7.18 (d, J=7.9Hz, 2H), 6.3 7 (s, 1H), 5.76 (s, 1H), 4.33-4.14 (m, 4H), 2.35 (s, 3H), 1.25 (s, 9H), 1.21 (t, J=7.4Hz, 6H). 13 C NMR (100MHz, CDCl3) δ169.1, 164.8, 162.2, 153.5, 151.7, 136.7, 131.3, 130.8, 129.5, 1 29.0, 128.4, 128.1, 127.8, 103.4, 80.2, 70.0, 70.0, 62.7, 60.1, 27.9, 21.0, 13.8, 13.6.

[0017] Embodiment 3:

[0018]

[0019] 0.2 mmol of acetylene imine compound 7 and 0.24 mmol of 1,3-dicarbonyl compound 8 were dissolved in 2 ml of solvent, and the reaction was completed at room temperature under the catalysis of 0.02 mmol of anhydrous copper acetate. The solvent was removed by extraction and reduced pressure, and the residue was separated and purified by column chromatography to obtain the target compound 9, which was a colorless oily liquid. 1H NMR (400MHz, CDCl3) δ8.41-8.19 (m, 4H), 7.59 (d, J=7.6Hz, 2H), 7.36 (s, 2H), 7.26 (s , 1H), 6.40 (s, 1H), 5.81 (s, 1H), 4.36-4.17 (m, 4H), 1.36 (s, 9H), 1.26-1.20 (m, 6H). 13 C NMR (100MHz, CDCl3) δ168.9, 162.8, 162.1, 153.4, 152.1, 149.2, 134.3, 133.5, 131.0 , 128.8, 128.7, 127.5, 123.2, 104.6, 80.3, 70.1, 70.1, 63.4, 60.9, 28.3, 14.1, 14.0.

[0020] Embodiment 4:

[0021]

[0022] 0.2 mol of alkynyl imine compound 10 and 0.24 mol of 1,3-dicarbonyl compound 11 were dissolved in 2 ml of solvent, and reacted completely at room temperature under the catalysis of 0.02 mol of anhydrous copper acetate, and then the solvent was removed under reduced pressure by extraction, and the residue was separated and purified by column chromatography to obtain the target compound 12, which was a yellow solid with a melting point of 112-113°C. 1 H NMR (400MHz, CDCl3) δ7.56 (d, J=7.6Hz, 3H), 7.41 (dd, J=13.6, 6.8Hz, 1H), 7.29 (t, J=8.0Hz, 4H), 7.19 (t, J=7.2Hz, 1H), 6.35 (s, 1H), 5.75 (s, 1H), 4.37-4.15 (m, 2H), 4.13-3.99 (m, 2H), 2.45 (s, 3H), 1.37 (s, 9H), 1.23 (t, J=7.2Hz, 3H), 1.08 (t, J=7.2Hz, 3H). 13 C NMR (100MHz, CDCl3) δ169.4, 167.1, 162.3, 153.3, 153.1, 138.0, 133.9, 130.6, 130.5, 130.3, 1 28.8, 128.6, 127.2, 125.3, 125.3, 103.9, 80.1, 69.4, 69.4, 63.2, 60.2, 28.4, 19.8, 14.1, 14.0.

[0023] Embodiment 5:

[0024]

[0025] 0.2 mmol of alkynyl imine compound 13 and 0.3 mmol of 1,3-dicarbonyl compound 14 were dissolved in 2 ml of solvent, and reacted completely at room temperature under the catalysis of 0.02 mol of anhydrous copper acetate, and then the solvent was removed under reduced pressure by extraction. The residue was separated and purified by column chromatography to obtain the target compound 15, which was a white solid with a melting point of 85-86°C. 1 H NMR (400MHz, CDCl3) δ7.57 (d, J=7.6Hz, 2H), 7.33 (t, J=7.2Hz, 2H), 7.23 (s, 1H), 6.30 (s, 1H), 5.65 (s, 1H), 4.29-4.17 (m, 4H), 2.51 (s, 3H), 1.34 (s, 9H), 1.30-1.16 (m, 6H). 13 C NMR (100MHz, CDCl3) δ169.5, 169.1, 163.2, 153.9, 153.1, 133.8, 128.8, 128.5, 127.2, 103.5, 79.9, 68.7, 68.7, 63.0, 60.1, 28.3, 14.3, 14.0, 14.0.

[0026] Embodiment 6:

[0027] 0.2 mmol of acetylenic imine compound 16 and 0.24 mmol of 1,3-dicarbonyl compound 17 were dissolved in 2 ml of solvent, and reacted completely at room temperature under the catalysis of 0.02 mmol of anhydrous copper acetate, and then the solvent was removed under reduced pressure by extraction. The residue was separated and purified by column chromatography to obtain the target compound 18, which was a white solid with a melting point of 87-88°C. 1 H NMR (400MHz, CDCl3) δ7.57 (d, J=7.6Hz, 2H), 7.34 (t, J=7.2Hz, 2H), 7.23 (d, J=7.2Hz, 1H), 6.26 (s, 1H), 5.66 (s, 1H), 4. 30-4.10 (m, 4H), 2.96 (d, J=89.6Hz, 2H), 1.30 (s, 9H), 1.45-1.27 (m, 3H), 1.24 (d, J=7.2Hz, 3H), 1.20 (t, J=7.2Hz, 3H). 13C NMR(100MHz,CDCl3)δ173.6,169.6,163.2,153.9,153.2,134.0,128.8,128.6,127.1,103.6,79.9,68.9,68.9,63.0,60.1,28.3,21.4,14.3,14.0,11.0。

Claims

1. A furan derivative I containing an exocyclic double bond, characterized in that: The structure is: Pg represents an amino protecting group, such as -Cbz, -Boc, R 1 , R 2 , R 3 , R 4 It represents C1-C12 straight-chain alkyl, C1-C12 branched-chain alkyl, aryl and alkyl containing different active functional groups.

2. The method for preparing the furan derivative 3 containing an exocyclic double bond and its analogues according to claim 1, characterized in that: The synthetic route is shown in Formula 1:

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