A kind of synthetic method of pyranocoumarin compound

Abstract

The present invention provides a method for synthesizing pyranocoumarin compounds, directly using acetophenones and 4-hydroxycoumarins as raw materials, morpholine as an additive, and heating the reaction in a dimethyl sulfoxide solution to obtain a pyranocoumarin derivative in a one-pot method. In the reaction, dimethyl sulfoxide is not only used as a reaction solvent, but also as a reaction reagent to provide a synthon after being activated by 4-hydroxycoumarin to participate in the reaction. The method provided by the present invention has cheap and easy-to-obtain raw material sources, simple experimental operation, and a high yield and substrate application range. In addition, no metal reagent or other oxidant is used in the reaction process, and the method has potential application value.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a synthesis method and application of a biologically active skeleton of a pyranocoumarin derivative. Background Art

[0002] Coumarin, as an important pharmaceutical intermediate, is often used in the production of anticoagulant drugs and has considerable research value in the application of anti-tumor drugs. Functionalized pyranocoumarin, as an important oxygen-containing heterocyclic compound among coumarin derivatives, has a wide range of applications. In recent years, there have been many reports on the application of this type of compound in biomedicine, such as anti-psoriasis, anti-mycobacterium tuberculosis, anti-inflammatory, antiviral hepatitis, anti-cytotoxicity, antifungal, anticoagulant, insecticidal, anticancer, antibacterial, antitumor, anti-HIV and anti-proliferative applications.

[0003] There are very few reports on the synthesis of pyranocoumarin derivatives. Among them, a non-patent document (3-Benzoyl-3,4-dihydro-2H,5H-1-benzopyrano[4,3-b]pyran-5-ones by condensation of 4-hydroxycoumarins with enonemannich bases. Journal of Heterocyclic Chemistry, Volume 35, Issue 6, 1455-1460) discloses a method for synthesizing a pyranocoumarin skeleton. The reaction equation is as follows:

[0004]

[0005] This method uses an acetophenone derivative to first obtain an enaminone intermediate through a two-step reaction, and then reacts with 4-hydroxycoumarin to obtain pyranocoumarin. The reaction process is complicated and the substrate application range is relatively narrow. In addition to the above methods, no other reports have been found. Summary of the invention

[0006] The invention provides a new method for efficiently synthesizing pyranocoumarin skeleton compounds under metal-free catalysis.

[0007] The technical solution of the present invention is as follows:

[0008] A method for synthesizing pyranocoumarin having a structure of formula (I), comprising the following steps:

[0009] (1) mixing a 4-hydroxycoumarin derivative (Formula (II)) and an acetophenone derivative (Formula (III)) in dimethyl sulfoxide, adding morpholine, and reacting under heating conditions. After the reaction is completed, the reaction solution is sequentially washed with water and extracted with ethyl acetate and then concentrated. The concentrated solution is purified by column chromatography to obtain the pyranocoumarin derivative of the structure of Formula (I);

[0010]

[0011] Wherein, the structural formula of the above-mentioned 4-hydroxycoumarin derivative (Formula (II)) is as follows:

[0012]

[0013] Wherein, the structural formula of the above-mentioned acetophenone derivative (Formula (III)) is as follows:

[0014]

[0015] Among them, R 1 and R 2 each independently represents hydrogen, an electron-withdrawing or electron-donating group;

[0016] Here, m and n each independently represent 0, 1, 2, or 3.

[0017] In the preferred technical solution of the present invention, R 1 It represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, cyano, nitro, amino, hydroxyl, or sulfonic acid.

[0018] In the preferred technical solution of the present invention, R 1 It represents hydrogen, methyl, methoxy, halogen, trifluoromethyl, cyano, nitro, amino, hydroxyl, or sulfonic acid.

[0019] In the preferred technical solution of the present invention, R 2 It represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, cyano, nitro, amino, hydroxyl, or sulfonic acid.

[0020] In the preferred technical solution of the present invention, R 3 It represents hydrogen, methyl, methoxy, halogen, trifluoromethyl, cyano, nitro, amino, hydroxyl, or sulfonic acid.

[0021] In the preferred technical solution of the present invention, m represents 0, 1, 2, or 3.

[0022] In the preferred technical solution of the present invention, n represents 0, 1, 2, or 3.

[0023] In the preferred technical solution of the present invention, the reaction temperature is 110-140 degrees and the reaction time is 10-30 hours.

[0024] In the preferred technical solution of the present invention, 4-hydroxycoumarin has a certain acidity and can activate dimethyl sulfoxide to participate in the reaction. At the same time, additional acidic activators can be added to the reaction, including common organic acids such as formic acid, acetic acid, propionic acid and common inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.

[0025] In a preferred technical solution of the present invention, the additive is a common carbonyl-activated amine, including tetrahydropyrrole, morpholine, hexahydropiperidine, and proline.

[0026] The advantages and effects achieved by the present invention are:

[0027] 1. The raw materials of the synthesis method of the present invention are cheap and easily available. Acetophenones, 4-hydroxycoumarins and dimethyl sulfoxide are directly selected as reaction raw materials. The operation is simple, the target product is directly obtained by a one-pot method and the reaction efficiency is high.

[0028] 2. The raw material 4-hydroxycoumarin in the present invention is not only a reactant, but also can be used as an acid to activate another raw material dimethyl sulfoxide to participate in the reaction. No other reagents need to be added, and it is a substrate-induced reaction; dimethyl sulfoxide is both a reaction solvent and a reaction raw material, and no other solvent needs to be added. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1-Figure 2 are the hydrogen spectrum and carbon spectrum of the target compound A in Example 1 of the present invention;

[0030] Figure 3-Figure 4 are the hydrogen spectrum and carbon spectrum of the target compound B in Example 2 of the present invention;

[0031] Figure 5-Figure 6 are the hydrogen spectrum and carbon spectrum of the target compound C in Example 3 of the present invention;

[0032] Figure 7-Figure 8 These are the hydrogen and carbon spectra of the target compound D in Example 4 of the present invention. DETAILED DESCRIPTION

[0033] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those skilled in the art without making creative work are within the scope of protection of the present invention. Unless otherwise defined, all technical and scientific terms used in this specification have the same meanings as those generally understood by those skilled in the art in the technical field of the present invention. The term "and / or" used in this specification includes any and all combinations of one or more related listed items.

[0034] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, instruments, etc. used in the following examples are all commercially available unless otherwise specified.

[0035] Example 1 Synthesis of Target Compound A

[0036] The reaction equation is as follows:

[0037]

[0038] 4-Hydroxycoumarin (0.4mmol, 49.2mg), acetophenone (0.2mmol, 24μL), morpholine (0.2mmol, 18μL) and dimethyl sulfoxide (2.0mL) were weighed in a 50mL reaction tube, and the reaction mixture was heated and stirred at 140°C for 24h. After the reaction was completed, the reaction solution was washed with water and then extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain the target product A (yellow solid, 37mg, yield 60%). The structure of the compound was confirmed by NMR as follows: 1 H NMR (600MHz, CDCl3) δ8.00(d,J=7.8Hz,2H),7.79(d,J=7.8Hz,1H),7.64(t,J=7.2Hz,1H),7.55-7.51(m,3H),7.33(d,J=8.4Hz,1H),7.29 (d,J=7.8Hz,1H),4.76-4.73(m,1H),4.38(dd,J=10.8,10.2Hz,1H),3.98-3.93(m,1H),3.05-3.00(m,1H),2.75(d,J=17.4,10.8Hz,1H); 13CNMR (150MHz, CDCl3) δ199.0,162.6,159.7,152.4,135.5,134.0,131.8,129.1,128.5,124.0,122.5,116.7,115.3,100.5,68.2,39.1,23.9;

[0039] The compound synthesized was confirmed to be the target compound A by structural identification.

[0040] Example 2 Synthesis of target compound B

[0041] The reaction equation is as follows:

[0042]

[0043] 4-Hydroxycoumarin (0.4mmol, 49.2mg), p-methylacetophenone (0.2mmol, 27μL), morpholine (0.2mmol, 18μL) and dimethyl sulfoxide (2.0mL) were weighed in a 50mL reaction tube, and the reaction mixture was heated and stirred at 140°C for 24h. After the reaction was completed, the reaction solution was washed with water and then extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain the target product B (yellow solid, 40.4mg, yield 63%). The structure of the compound was confirmed by NMR as follows: 1 HNMR(600MHz, CDCl3) δ7.89(d,J=8.4Hz,2H),7.78(d,J=7.8Hz,1H),7.53(t,J=7.2Hz,1H),7.34-7.28(m,4H),4.73(ddd,J=11.4,3.0,1.8 Hz,1H),4.37(dd,J=10.8,10.2Hz,1H),3.95-3.91(m,1H),3.01(ddd,J=16.8,5.4,1.8Hz,1H),2.73(dd,J=16.8,10.8Hz,1H),2.44(s,3H); 13 C NMR (150MHz, CDCl3) δ198.7,162.8,159.8,152.5,145.1,133.1,131.8,129.0,128.7,124.1,122.6,116.8,115.5,100.7,68.4,39.1,24.1,21.9;

[0044] The compound synthesized was confirmed to be the target compound B as shown by structural identification.

[0045] Example 3 Synthesis of Target Compound C

[0046] The reaction equation is as follows:

[0047]

[0048] 4-Hydroxycoumarin (0.4mmol, 49.2mg), p-bromoacetophenone (0.2mmol, 39.8mg), morpholine (0.2mmol, 18μL) and dimethyl sulfoxide (2.0mL) were weighed in a 50mL reaction tube, and the reaction mixture was heated and stirred at 140°C for 24h. After the reaction was completed, the reaction solution was washed with water and then extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain the target product C (yellow solid, 42.4mg, yield 55%). The structure of the compound was confirmed by NMR as follows: 1 H NMR (600MHz, CDCl3) δ7.86(d,J=8.4Hz,2H),7.78(d,J=7.8Hz,1H),7.67(d,J =8.4Hz,2H),7.54(t,J=7.2Hz,1H),7.33(d,J=8.4Hz,1H),7.30(t,J=7.8Hz,1 H),4.72(ddd,J=10.8,5.4,2.4Hz,1H),4.37(dd,J=11.4,9.6Hz,1H),3.92-3. 87(m,1H),3.01(ddd,J=16.8,5.4,1.8Hz,1H),2.73(dd,J=16.8,10.2Hz,1H); 13 C NMR (150MHz, CDCl3) δ198.1,162.7,159.8,152.5,134.2,132.6,131.9,130.1,129.5,124.2,122.6,116.8,115.4,100.5,68.1,39.3,24.0;

[0049] The compound synthesized was confirmed to be the target compound C by structural identification.

[0050] Example 4 Synthesis of Target Compound D

[0051] The reaction equation is as follows:

[0052]

[0053] 4-Hydroxycoumarin (0.4mmol, 76.7mg), acetophenone (0.2mmol, 24μL), morpholine (0.2mmol, 18μL) and dimethyl sulfoxide (2.0mL) were weighed in a 50mL reaction tube, and the reaction mixture was heated and stirred at 140°C for 24h. After the reaction was completed, the reaction solution was washed with water and then extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to obtain the target product D (yellow solid, 44.3mg, yield: 66%). The structure of the compound was confirmed by NMR as follows: 1 H NMR (600MHz, CDCl3) δ7.98(d,J=7.8Hz,2H),7.63(t,J=7.2Hz,1H),7.52(t,J =7.8Hz,2H),7.24(d,J=9.0Hz,1H),7.18(d,J=3.6Hz,1H),7.10(dd,J=9.0,3 .0Hz,1H),4.73-4.68(m,1H),4.34(dd,J=10.8,10.2Hz,1H),3.98-3.92(m,1 H),3.85(s,3H),3.02(dd,J=16.8,3.6Hz,1H),2.73(dd,J=16.8,10.2Hz,1H); 13 C NMR (150MHz, CDCl3) δ199.1,162.8,159.5,156.1,146.9,135.6,134.0,129.1,128.6,120.0,117.9,115.7,104.5,100.8,68.2,56.0,39.2,24.0;

[0054] The compound synthesized was confirmed to be the target compound D as shown by structural identification.

Claims

1. A method for synthesizing pyranocoumarin having a structure of formula (I), characterized in that: The following steps are involved: The 4-hydroxycoumarin derivative (formula (II)) and the acetophenone derivative (formula (III)) are uniformly mixed in dimethyl sulfoxide, and morpholine is added to react under heating conditions. After the reaction is completed, the reaction solution is sequentially washed with water and extracted with ethyl acetate and then concentrated. The concentrated solution is purified by column chromatography to obtain the pyranocoumarin derivative with the structure of formula (I); Wherein, the structural formula of the above-mentioned 4-hydroxycoumarin derivative (Formula (II)) is as follows: Wherein, the structural formula of the above-mentioned acetophenone derivative (Formula (III)) is as follows: Among them, R 1 represents hydrogen, methoxy, halo, methyl, C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, cyano, nitro, amino, hydroxyl, sulfonic acid, methyl, methoxy, halogen or trifluoromethyl; R 2 represents hydrogen, methoxy, halo, methyl, C1-C6 alkyl, C1-C6 alkoxy, halogen, halo-substituted C1-C6 alkyl, cyano, nitro, amino, hydroxyl or sulfonic acid; Here, m and n each independently represent 0, 1, 2, or 3.

2. The method according to claim 1, characterized in that m represents 0, 1, 2, 3.

3. The method according to claim 1, characterized in that n represents 0, 1, 2, 3.

4. The method according to claim 1, characterized in that: The reaction temperature is 110-140 degrees, and the reaction time is 10-30 hours.

5. The method according to claim 1, characterized in that Since 4-hydroxycoumarin has a certain acidity, it can activate dimethyl sulfoxide to participate in the reaction. At the same time, an acidic activator is additionally added in the reaction. The acidic activator is an organic acid such as formic acid, acetic acid, propionic acid or an inorganic acid such as hydrochloric acid, sulfuric acid, and phosphoric acid.

6. The method according to claim 1, characterized in that An amine additive is also added, wherein the amine is tetrahydropyrrole, morpholine, piperidine or proline.

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