Thieno [2, 3-b] pyrone heterocyclic ring and synthesis method thereof

Abstract

The invention provides a thieno [2, 3-b] pyrone heterocyclic ring and a synthesis method thereof, and relates to the technical field of organic synthetic chemistry. The structural formula of the thieno [2, 3-b] pyrone heterocyclic ring is # imgabs0 #, wherein R1 is methyl, ethyl or propyl, and R2 is F, Cl, I or methoxyl. The synthesis method of the thieno [2, 3-b] pyrone heterocyclic ring is characterized in that the thieno [2, 3-b] pyrone heterocyclic ring is synthesized by reacting beta-oxo dithio ester and acetylpyrone under alkaline conditions, and the synthesis method has the advantages of simple raw material acquisition and mild reaction conditions, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic chemistry, and in particular to a thieno[2,3-b]pyrone heterocycle and a synthesis method thereof. Background Art

[0002] Heterocyclic compounds are commonly found in natural and synthetic molecules. Their unique physical and chemical properties, as well as pharmacological effects, have attracted more and more researchers in the fields of chemistry and medicine. Therefore, the development of powerful synthetic routes that can effectively produce a variety of heterocyclic compounds will help accelerate drug development. It is well known that thiophenes and pyrones are important heterocyclic compounds that are widely present in natural products and many active drug molecules. At present, the strategies for synthesizing these two types of compounds have reached a relatively mature level.

[0003] Based on the practicality and importance of these two heterocyclic compounds, the synthesis methods of thienopyrone heterocycles have been continuously explored. However, relatively speaking, there are few reports on the specific synthesis of thienopyrone heterocycles. These methods have the disadvantages of harsh reaction conditions, narrow substrate range, low reaction yield, etc.

[0004] More importantly, among these reports on the synthesis of thienopyrone heterocycles, the synthesis of thieno[2,3-b]pyrone has not been reported.

[0005] Therefore, there is a real need to provide a synthetic thieno[2,3-b]pyrone heterocycle and a synthetic method thereof. Summary of the invention

[0006] The object of the present invention is to provide a novel thieno[2,3-b]pyrone heterocycle and a synthesis method thereof.

[0007] The present invention provides the following technical solutions:

[0008] In one aspect of the present invention, a thieno[2,3-b]pyrone heterocycle is provided, wherein the structural formula of the thieno[2,3-b]pyrone heterocycle is:

[0009]

[0010] Wherein R1 is methyl, ethyl or propyl, and R2 is F, Cl, I or methoxy.

[0011] In a second aspect of the present invention, a method for synthesizing the above-mentioned thieno[2,3-b]pyrone heterocycle is provided, wherein the method comprises: using acetylpyrone of the structure shown in formula (I) and β-oxydithioester of the structure shown in formula (II) as reaction raw materials, and reacting in an alkaline environment to obtain a thieno[2,3-b]pyrone heterocycle of the structure shown in formula (III);

[0012] The reaction equation is shown below:

[0013]

[0014] Wherein R1 in the compound of formula (I) is methyl, ethyl or propyl; R2 in the compound of formula (II) is F, Cl, I or methoxy.

[0015] In some embodiments of the present invention, the reaction in an alkaline environment specifically comprises: dissolving the acetyl pyrone and the β-oxydithioester in an organic solvent, adding NaH, and reacting at room temperature.

[0016] In some embodiments of the present invention, the organic solvent is at least one of N,N-dimethylformamide, dichloromethane, ethyl acetate, chloroform, n-hexane, acetonitrile, 1,4-dioxane, toluene, tetrahydrofuran, ether, and carbon tetrachloride.

[0017] In some embodiments of the present invention, the molar ratio of the acetyl pyrone to the β-oxydithioester is 1:(1-2).

[0018] In some embodiments of the present invention, the molar ratio of the acetyl pyrone to the β-oxydithioester is 1:1.

[0019] In some embodiments of the present invention, the reaction time is 6h-18h.

[0020] In some embodiments of the present invention, the synthesis method further comprises: after the reaction is completed, the reaction solution is decompressed to remove the solvent to obtain a crude product, and the crude product is purified by column chromatography to obtain a thieno[2,3-b]pyrone heterocycle having a structure shown in formula (III).

[0021] In some embodiments of the present invention, the eluent used in the column chromatography is a mixture of petroleum ether and ethyl acetate.

[0022] In some embodiments of the present invention, in the eluent, the volume ratio of petroleum ether to ethyl acetate is (10-60):1.

[0023] The thieno[2,3-b]pyrone heterocycle and the synthesis method thereof according to the embodiment of the present invention have at least one of the following advantages:

[0024] (1) The thieno[2,3-b]pyrone heterocycle provided by the present invention has a new skeleton structure, good functional group compatibility, simple post-processing, and good application potential.

[0025] (2) The present invention uses β-oxydithioester and acetylpyrone as two raw materials to react under alkaline conditions to synthesize thieno[2,3-b]pyrone heterocycle. The raw materials are easy to obtain, high temperature and high pressure conditions are not used, the reaction conditions are mild, and it is suitable for industrial production.

[0026] (3) The synthesis method provided by the present invention can obtain the target product in only one step with high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] These and / or other aspects and advantages of the present invention will become apparent and readily understood from the following description of the preferred embodiments in conjunction with the accompanying drawings, in which:

[0028] Figure 1 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4a) provided in Example 1 of the present invention;

[0029] Figure 2 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4a) provided in Example 1 of the present invention;

[0030] Figure 3 The nuclear magnetic resonance NOESY spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4a) provided in Example 1 of the present invention;

[0031] Figure 4 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4b) provided in Example 2 of the present invention;

[0032] Figure 5 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4b) provided in Example 2 of the present invention;

[0033] Figure 6 The nuclear magnetic resonance NOESY spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4b) provided in Example 2 of the present invention;

[0034] Figure 7 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4c) provided in Example 3 of the present invention;

[0035] Figure 8 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4c) provided in Example 3 of the present invention;

[0036] Fig. 9 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4d) provided in Example 4 of the present invention;

[0037] Fig.10 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4d) provided in Example 4 of the present invention;

[0038] Fig.11 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4e) provided in Example 5 of the present invention;

[0039] Fig.12 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4e) provided in Example 5 of the present invention;

[0040] Fig.13 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5a) provided in Example 6 of the present invention;

[0041] Fig.14 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5a) provided in Example 6 of the present invention;

[0042] Fig.15 The nuclear magnetic resonance NOESY spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5a) provided in Example 6 of the present invention;

[0043] Fig.16 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5b) provided in Example 7 of the present invention;

[0044] Fig.17 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5b) provided in Example 7 of the present invention;

[0045] Fig.18 The nuclear magnetic resonance NOESY spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5b) provided in Example 7 of the present invention;

[0046] Fig.19 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5c) provided in Example 8 of the present invention;

[0047] Fig. 20 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5c) provided in Example 8 of the present invention;

[0048] Fig.21 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5d) provided in Example 9 of the present invention;

[0049] Fig. 22 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5d) provided in Example 9 of the present invention;

[0050] Fig.23 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5e) provided in Example 10 of the present invention;

[0051] Fig.24 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5e) provided in Example 10 of the present invention. DETAILED DESCRIPTION

[0052] The technical solution of the present invention is further specifically described below by examples and in conjunction with the accompanying drawings. In the specification, the same or similar reference numerals indicate the same or similar components. The following description of the embodiments of the present invention with reference to the accompanying drawings is intended to explain the overall inventive concept of the present invention and should not be construed as a limitation of the present invention.

[0053] Some embodiments of the present invention provide the following technical solutions:

[0054] First, a thieno[2,3-b]pyrone heterocycle is provided, wherein the structural formula of the thieno[2,3-b]pyrone heterocycle is:

[0055]

[0056] Wherein R1 is methyl, ethyl or propyl, and R2 is F, Cl, I or methoxy.

[0057] Secondly, a method for synthesizing the thieno[2,3-b]pyrone heterocycle is provided, wherein the method comprises: using acetylpyrone of the structure shown in formula (I) and β-oxydithioester of the structure shown in formula (II) as reaction raw materials, and reacting in an alkaline environment to obtain a thieno[2,3-b]pyrone heterocycle of the structure shown in formula (III);

[0058] The reaction equation is shown below:

[0059]

[0060] Wherein R1 in the compound of formula (I) is methyl, ethyl or propyl; R2 in the compound of formula (II) is F, Cl, I or methoxy.

[0061] Specifically, a method for synthesizing a thieno[2,3-b]pyrone heterocycle comprises the following steps: in an organic solvent, using acetylpyrone having a structure as shown in formula (I) and β-oxydithioester having a structure as shown in formula (II) as reaction raw materials, reacting in the presence of NaH, after the reaction, pouring the reaction solution into ice water, extracting with an organic solvent, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain a thieno[2,3-b]pyrone heterocycle having a structure as shown in formula (III);

[0062] The reaction equation is shown below:

[0063]

[0064] Wherein R1 in the compound of formula (I) is methyl, ethyl and propyl. R2 in the compound of formula (II) is F, Cl and methoxy.

[0065] Example 1

[0066] The reaction equation is shown below:

[0067]

[0068] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-oxo-3-phenylpropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-methyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200-300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 48.9 mg of a white solid (4a) with a yield of 60.4%.

[0069] Figure 1 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4a) provided in Example 1 of the present invention; Figure 2 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4a) provided in Example 1 of the present invention; Figure 3 This is the nuclear magnetic resonance NOESY spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4a) provided in Example 1 of the present invention.

[0070] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.65–7.58(m,2H,ArH),7.55–7.49(m,1H,ArH),7.43(dd,J=8.2,6.7Hz,2H,ArH),5.57(d,J=7.4Hz,1H,H-2),4.25(dt,J=9.5,7.3Hz ,1H,H-3),3.99(q,J=7.0Hz,1H,H-6),2.67(dd,J=14.6,9.6Hz,1H,H-4),2.5 0(dd,J=14.7,7.1Hz,1H,H-4),2.45(s,3H,SCH3),1.38(d,J=6.9Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ211.1,190.2,156.4,139.7,132.0,128.7,128.2,127.7,83.7,80.9,51.1,38.3,17.6,16.7.

[0071] Example 2

[0072] The reaction equation is shown below:

[0073]

[0074] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-oxo-3-phenylpropanedithiomethyl ester (0.47 mmol), (2R, 6S)-6-methyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 50.1 mg of a white solid (4b) with a yield of 62.3%.

[0075] Figure 4 The 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4b) provided in Example 2 of the present invention; Figure 5 The nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4b) provided in Example 2 of the present invention; Figure 6 This is the nuclear magnetic resonance NOESY spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4b) provided in Example 2 of the present invention.

[0076] The NMR spectrum data of the obtained product are:1 H NMR (400MHz, CDCl3) δ7.57–7.46(m,3H,ArH),7.46–7.39(m,2H,ArH)6.27(d,J=8.8Hz,1H,H-2),4.57(ddd,J=8.5,5.4,2.6Hz,1H,H-3),4.2 3(q,J=6.8Hz,1H,H-6),2.85(dd,J=15.7,5.4Hz,1H,H-4),2.57(dd,J=15.7,2.7Hz,1H,H-4),2.41(s,3H,SCH3),1.37(d,J=6.9Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ210.8,190.1,157.5,139.6,132.1,128.7,128.1,127.8,84.7,73.5,49.6,36.5,17.8,15.6.

[0077] Example 3

[0078] The reaction equation is shown below:

[0079]

[0080] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-oxo-3-phenylpropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-ethyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200-300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 56.1 mg of a white solid (4c) with a yield of 70.4%.

[0081] Figure 7 This is the 1H nuclear magnetic resonance spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4c) provided in Example 3 of the present invention. Figure 8 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4c) provided in Example 3 of the present invention.

[0082] The NMR spectrum data of the obtained product are: 1H NMR(400MHz,Chloroform-d)δ7.67–7.58(m,2H,ArH),7.58–7.48(m,1H,ArH),7.48–7.37(m,2H,ArH),5.54(d,J=7.4Hz,1H,H-2),4.23(dt,J=9.8,7.3H z,1H,H-3),3.80(dd,J=7.7,4.7Hz,1H,H-6),2.60(dd,J=14.4,9.9Hz,1H,H -4),2.48(dd,J=14.4,7.2Hz,1H,H-4),2.46(s,3H,SCH3),1.92–1.66(m,2H, CH 2CH3),1.00(t,J=7.4Hz,3H,CH2 CH 3). 13 C NMR (100MHz, CDCl3) δ211.3,190.2,156.8,139.7,131.9,128.7,128.1,127.7,85.9,83.8,51.9,39.4,24.8,17.6,9.7.

[0083] Example 4

[0084] The reaction equation is shown below:

[0085]

[0086] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-oxo-3-phenylpropanedithiomethyl ester (0.47 mmol), (2S,6S)-6-ethyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 52.3 mg of a white solid (4d) with a yield of 65.4%.

[0087] Fig. 9 This is the 1H nuclear magnetic resonance spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4d) provided in Example 4 of the present invention. Fig.10 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4d) provided in Example 4 of the present invention.

[0088] The NMR spectrum data of the obtained product are:1 H NMR (400MHz, CDCl3) δ7.57–7.46(m,3H,ArH),7.46–7.39(m,2H,ArH)6.27(d,J=8.8Hz,1H,H-2),4.57(ddd,J=8.5,5.4,2.6Hz,1H,H-3),4.2 3(q,J=6.8Hz,1H,H-6),2.85(dd,J=15.7,5.4Hz,1H,H-4),2.57(dd,J=15.7,2.7Hz,1H,H-4),2.41(s,3H,SCH3),1.37(d,J=6.9Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ210.8,190.1,157.5,139.6,132.1,128.7,128.1,127.8,84.7,73.5,49.6,36.5,17.8,15.6.

[0089] Example 5

[0090] The reaction equation is shown below:

[0091]

[0092] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-methoxyphenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-propyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was completed, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 54.8 mg of a white solid (4e) with a yield of 68.5%.

[0093] Fig.11 This is the 1H nuclear magnetic resonance spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4e) provided in Example 5 of the present invention. Fig.12 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (4e) provided in Example 5 of the present invention.

[0094] The NMR spectrum data of the obtained product are: 1H NMR(400MHz,)δ7.63–7.59(m,2H,ArH),7.56–7.49(m,1H,ArH),7.47–7.40(m,2H,Ar H),5.53(d,J=7.5Hz,1H,H-2),4.23(dt,J=9.8,7.3Hz,1H,H-3),3.86(dd,J=7.0,5.6 Hz,1H,H-6),2.61(dd,J=14.5,10.0Hz,1H,H-4),2.49(dd,J=14.5,7.1Hz,1H,H-4), 2.46(s,3H,SCH3),1.74–1.66(m,2H),1.55–1.41(m,2H),0.91(t,J=7.4Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ211.4,190.2,156.7,139.7,131.9,128.7,128.1,127.7,84.7,83.8,51.1,39.1,33.4,18.5,17.6,13.7.

[0095] Example 6

[0096] The reaction equation is shown below:

[0097]

[0098] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-methoxyphenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-methyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was completed, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 62.7 mg of a white solid (4f) with a yield of 62.7%.

[0099] Fig.13 This is the 1H nuclear magnetic resonance spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5a) provided in Example 6 of the present invention. Fig.14 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5a) provided in Example 6 of the present invention. Fig.15 This is the nuclear magnetic resonance NOESY spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5a) provided in Example 6 of the present invention.

[0100] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ7.69(d,J=8.7Hz,2H,ArH),6.93(d,J=8.8Hz,2H,ArH),5.54(d,J=7.3Hz,1H,H-2),4.26(dt,J=9.1,7.3Hz,1H,H-3),4.01(q,J=6 .8Hz,1H,H-6),3.87(s,3H,OCH3),2.69(dd,J=14.7,9.2Hz,1H,H-4),2.62( dd,J=14.7,7.4Hz,1H,H-4),2.42(s,3H,SCH3),1.39(d,J=7.0Hz,3H,CH3). 13 C NMR (100MzHz, CDCl3) δ211.3,189.5,163.1,151.9,131.8,130.7,129.2,113.9,83.6,80.9,55.5,51.7,38.1,17.5,16.8.

[0101] Example 7

[0102] The reaction equation is shown below:

[0103]

[0104] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-chlorophenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-methyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification of 200 mesh to 300 mesh, eluent of petroleum ether / ethyl acetate = 30:1) to obtain 64.3 mg of a white solid (4 g) with a yield of 80.4%.

[0105] Fig.16 This is the 1H nuclear magnetic resonance spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5b) provided in Example 7 of the present invention. Fig.17 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5b) provided in Example 7 of the present invention. Fig.18This is the nuclear magnetic resonance NOESY spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5b) provided in Example 7 of the present invention.

[0106] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ7.60–7.55(m,2H,ArH),7.45–7.39(m,2H,ArH),5.57(d,J=7.4Hz,1H,H-2),4.23(dt,J=9.4,7.3Hz,1H,H-3),4.01( q,J=7.0Hz,1H,H-6),2.68(dd,J=14.6,9.4Hz,1H,H-4),2.58(dd,J=14.6,7.2Hz,1H,H-4),2.46(s,3H,SCH3),1.39(d,J=7.0Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ210.9,189.0,156.8,138.4,137.9,129.4,129.0,128.0,83.6,80.9,51.1,38.3,17.7,16.8.

[0107] Example 8

[0108] The reaction equation is shown below:

[0109]

[0110] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-iodophenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-methyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was completed, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification is 200 mesh to 300 mesh, and the eluent is petroleum ether / ethyl acetate = 30:1) to obtain 70.7 mg of a white solid (4h) with a yield of 56.9%.

[0111] Fig.19 This is the 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5c) provided in Example 8 of the present invention. Fig. 20 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5c) provided in Example 8 of the present invention.

[0112] The NMR spectrum data of the obtained product are: 1 H NMR (400MHz, CDCl3) δ7.85–7.73(m,2H,ArH),7.39–7.30(m,2H,ArH),5.57(d,J=7.4Hz,1H,H-2),4.22(dt,J=9.4,7.3Hz,1H,H-3),4. 01(q,J=7.0Hz,1H,H-6),2.67(dd,J=14.6,9.4Hz,1H,H-4),2.62–2.55(d,1H,H-4),2.46(s,3H,SCH3),1.39(d,J=7.0Hz,3H,6-CH3). 13 C NMR (100MHz, CDCl3) δ210.9,189.2,157.2,138.9,137.9,129.4,127.8,99.3,83.6,80.9,51.1,38.3,17.6,16.7.

[0113] Example 9

[0114] The reaction equation is shown below:

[0115]

[0116] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-methoxyphenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-ethyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 62.2 mg of a white solid (4i) with a yield of 77.8%.

[0117] Fig.21 This is the 1H NMR spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5d) provided in Example 9 of the present invention. Fig. 22 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5d) provided in Example 9 of the present invention.

[0118] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.71–7.64(m,2H,ArH),6.98–6.85(m,2H,ArH),5.52(d,J=7.4Hz,1H,H-2),4.24(q,J=8.1Hz,1H ,H-3),3.87(s,3H,OCH3),3.82(dd,J=7.4,4.5Hz,1H,H-6),2.61(d,J=8.5Hz,2H,H-4),2.43(s,3H,SCH3),1.78(m,2H, CH 2CH3),1.01(t,J=7.4Hz,3H,CH2 CH 3). 13 C NMR (100MHz, CDCl3) δ211.4,189.4,163.0,131.9,130.5,129.1,113.9,85.9,83.7,55.4,51.6,39.2,24.8,17.5,9.7.

[0119] Example 10

[0120] The reaction equation is shown below:

[0121]

[0122] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-chlorophenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-ethyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 63.7 mg of a white solid (4j) with a yield of 79.6%.

[0123] Fig.23 This is the 1H nuclear magnetic resonance spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5e) provided in Example 10 of the present invention. Fig.24 This is the nuclear magnetic resonance 13C spectrum of the thieno[2,3-b]pyrone heterocyclic compound (5e) provided in Example 10 of the present invention.

[0124] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.57(d,J=8.4Hz,2H,ArH),7.41(d,J=8.4Hz,2H,ArH),5.54(d,J=7.4Hz,1H,H-2),4.21(dt,J=9.4,7.5Hz,1H,H- 3),3.82(dd,J=7.7,4.6Hz,1H,H-6),2.58(dd,J=8.4,6.9Hz,2H,H-4),2.46(s,3H,SCH3),1.86–1.71(dq,2H),1.00(t,J=7.4Hz,3H,CH2 CH 3). 13 C NMR (100MHz, CDCl3) δ211.0,188.9,157.1,138.2,137.9,129.3,129.1,127.9,85.9,83.7,51.1,39.3,24.8,17.6,9.7.

[0125] Embodiment 11

[0126] The reaction equation is shown below:

[0127]

[0128] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-fluorophenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-ethyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was completed, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 60.3 mg of a white solid (4k) with a yield of 75.4%.

[0129] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.71–7.61(m,2H,ArH),7.17–7.07(m,2H,ArH),5.54(d,J=7.4Hz,1H,H-2),4.22(dt,J=9.3,7.5Hz,1H,H-3),3 .82(dd,J=7.7,4.6Hz,1H,H-6),2.59(dd,J=8.4,5.6Hz,2H,H-4),2.46(s,3H,SCH3),1.90–1.67(m,2H),1.01(t,J=7.4Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ211.1,188.9,166.3,163.8,156.1,135.8,130.5,130.5,128.2,116.0,115.8,86.0,83.7,51.3,39.3,24.8,17.6,9.8.

[0130] Example 12

[0131] The reaction equation is shown below:

[0132]

[0133] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-methoxyphenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-propyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 58.7 mg of a white solid (4l) with a yield of 73.4%.

[0134] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.72–7.63(m,2H,ArH),6.98–6.89(m,2H,ArH),5.51(d,J=7.4Hz,1H,H-2),4.24(dt,J=9.2,7.5Hz,1H,H-3),3.90–3.84 (m,1H,H-6),3.87(s,3H,OCH3),2.69–2.54(m,2H,H-4),2.43(s,3H,SCH3),1.78–1.63(m,2H),1.53–1.42(m,2H),0.92(t,J=7.3Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ211.5,189.4,163.0,152.3,131.9,130.5,129.1,113.9,84.7,83.6,55.4,51.6,39.0,33.4,18.5,17.5,13.7.

[0135] Example 13

[0136] The reaction equation is shown below:

[0137]

[0138] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-chlorophenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-propyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was completed, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification of 200 mesh to 300 mesh, eluent of petroleum ether / ethyl acetate = 30:1) to obtain 61.2 mg of a white solid (4m) with a yield of 76.5%.

[0139] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.54–7.48(m,2H,ArH),7.46–7.39(m,2H,ArH),6.30(d,J=8.9 Hz,1H,H-2),4.58(dt,J=8.6,5.3,2.6Hz,1H,H-3),4.14–4.06(dd,1H,H-6),2.82(dd ,J=15.4,5.4Hz,1H,H-4),2.55(dd,J=15.4,2.7Hz,1H,H-4),2.40(s,3H,SCH3),1.92 –1.79(m,1H),1.71–1.57(m,1H),1.43(dq,J=7.4Hz,2H),0.93(t,J=7.4Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ211.2,188.9,157.2,138.2,137.9,129.3,129.0,127.9,84.7,83.7,51.1,39.1,33.4,18.5,17.6,14.1,13.7.

[0140] Embodiment 14

[0141] The reaction equation is shown below:

[0142]

[0143] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-(4-fluorophenyl)-3-oxopropanedithiomethyl ester (0.47 mmol), (2R, 6R)-6-propyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 65.1 mg of a white solid (4n) with a yield of 81.4%.

[0144] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.71–7.62(m,2H,ArH),7.16–7.09(m,2H,ArH),5.54(d,J=7.5H z,1H,H-2),4.22(dt,J=9.6,7.5Hz,1H,H-3),3.88(dd,J=7.2,5.4Hz,1H,H-6),2.63(d d,J=14.4,9.5Hz,1H,H-4),2.56(dd,J=14.4,7.3Hz,1H,H-4),2.45(s,3H,SCH3),1.71 (dq,J=7.7,5.6,2.1Hz,2H),1.46(dt,J=15.1,7.7Hz,2H),0.92(t,J=7.3Hz,3H,CH3). 13 C NMR (100MHz,CDCl3)δ 13 C NMR (101MHz, CDCl3) δ211.2,188.8,166.3,163.8,156.0,135.8,130.5,128.1,115.9,84.4,83.6,51.1,39.1,33.4,18.5,17.6,13.3.

[0145] Embodiment 15

[0146] The reaction equation is shown below:

[0147]

[0148] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-oxo-3-phenylpropanedithiomethyl ester (0.47 mmol), (2S,6R)-6-methyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200-300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 63.8 mg of a white solid (5a) with a yield of 79.8%.

[0149] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.55–7.48(m,3H,ArH),7.44–7.39(m,2H,ArH),6.27(dd,J=8.8,0.9Hz,1H,H-2),4.57(ddd,J=8.2,5.2,2.5Hz,1H,H-3),4 .23(q,J=6.8Hz,1H,H-6),2.85(dd,J=15.7,5.3Hz,1H,H-4),2.57(dd,J=15.7,2.6Hz,1H,H-4),2.41(s,3H,CH3),1.37(d,J=6.9Hz,3H,6-CH3). 13 C NMR (100MHz, CDCl3) δ210.7,190.0,157.4,139.6,132.0,128.9,128.1,127.9,84.2,73.4,49.6,36.5,17.8,15.6.

[0150] Example 16

[0151] The reaction equation is shown below:

[0152]

[0153] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-oxo-3-phenylpropanedithiomethyl ester (0.47 mmol), (2S,6S)-6-methyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200-300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 60.0 mg of a white solid (5b) with a yield of 74.7%.

[0154] The NMR spectrum data of the obtained product are: 1H NMR (400MHz, CDCl3) δ7.67–7.58(m,2H,ArH),7.56–7.50(m,1H,ArH),7.46–7.40(m,2H,ArH),5.57(d,J=7.3Hz,1H,H-2),4.25(dt,J=9.5,7.2Hz,1H,H -3),3.99(q,J=7.0Hz,1H,H-6),2.67(dd,J=14.5,9.6Hz,1H,H-4),2.50(dd ,J=14.6,7.2Hz,1H,H-4),2.45(s,3H,SCH3),1.38(d,J=6.9Hz,3H,6-CH3). 13 C NMR (100MHz, CDCl3) δ211.2,190.2,156.5,139.7,132.1,128.1,128.9,128.1,127.8,83.7,80.9,77.2,51.0,38.3,17.6,16.7.

[0155] Embodiment 17

[0156] The reaction equation is shown below:

[0157]

[0158] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-oxo-3-phenylpropanedithiomethyl ester (0.47 mmol), (2S,6R)-6-ethyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200 mesh to 300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 60.6 mg of a white solid (5c) with a yield of 75.7%.

[0159] The NMR spectrum data of the obtained product are: 1H NMR(400MHz,)δ7.56–7.47(m,3H,ArH),7.45–7.38(m,2H,ArH),6.31(d,J=8.9Hz,1H,H -2),4.58(ddd,J=8.7,5.3,2.6Hz,1H,H-3),4.05(dd,J=7.6,3.9Hz,1H,H-6),2.81(dd ,J=15.4,5.4Hz,1H,H-4),2.56(dd,J=15.5,2.6Hz,1H,H-4),2.40(s,3H,SCH3)1.92(d qd,J=14.9,7.5,3.8Hz,1H),1.72(dt,J=14.6,7.3Hz,1H),0.96(t,J=7.4Hz,3H,CH3). 13 C NMR (100MHz, CDCl3) δ210.7,190.1,157.4,139.7,132.1,128.7,128.1,128.0,84.8,78.1,49.8,37.4,23.4,17.9,9.4.

[0160] Embodiment 18

[0161] The reaction equation is shown below:

[0162]

[0163] At 0°C and nitrogen atmosphere, a 25 ml reaction tube equipped with a magnetic stirrer was charged with 3-oxo-3-phenylpropanedithiomethyl ester (0.47 mmol), (2S,6S)-6-ethyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (0.47 mmol), sodium hydride (0.47 mmol), and tetrahydrofuran (2 ml). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate (3x10 ml). The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (silica gel specification: 200-300 mesh, eluent: petroleum ether / ethyl acetate = 30:1) to obtain 48.3 mg of a white solid (5d) with a yield of 60.4%.

Claims

1. A thieno[2,3-b]pyrone heterocycle, characterized in that The structural formula of the thieno[2,3-b]pyrone heterocycle is: Wherein R1 is methyl, ethyl or propyl, and R2 is F, Cl, I or methoxy.

2. A method for synthesizing the thieno[2,3-b]pyrone heterocycle according to claim 1, characterized in that: The synthesis method comprises: using acetyl pyrone of the structure shown in formula (I) and β-oxydithioester of the structure shown in formula (II) as reaction raw materials, reacting in an alkaline environment to obtain a thieno[2,3-b]pyrone heterocycle of the structure shown in formula (III); The reaction equation is shown below: Wherein R1 in the compound of formula (I) is methyl, ethyl or propyl; R2 in the compound of formula (II) is F, Cl, I or methoxy.

3. The synthesis method according to claim 2, characterized in that The reaction in an alkaline environment specifically comprises: dissolving the acetyl pyrone and the β-oxydithioester in an organic solvent, adding NaH, and reacting at room temperature.

4. The synthesis method according to claim 2, characterized in that The organic solvent is at least one of N,N-dimethylformamide, dichloromethane, ethyl acetate, chloroform, n-hexane, acetonitrile, 1,4-dioxane, toluene, tetrahydrofuran, ether and carbon tetrachloride.

5. The synthesis method according to claim 2, characterized in that The molar ratio of the acetyl pyrone to the β-oxydithioester is 1:(1-2).

6. The synthesis method according to claim 5, characterized in that The molar ratio of the acetyl pyrone to the β-oxydithioester is 1:

1.

7. The synthesis method according to claim 2, characterized in that The reaction time is 6h-18h.

8. The synthesis method according to any one of claims 2 to 4, characterized in that The synthesis method further comprises: after the reaction is completed, removing the solvent from the reaction solution under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain a thieno[2,3-b]pyrone heterocycle having a structure shown in formula (III).

9. The synthesis method according to claim 8, characterized in that The eluent used in the column chromatography is a mixture of petroleum ether and ethyl acetate.

10. The synthesis method according to claim 9, characterized in that In the eluent, the volume ratio of petroleum ether to ethyl acetate is (10-60):1.

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