A 1,3-dithiocyclobutane-2,4-diylidene compound and its synthesis and application

Abstract

The invention discloses a 1,3-dithioheterocyclobutane-2,4-diyl compound and its synthesis and application. At room temperature, in a reaction bottle, α-methylene ketone is dissolved in a solvent, and a base is added under stirring, and then carbon disulfide is added; the reaction system reacts at a temperature lower than the boiling point of carbon disulfide in a closed reactor, and the reaction progress is detected by TLC; after the reaction is completed, an aqueous hydrochloric acid solution is added until the color of the solution does not change after the reaction; it is extracted with ethyl acetate, washed with water, washed with saturated salt water, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified and separated by rapid column chromatography to obtain. The mixture has a good inhibitory effect on cancer cells and has the potential to be used for the preparation of anti-tumor drugs. The synthesis method is easy to operate, the system is insensitive to light, water and oxygen, the reaction conditions are mild, and there is no danger of violent heat release or volume expansion.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound process application, and relates to a 1,3-dithioheterocyclobutane-2,4-diylidene compound and a synthesis method and application thereof. Background Art

[0002] Sulfur-containing organic compounds play an important role in life in nature, such as sulfur-containing cysteine, sulfur-containing methionine, and disulfide bonds that determine the secondary / tertiary spatial structure of proteins, which have irreplaceable roles and functions in life. Sulfur-containing organic compounds also have a wide range of biological activities, such as anti-tumor, anti-fungal, blood pressure reduction, protection of nerve cells, and treatment of cardiovascular and cerebrovascular diseases. 1,3-dithiobutane-2,4-diyl compounds have great application and development value. There have been few methods for obtaining 1,3-dithiobutane-2,4-diyl compounds through artificial synthesis, and even fewer methods for directly converting carbon disulfide (CS2), which is widely available, difficult to store, and highly toxic, into 1,3-dithiobutane-2,4-diyl compounds. The few existing methods require transition metal copper heating desulfurization catalytic reaction, and the synthesis method of 1,3-dithiobutane-2,4-diyl compounds without metal participation has not been explored. Summary of the invention

[0003] The object of the present invention is to provide a 1,3-dithiacyclotane-2,4-diylidene compound which is synthesized by using carbon disulfide as a raw material without metal catalysis.

[0004] The second object of the present invention is to provide a method for synthesizing the above compound.

[0005] The third object of the present invention is to provide a use of the above compound.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is: a 1,3-dithioheterocyclobutane-2,4-diylidene compound, the general chemical structure of which is:

[0007]

[0008] Among them, R1 = CH3, Ph, pF-Ph, p-Br-Ph, p-CH3-Ph, p-OCH3-Ph, p-Cl-Ph, and various alkyl, cycloalkyl, alkoxy, aryl, substituted aryl. R2 = COCH3, COOCH3, COOCH2CH3, CN, and various acyl, cycloacyl, cyano, ester groups.

[0009] Another technical solution adopted by the present invention is: a method for synthesizing the above compound, specifically:

[0010] 1) Take α-methylene ketone and solvent respectively, and then take alkali, carbon disulfide and hydrochloric acid aqueous solution at a molar ratio of 1:0.5-5. The molar ratio of α-methylene ketone to alkali is 1:0.1-4, and the molar ratio of α-methylene ketone to carbon disulfide is 1:0.1-40. 1 mmol of α-methylene ketone requires 15 mL of 1M hydrochloric acid aqueous solution;

[0011] 2) At room temperature, in a reaction bottle, dissolve α-methylene ketone in a solvent, add a base under stirring, stir until the color changes, and then add carbon disulfide; the reaction system is reacted at a temperature of -28°C to 46°C in a closed reactor, and the reaction progress is monitored by TLC; after the reaction is completed, add aqueous hydrochloric acid until the color of the solution no longer changes after the reaction; then extract with ethyl acetate, wash with water, wash with saturated brine, and then dry with anhydrous sodium sulfate or anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and purify and separate by rapid column chromatography to obtain 1,3-dithiacyclobutane-2,4-diylidene compounds.

[0012] The order of adding materials is the safest and most efficient with carbon disulfide added last.

[0013] The reaction temperature should be controlled below the boiling point of carbon disulfide.

[0014] The reaction time is generally measured by TLC. When the raw material no longer decreases with increasing reaction time, the reaction time of different α-methylene ketones and carbon disulfide is based on the specific time when the raw material spot displayed on the corresponding thin layer chromatography spot plate disappears or no longer decreases.

[0015] The synthesis method of the present invention directly converts carbon disulfide into sulfur-containing organic compounds. Its structural feature is to construct a 1,3-dithiocyclobutane-2,4-diylidene skeleton, and different substituents can be introduced through the design of the substrate. Inexpensive carbon disulfide and α-methylene ketone are used in a reaction solvent, and a catalytic reaction is performed under the action of a base catalyst to obtain a 1,3-dithiocyclobutane-2,4-diylidene compound.

[0016] The reaction process of the synthesis method of the present invention is:

[0017]

[0018] Wherein, R1=CH3, Ph, pF-Ph, p-Br-Ph, p-CH3-Ph, p-OCH3-Ph, p-Cl-Ph, alkyl, cycloalkyl, alkoxy, aryl or substituted aryl. R2=COCH3, COOCH3, COOCH2CH3, CN, acyl, cycloacyl, cyano or ester.

[0019] α-Methylene ketone and carbon disulfide (CS2) are both common commodities with wide sources and low prices. There is no special requirement for the purity of the carbon disulfide raw material, and the purity of ordinary reagents can be used.

[0020] α-Methylene ketones include R1=CH3, Ph, pF-Ph, p-Br-Ph, p-CH3-Ph, p-OCH3-Ph, p-Cl-Ph, alkyl, cycloalkyl, alkoxy, aryl or substituted aryl. R2=COCH3, COOCH3, COOCH2CH3, CN, acyl, cycloacyl, cyano or ester.

[0021] The base is a catalyst, including inorganic bases and organic bases. The inorganic base includes: KOH, NaOH, K2CO3 or NaH. The organic base includes: triethylamine, pyridine, imidazole, DBU, n-butyl lithium, guanidine carbonate, pyrrole, tetramethylguanidine, nitroguanidine, 4-aminopyridine or methylnitroguanidine.

[0022] The solvent used is toluene, dichloromethane, chloroform, dimethyl sulfoxide, ethanol, isopropanol, water, ethyl acetate, tetrahydrofuran, acetone, triethylamine, n-pentane, acetonitrile or carbon disulfide.

[0023] In the synthesis method of the present invention, under alkaline conditions, active methylene groups attack carbon disulfide molecules by nucleophilic addition, and then generate products through proton exchange, acid desulfurization and bimolecular cyclization steps. This reaction pathway has very mild conditions, fast and convenient operation, high atomic utilization of carbon disulfide, and ingeniously achieves the construction of 1,3-dithiacyclobutane-2,4-disubunit skeleton and efficient utilization of carbon disulfide through nucleophilic addition induced tandem and cyclization reactions.

[0024] The third technical solution adopted by the present invention is: an application of the above-mentioned compound in a drug for treating cancer. The 1,3-dithioheterocyclobutane-2,4-diylidene skeleton constructed by the present invention can not only introduce different substituents by designing the substrate of α-methylene ketone, but also carry out derivatization reaction on olefinic bonds, α-keto carbonyl / ester carbonyl of some products, and sulfur heterocycle. Furthermore, the research results of the present invention on the inhibitory activity of the product on cancer cells show that it has a good inhibitory effect on the growth of cancer cells and is expected to be used in the development of innovative drugs for treating cancer.

[0025] The invention prepares a sulfur-containing compound, and typical sulfur-containing compounds exist in different drug molecular structures, such as ADT-OH, a drug used to protect HT-22 hippocampal nerve cells from glutamate damage, and Disulfiram, a drug used to resist alcoholism and cancer.

[0026]

[0027] The various raw materials used in the synthesis method of the present invention are simple, all of which are readily available commodities with a wide range of sources and low prices, and have stable chemical properties and do not require special storage. In particular, the present invention converts carbon disulfide, which has a low boiling point, is difficult to store, and is easy to quickly cause toxicity and discomfort to the body, into a sulfur-containing organic compound that is odorless, stable and easy to store. Secondly, the present invention is easy to operate, the system is insensitive to light, water and oxygen, the reaction conditions are mild, and there will be no severe heat release or volume expansion that will cause danger. The reaction time is short and the reaction is highly applicable.

[0028] Through the activity test of the compounds on cancer cells, it was found that 1,3-dithioheterocyclobutane-2,4-diyl compounds have a good inhibitory effect on cancer cells. This is of great significance for the discovery of medicines and pesticides with potential application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the single crystal structure diagram of product B18 in Example 18. DETAILED DESCRIPTION

[0030] The present invention is further described in detail with reference to the following specific embodiments.

[0031] The synthesis method of 1,3-dithioheterocyclobutane-2,4-diylidene core skeleton in the prior art:

[0032]

[0033] This method has complex raw materials and reaction procedures, requires the use of transition metal copper to achieve desulfurization, has a high reaction temperature, and requires step-by-step control of high and low temperatures, all of which limit the further application of the reaction.

[0034] The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. Embodiments 9-11 Because the polarity of the product is similar to that of the raw material, the product spectra contain a small amount of raw materials, and the authenticity and accuracy of the product structure and other data are not affected by detailed analysis of the spectra. The data given in the following examples include specific operations, reaction conditions and products. The product structure is identified by means such as nuclear magnetic resonance.

[0035] Example 1

[0036] 3,3'-(1,3-dithietane-2,4-diylidene)bis(pentane-2,4-dione)

[0037]

[0038] In a 25 mL reaction tube, add a magnetic bar and dissolve A1 (100 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 10:1 as the eluent. The theoretical yield of the chromatographic reaction was 74%, and 30.0 mg (21.13% isolated yield) of yellow solid product B1 was obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 2.65 (s, 6H), 2.52 (s, 6H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 212.74, 198.15, 174.67, 147.61, 30.51,19.09.HRMS (ESI) m / z: Calc. for C 11 H 12 O4S2[M+H] + : 285.0250, found: 285.0339.

[0039] Example 2

[0040] 2,2'-(1,3-dithietane-2,4-diylidene)bis(cyclohexane-1,3-dione)

[0041]

[0042] In a 25 mL reaction tube, add a magnetic bar and dissolve A2 (112.13 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 5:1 as the eluent. The theoretical yield of the chromatographic chromatography is 70%, and 27.9 mg (18.12% isolated yield) of brick-red solid product B2 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 3.11 (t, J = 6.2 Hz,4H), 2.69 – 2.63 (m, 4H),2.24 (t, J = 6.5 Hz,4H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ212.40, 189.71, 188.14, 135.21, 39.32,31.32, 23.29.HRMS (ESI) m / z: Calc. forC 14 H 12 O4S2[M+H] + : 309.0249, found: 309.0207.

[0043] Example 3

[0044] Dimethyl 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-oxobutanoate)

[0045]

[0046] In a 25 mL reaction tube, add a magnetic bar and dissolve A3 (116 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 20:1 as the eluent. The theoretical yield of the chromatography is 65%, and 10.2 mg (6.46%isolatedyield) of a yellow-brown liquid product B3 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 3.94 (s, 6H), 2.58 (s, 6H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 211.71, 174.32, 163.59, 140.47, 52.98,19.04.HRMS (ESI) m / z: Calc. for C 12 H 12 O6S2[M+H] + : 317.0148, found: 317.0149.

[0047] Example 4

[0048] Diethyl 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-oxobutanoate)

[0049]

[0050] In a 25 mL reaction tube, add a magnetic bar and dissolve A4 (130.14 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 30:1 as the eluent. The theoretical yield of the chromatography is 60%, and 12.8 mg (7.44%isolatedyield) of a yellow-brown liquid product B4 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 4.41 (q, J = 7.1 Hz, 4H), 2.58 (s, 6H), 1.39 (t, J = 7.1 Hz, 6H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ211.72, 173.72, 163.15, 140.70, 62.34, 18.89, 14.17.HRMS (ESI) m / z: Calc. forC 14 H 16 O6S2[M+K] + : 383.0020, found: 383.0019.

[0051] Example 5

[0052] 2,2'-(1,3-dithietane-2,4-diylidene)bis(5-methylcyclohexane-1,3-dione)

[0053]

[0054] In a 25 mL reaction tube, add a magnetic bar and dissolve A5 (126.12 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate in a volume ratio of 2:1 as the eluent. The theoretical yield of the chromatographic chromatography is 67%, and 30.7 mg (18.27%isolatedyield) of brick-red solid product B5 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 3.16 (ddd, J = 17.6,4.2, 1.6 Hz, 2H), 2.80 – 2.70 (m, 4H),2.48 (dddt, J = 11.3, 10.1, 6.4, 3.9Hz, 2H), 2.35 (dd, J = 16.2, 11.7 Hz, 2H), 1.20 (s, 3H), 1.19 (s, 3H). 13 C{ 1 H}NMR (101 MHz, CDCl3) δ 212.13, 189.60, 187.75, 135.00, 47.44,38.73, 31.05,20.48.HRMS (ESI) m / z: Calc. for C 16 H 16 O4S2[M+H] + : 337.0563, found: 337.0562.

[0055] Example 6

[0056] 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-oxo-3-phenylpropanenitrile)

[0057]

[0058] In a 25 mL reaction tube, add a magnetic bar and dissolve A6 (145.16 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 10:1 as the eluent. The theoretical yield of the chromatography is 71%, and 99.7 mg (28.72% isolated yield) of reddish brown solid product B6 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.0, 1.5Hz, 4H), 7.68 (d, J = 7.5 Hz, 2H), 7.60 (td, J = 7.3, 1.4 Hz, 4H). 13 C{ 1 H} NMR (101MHz, CDCl3) δ 209.87, 180.54, 133.67, 129.94, 128.98, 128.01, 120.72,113.35.HRMS (ESI) m / z: Calc. for C 20 H 10 N2O2S2[M+H] + : 375.0256, found: 375.0217.

[0059] Example 7

[0060] Diethyl 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(4-fluorophenyl)-3-oxopropanoate)

[0061]

[0062] In a 25 mL reaction tube, add a magnetic bar and dissolve A7 (179.04 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 60:1 as the eluent. The theoretical yield of the chromatography is 83%, and 68 mg (26.96% isolated yield) of red oily liquid product B7 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 8.8,5.1 Hz, 4H), 7.19 (dd, J = 8.9, 8.2 Hz, 4H), 4.25 (q, J = 7.1 Hz, 4H), 1.18 (t, J =7.1 Hz, 6H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 211.20, 170.99, 166.05, 163.52 / 163.38, 140.92, 130.17 / 130.08, 127.44 / 127.40, 116.85 / 116.63,62.62, 13.92. 19 FNMR (376 MHz, CDCl3) δ -106.41.HRMS (ESI) m / z: Calc. for C 24 H 18 F2O6S2[M+H] + :505.0586, found: 505.0542.

[0063] Example 8

[0064] Diethyl 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(4-bromophenyl)-3-oxopropanoate)

[0065]

[0066] In a 25 mL reaction tube, add a magnetic bar and dissolve A8 (189.3 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 60:1 as the eluent. The theoretical yield of the chromatography is 81%, and 91.7 mg (29.3%isolatedyield) of red oily liquid product B8 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.6 Hz,4H), 7.45 (d, J = 8.6 Hz, 4H), 4.26 (q, J = 7.1 Hz, 4H), 1.19 (t, J = 7.1 Hz, 6H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 211.12, 170.73, 163.23, 140.85, 132.66,130.10, 129.24, 126.67, 62.65, 13.89.HRMS (ESI) m / z:Calc. for C 24 H 18 Br2O6S2[M+Na] + : 646.8804, found: 646.8895.

[0067] Example 9

[0068] Diethyl 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-oxo-3-(p-tolyl)propanoate)

[0069]

[0070] In a 25 mL reaction tube, add a magnetic particle and dissolve A9 (195.3 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 60:1 as the eluent. Use fast column chromatography to separate 115.8 mg of a mixture of yellow-brown solid product B9, which contains raw material A9 and the tautomeric enol form of raw material A9. The yield of the target product B9 in the mixture identified by nuclear magnetic resonance is 52.8%. 1 HNMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 4H), 7.47 (d, J = 8.2 Hz, 4H), 4.21(q, J = 7.2 Hz, 4H), 2.42 (s, 6H), 1.26 (t, J = 7.1 Hz, 6H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 211.35, 171.64, 163.69, 130.10, 129.45, 128.64, 127.70, 86.65,61.39, 21.68,14.09.HRMS (ESI) m / z: Calc. for C 26 H 24 O6S2[M+H] + : 497.1087, found:497.1105.

[0071] Example 10

[0072] Diethyl 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(4-chlorophenyl)-3-oxopropanoate)

[0073]

[0074] In a 25 mL reaction tube, add a magnetic particle and dissolve A10 (226.66 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed manner at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 60:1 as the eluent. Use fast column chromatography to separate 106.4 mg of a mixture of yellow oily liquid product B10, which contains raw material A10 and the tautomeric enol form of raw material A10. The yield of the target product B10 in the mixture identified by nuclear magnetic resonance is 57.3%. 1 H NMR (400 MHz, CDCl3) δ 7.54 – 7.47 (m, 8H), 4.25 (q, J = 7.1 Hz, 4H),1.19 (t, J = 7.1 Hz, 6H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 211.16, 170.14, 163.25,138.36, 129.91, 129.69, 129.13, 87.69, 62.63, 13.89.HRMS (ESI) m / z: Calc. forC 24 H 18 Cl2O6S2[M+H] + : 568.9715, found: 568.9663.

[0075] Embodiment 11

[0076] Diethyl 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(4-methoxyphenyl)-3-oxopropanoate)

[0077]

[0078] In a 25 mL reaction tube, add a magnetic particle and dissolve A11 (191.58 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 20:1 as the eluent. Use fast column chromatography to separate 70.4 mg of a mixture of red oily liquid product B11, which contains raw material A11 and the tautomeric enol form of raw material A11. The yield of the target product B11 in the mixture identified by nuclear magnetic resonance is 62.11%. 1 H NMR (400 MHz, CDCl3) δ 7.96 – 7.90 (m, 4H), 6.96 – 6.93 (m, 4H), 4.21 (q, J = 7.1 Hz, 4H), 3.88 (s, 6H), 1.26 (t, J = 7.2 Hz, 6H). 13 C{ 1 H} NMR (101MHz, CDCl3) δ 211.20, 163.95, 162.67, 130.84, 129.42, 114.82, 113.89, 85.67,61.33, 55.48, 14.04.HRMS (ESI) m / z: Calc. for C 26 H 24 O8S2[M+Na] + : 551.0805,found: 551.0818.

[0079] Example 12

[0080] 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(4-chlorophenyl)-3-oxopropanenitrile)

[0081]

[0082] In a 25 mL reaction tube, add a magnetic bar and dissolve A12 (145.26 μL, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 20:1 as the eluent. The theoretical yield of the chromatogram is 53%, and 17.1 mg (7.76%isolatedyield) of orange-yellow solid product B12 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.6 Hz,4H), 7.58 (d, J = 8.6 Hz, 4H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 209.45, 178.78,140.31, 130.34, 129.25, 128.30, 120.90, 113.13.HRMS (ESI) m / z:Calc. forC 20 H8Cl2N2O2S2[M+H] + : 442.9477, found: 442.9543.

[0083] Example 13

[0084] 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(4-fluorophenyl)-3-oxopropanenitrile)

[0085]

[0086] In a 25 mL reaction tube, add a magnetic bar and dissolve A13 (163.15 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 30:1 as the eluent. The theoretical yield of the chromatogram is 48%, and 81.0 mg (39.51% isolated yield) of orange-yellow solid product B13 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 7.88 – 7.83 (m,4H), 7.33 – 7.27 (m, 4H). 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 209.52, 178.93,131.73 / 131.63, 130.50 / 130.41, 120.78, 117.53 / 117.31, 116.87 / 116.65, 113.22. 19 FNMR (376 MHz, CDCl3) δ -102.91.HRMS (ESI) m / z: Calc. for C 20 H8F2N2O2S2[M+H] + :411.0068, found: 441.0406.

[0087] Embodiment 14

[0088] 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(4-bromophenyl)-3-oxopropanenitrile)

[0089]

[0090] In a 25 mL reaction tube, add a magnetic bar and dissolve A14 (224.05 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 30:1 as the eluent. The theoretical yield of the chromatogram is 13%, and 7.1 mg (9.70% isolated yield) of orange-red solid product B14 is separated by rapid column chromatography. 1 H NMR (400 MHz, DMSO) δ 7.93 – 7.88 (m, 4H),7.85 – 7.77 (m, 4H). 13 C{ 1 H}NMR (101 MHz, DMSO) δ 211.42, 181.18, 132.79,132.75, 130.23, 129.65, 128.95, 127.24, 120.73, 113.50.HRMS (ESI) m / z: Calc.for C 20 H8Br2N2O2S2[M+H] + : 562.8365, found: 562.8624.

[0091] Embodiment 15

[0092] 2,2'-(1,3-dithietane-2,4-diylidene)bis(1-cyclopropylbutane-1,3-dione)

[0093]

[0094] In a 25 mL reaction tube, add a magnetic bar and dissolve A15 (126.15 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 30:1 as the eluent. The theoretical yield of the chromatographic chromatography is 55%, and 16.3 mg (9.7% isolated yield) of orange-yellow solid product B15 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 2.57 (m, 2H), 2.50 (s,6H), 1.30 – 1.25 (m, 4H), 1.09 (m,4H). 13 C{ 1 H}NMR (101 MHz, CDCl3) δ 212.79,200.71, 173.76, 148.07, 22.48, 18.88, 13.47.HRMS (ESI) m / z: Calc. forC 16 H 16 O4S2[M+H] + : 337.0563, found: 337.0596.

[0095] Example 16

[0096] 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(3-chlorophenyl)-3-oxopropanenitrile)

[0097]

[0098] In a 25 mL reaction tube, add a magnetic bar and dissolve A16 (179.6 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 20:1 as the eluent. The theoretical yield of the chromatogram is 51%, and 14.8 mg (6.71% isolated yield) of yellow solid product B16 is obtained by rapid column chromatography. 1 H NMR (400 MHz, DMSO) δ 7.98 (t, J = 1.9 Hz,2H), 7.85 – 7.80 (m, 4H),7.70 (t, J = 7.9 Hz, 2H). 13 C{ 1 H}NMR (101 MHz, DMSO) δ211.29, 180.51, 134.16, 132.83, 131.54,131.53, 127.92, 127.16, 121.26,113.35.HRMS (ESI) m / z: Calc. for C 20 H8Cl2N2O2S2[M+H] + : 442.9477, found:442.9379.

[0099] Embodiment 17

[0100] Dimethyl 2,2'-(1,3-dithietane-2,4-diylidene)bis(3-(4-fluorophenyl)-3-oxopropanoate)

[0101]

[0102] In a 25 mL reaction tube, add a magnetic bar and dissolve A17 (196.17 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 10:1 as the eluent. The theoretical yield of the chromatogram is 62%, and 25.1 mg (19.73% isolated yield) of orange-red solid product B17 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 7.61 – 7.55 (m,4H), 7.23 – 7.16 (m, 4H), 3.78 (s, 6H). 13 C{ 1 H}NMR (101 MHz, CDCl3) δ 211.15,171.16, 166.08, 163.94, 163.55,140.74, 130.08, 129.99, 127.35, 127.31,116.97, 116.75, 53.36. 19 F NMR (376 MHz, CDCl3) δ -106.17.HRMS (ESI) m / z: Calc.for C 22 H 14 F2O6S2[M+H] + : 477.0273, found: 477.0262.

[0103] Embodiment 18

[0104] 4,4'-(1,3-dithietane-2,4-diylidene)bis(2,6-dimethylheptane-3,5-dione)

[0105]

[0106] In a 25 mL reaction tube, add a magnetic bar and dissolve A18 (156.2 mg, 1 mmol) in 3 mL of DMSO. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) in sequence. Stir in a closed container at room temperature and monitor the reaction by TLC. When the raw material no longer decreases with the increase of reaction time, add a 1M hydrochloric acid aqueous solution until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate 3×20 mL. Combine the organic phases, wash with saturated brine 3×15 mL, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Use petroleum ether (60-90 ℃) / ethyl acetate with a volume ratio of 30:1 as the eluent. The theoretical yield of the chromatogram is 57%, and 44.6 mg (22.53% isolated yield) of yellow product B18 is obtained by rapid column chromatography. 1 H NMR (400 MHz, CDCl3) δ 3.62 – 2.43 (m, 4H), 1.43 – 1.14 (m, 24H). 13 C{ 1 H}NMR (101 MHz, CDCl3) δ 213.05, 205.65, 202.94, 185.07,164.84, 146.60, 127.23, 94.98, 39.95, 39.87, 36.78, 33.45, 24.32, 23.13,19.37, 18.75, 17.97,17.82.HRMS (ESI) m / z: Calc. for C 20 H 28 O4S2[M+H] + : 397.1502, found: 397.1528. CCDC No. 2129689.

[0107] X-ray single crystal diffraction data of product B18, tested on single crystal of product B15 using Bruker D8 Venture. The structure was calculated using Olex26, ShelXT7 structure solver (using intrinsic phase), and optimized using ShelXL8, with 30% ellipsoidality, CCDC No.2129689.

[0108] Identification code CCDC 2129689

[0109] Empirical formula C 20 H 28 O4S2

[0110] Formula weight 396.54

[0111] Temperature 173.0 K

[0112] Wavelength 1.54178Å

[0113] Crystal system Monoclinic

[0114] Space group C 1 2 / c 1

[0115] Unit cell dimensions a = 16.567(4) Å a= 90°

[0116] b = 13.915(3) Å

[0117] b=107.521(13)°

[0118] c = 9.4940(18)Å g = 90°

[0119] Volume 2087.1(7) Å3

[0120] Z 4

[0121] Density (calculated) 1.262 Mg / m3

[0122] Absorption coefficient 2.486 mm-1

[0123] F(000) 848

[0124] Crystal size 0.11 x 0.07 x 0.06 mm3

[0125] Theta range for data collection 5.601 to 68.547°

[0126] Index ranges -19<=h<=12, -16<=k<=16, -10<=l<=11

[0127] Reflections collected 8580

[0128] Independent reflections 1891 [R(int) = 0.0572]

[0129] Completeness to theta = 67.679 98.9 %

[0130] Absorption correction Semi-empirical from equivalents

[0131] Max. and min. transmission 0.7531 and 0.5649

[0132] Refinement method Full-matrix least-squares on F2

[0133] Data / restraints / parameters 1891 / 0 / 122

[0134] Goodness-of-fit on F2 1.042

[0135] Final R indices [I>2sigma(I)] R1 = 0.0358, wR2 = 0.0913

[0136] R indices (all data) R1 = 0.0409, wR2 = 0.0956

[0137] Extinction coefficient n / a

[0138] Largest diff. peak and hole 0.301 and -0.237 e.Å-3

[0139] Optimization of base catalysts

[0140]

[0141] Take 15 25 mL reaction tubes, add a magnetic particle to each reaction tube, and dissolve A1 (100 μL, 1 mmol) in 3 mL of DMSO in each reaction tube. Then, add a base (1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) to each reaction tube in turn, and the base added to each reaction tube is different. Then stir in a closed manner at room temperature, and detect the reaction by TLC. The reaction is uniformly carried out for 30 minutes. A 1M hydrochloric acid aqueous solution is added to each reaction tube until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate. The chromatographic theoretical yield (%) corresponding to various bases is shown in Table 1.

[0142] Table 1 Chromatographic theoretical yields corresponding to various bases (%)

[0143]

[0144] In summary, the preferred base catalyst is tetramethylguanidine (TMG).

[0145] Solvent Optimization

[0146]

[0147] Take 15 25 mL reaction tubes, add a magnetic particle and 3 mL of solvent to each reaction tube, and the solvent added to each reaction tube is different. Then, add A1 (100 μL, 1 mmol) to each reaction tube and dissolve it. Then, add the base TMG (96 μL, 1.5 mmol) and CS2 (74.25 μL, 1.5 mmol) to each reaction tube in turn. Stir in a closed manner at room temperature, and detect the reaction by TLC. The reaction is uniformly carried out for 30 minutes. A 1M hydrochloric acid aqueous solution is added to each reaction tube until the color of the solution no longer changes after the reaction. Then extract with ethyl acetate. The chromatographic theoretical yield (%) corresponding to various solvents is shown in Table 2.

[0148] Table 2 Chromatographic theoretical yields corresponding to various solvents (%)

[0149]

[0150] In summary, the preferred solvent is dimethyl sulfoxide (DMSO).

[0151] Antitumor activity studies

[0152] Using MGC803 (human gastric poorly differentiated adenocarcinoma cell line), MFC (mouse gastric cancer cell line - purchased from Wuhan Pronocell Biotechnology Co., Ltd.), HGC27 (human gastric undifferentiated adenocarcinoma cell line - Shanghai Cell Bank, Chinese Academy of Sciences) and human normal gastric mucosal epithelial cells GES-1 as the objects, the MTT method was used to determine the inhibitory activity of target compound B2 on tumor cell lines using target compound B2 as an example.

[0153] 1. Preparation of culture medium

[0154] According to the instructions provided by the manufacturer, MGC803, HGC27 and MFC gastric cancer cells were subsequently cultured with 1640 complete medium (containing 1640 basal medium, 10% serum and 1% double antibody solution). GES-1 cells were cultured with DMEM complete medium (containing DMEM basal medium, 10% serum and 1% double antibody solution).

[0155] 2. Cell recovery

[0156] Prepare a 15 mL centrifuge tube containing 4 mL of complete culture medium in advance, take out the cell cryopreservation tube frozen in the liquid nitrogen tank, place it in a 37°C water bath for rapid thawing, and quickly transfer it to a centrifuge tube containing complete culture medium. Centrifuge at 1000 r / min for 5 min, discard the supernatant, add an appropriate amount of culture medium to resuspend the cells, gently pipet until completely mixed, transfer a certain volume according to the cell amount to the culture bottle containing complete culture medium, shake well and place in the incubator for culture.

[0157] 3. Cell passaging

[0158] When the cells at the bottom of the culture flask grow to 80%, add an appropriate amount of trypsin digestion solution for cell digestion, observe and record the digestion time under a microscope, and when the cells become round, quickly add complete culture medium to terminate digestion. Use a 5mL pipette tip to gently blow the cells to completely fall off the wall of the culture flask, transfer the cell suspension to a centrifuge tube, centrifuge at 1000r / min for 5 min, discard the supernatant, add an appropriate amount of culture medium to resuspend the cells, gently blow until completely mixed, and transfer a certain volume to the culture flask containing complete culture medium according to the cell amount to complete the subculture process.

[0159] 4. Cell counting

[0160] Use a blood cell counting plate to count cells. The blood cell counting plate has an H-shaped groove, forming two counting pools with a height of 0.1 mm. Each counting pool contains 9 large squares, and the cell counting area is the 4 large squares in the four corners. The number of cells = (total number of cells in the 4 large squares / 4) × 104 × dilution factor. After the number of cells is determined, the cell density can be adjusted according to the experimental needs.

[0161] 5. MTT method to screen compounds with inhibitory activity on tumor cell proliferation

[0162] Select cells in the logarithmic growth phase, digest and resuspend them, adjust the concentration of the cell suspension and inoculate them in a 96-well culture plate, with 100 μL per well and a cell volume of 0.8×10 4 ~1.3×10 4 Each well was cultured at 37°C and 5% CO2 in a humidified incubator for 24 h, and the cell fusion in the well was about 80%. Different monomer compounds were used as samples, and blank solvent control group, positive control group and experimental groups with different sample concentrations were set up. Three wells were set up in each group as parallel.

[0163] After 24 hours, the original culture medium was aspirated, and the cells were washed once with 37°C PBS. Then, 100 μL of drug-containing culture medium was added to each well, and the cells were cultured in a humidified incubator at 37°C and 5% CO2 for 24 hours. 20 μL / well of freshly prepared MTT solution (5 mg / mL) was added and cultured in the dark for 4 hours. The culture was terminated, and the supernatant of each well was carefully aspirated. 150 μL of DMSO was added to each well, and the cells were placed on a shaker and shaken at low speed for 15 minutes to fully dissolve the crystals. The optical density (OD) of each well was measured at 540 nm (490 nm) using an automatic microplate reader. The tumor cell growth inhibition rate was calculated, and the IC was fitted using software. 50 value.

[0164] Table 3 Effects of target compound B2 monomer on HGC27, MGC803, MFC cancer cells and GES-1 normal cells

[0165]

[0166] As shown in Table 3, the 1,3-dithiocyclobutane-2,4-diyl compounds of the present invention have good anti-tumor activity and good development prospects for use in anti-tumor drugs.

Claims

1. A method for synthesizing a 1,3-dithioethane-2,4-diylidene compound, characterized in that: The synthesis method is specifically carried out according to the following steps: 1) Take α-methylene ketone and solvent, and then take alkali and carbon disulfide in a molar ratio of 1:0.5-5, the molar ratio of α-methylene ketone to alkali is 1:0.1-4, and the molar ratio of α-methylene ketone to carbon disulfide is 1:0.1-40; 2) At room temperature, α-methylene ketone is dissolved in a solvent, and a base is added under stirring conditions, and the mixture is stirred until the color changes, and then carbon disulfide is added; the reaction system is reacted in a closed reactor at -28°C to 46°C, and the reaction progress is detected by TLC; after the reaction is completed, an aqueous hydrochloric acid solution is added until the color of the solution does not change after the reaction; then the mixture is extracted with ethyl acetate, washed with water, washed with saturated brine, and then dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified and separated by rapid column chromatography to obtain 1,3-dithioethane-2,4-diylidene compounds; The chemical structure of the 1,3-dithiocyclobutane-2,4-diylidene compound is as follows: Wherein, R1 is CH3, Ph, pF-Ph, p-Br-Ph, p-CH3-Ph, p-OCH3-Ph, p-Cl-Ph alkyl, cycloalkyl, alkoxy, aryl or substituted aryl; R2 is COCH3, COOCH3, COOCH2CH3, CN, acyl, cycloacyl, cyano or ester; The base is guanidine carbonate, tetramethylguanidine, nitroguanidine or methylnitroguanidine.

2. The method for synthesizing 1,3-dithioethane-2,4-diylidene compounds according to claim 1, characterized in that: In the step 2), the α-methylene ketone includes R1=CH3, Ph, pF-Ph, p-Br-Ph, p-CH3-Ph, p-OCH3-Ph, p-Cl-Ph, alkyl, cycloalkyl, alkoxy, aryl or substituted aryl; R2=COCH3, COOCH3, COOCH2CH3, CN, acyl, cycloacyl, cyano or ester.

3. The method for synthesizing 1,3-dithioethane-2,4-diylidene compounds according to claim 1, characterized in that: In the step 2), the solvent is toluene, dichloromethane, chloroform, dimethyl sulfoxide, ethanol, isopropanol, water, ethyl acetate, tetrahydrofuran, acetone, triethylamine, n-pentane, acetonitrile or carbon disulfide.

4. The method for synthesizing 1,3-dithioethane-2,4-diylidene compounds according to claim 1, characterized in that: In the step 2), the molar concentration of the hydrochloric acid aqueous solution is 1M.

5. Use of a 1,3-dithiocyclobutane-2,4-diylidene compound synthesized by the synthesis method of claim 1 in the preparation of anti-tumor drugs.

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