Method for synthesizing drug intermediate 6-amino-2-thiocarbonyl-2H-thiapyran derivative in one step

Abstract

The invention relates to the field of synthesis of drug intermediates, and particularly discloses a one-step synthesis method of a drug intermediate 6-amino-2-thiocarbonyl-2H-thiapyran derivative, which comprises the following steps: taking mono-substituted acetophenone, malononitrile and carbon disulfide as reaction raw materials; under the catalytic action of heating and an alkaline functional deep eutectic solvent, the 6-amino-2-thiocarbonyl-2H-thiapyran derivative is directly synthesized through a one-step reaction. The whole synthesis process is simple and convenient in operation steps, high in target product and production efficiency, and good in economic benefit. Besides, the alkaline functional deep-eutectic solvent can be recycled, so that the utilization rate of the raw materials is increased, the environmental pollution is reduced, and the purpose of green synthesis of the 6-amino-2-thiocarbonyl-2H-thiapyran derivative is achieved.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a pharmaceutical intermediate, in particular to a method for synthesizing a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative in one step, and belongs to the field of pharmaceutical intermediate synthesis. Background Art

[0002] Heterocyclic compounds not only exist in biological macromolecules such as DNA or RNA that are essential to life, but they are also widely distributed in drug molecules and natural products with various unique pharmacological activities. Among various complex heterocyclic compounds, sulfur-containing heterocyclic skeletons have attracted the research interests of many medicinal chemists and synthetic chemists. In addition, compounds containing thiopyran skeletons are also an important class of heterocyclic compounds with good physiological activity and are widely used in the fields of medicine and pesticides. For example, drugs used for antifungal, antiproliferative, and antitumor contain benzothiazole skeletons. 6-amino-2-thiocarbonyl-2H-thiopyran derivatives containing both sulfur and thiopyran structures have also been proven to have good biological activity. Therefore, the synthesis of 6-amino-2-thiocarbonyl-2H-thiopyran derivatives has attracted the attention of many drug researchers and organic synthesizers.

[0003] Generally, the synthesis of 6-amino-2-thiocarbonyl-2H-thiopyran derivatives often adopts a two-step method, namely: the first step is to react aromatic ketone with malononitrile to produce aryl ethylidene malononitrile by Knoevenagel condensation under the action of an alkaline catalyst; the second step is to react aryl ethylidene malononitrile with carbon disulfide under an alkaline environment to synthesize 6-amino-2-thiocarbonyl-2H-thiopyran derivatives. It is well known that the longer the synthesis step, the lower the yield of the target product, and the alkaline catalyst used is not easy to recover, causing great environmental pollution. In addition, the operating procedures of this method are relatively harsh and cumbersome, consuming a lot of manpower and material resources.

[0004] Low eutectic solvents are composed of hydrogen bond acceptors and hydrogen bond donors or quaternary ammonium salts and metal salts, and most of the substances that make up low eutectic solvents are renewable, so low eutectic solvents are used as a new type of green solvent. Functionalized low eutectic solvents composed of a large number of functionalized hydrogen bond donors or hydrogen bond acceptors not only have the function of green solvents, but also have other functions. For example, amine-functionalized low eutectic solvents can be used to absorb SO2, and acid-functionalized low eutectic solvents can replace traditional acid catalysts to catalyze organic chemical reactions.

[0005] Based on the advantages of the above functionalized deep eutectic solvents and the requirement that the synthesis process of 6-amino-2-thiocarbonyl-2H-thiopyran derivatives requires an alkaline environment, in order to overcome the disadvantages of the two-step method, the present invention intends to use an alkaline functionalized deep eutectic solvent with appropriate basicity as a solvent and catalyst, monosubstituted acetophenone, malononitrile and carbon disulfide as reaction raw materials, and a three-component one-step method to synthesize 6-amino-2-thiocarbonyl-2H-thiopyran derivatives, so as to obtain the advantages of increased yield of the target product, simple synthesis process, reduced environmental pollution, and reduced economic cost. Summary of the invention

[0006] In view of the problems in the prior art, the present invention provides a one-step method for synthesizing a drug intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] A one-step method for synthesizing a drug intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative. The drug intermediate synthesis method uses monosubstituted acetophenone, malononitrile and carbon disulfide as reaction raw materials, and directly synthesizes the 6-amino-2-thiocarbonyl-2H-thiopyran derivative through a one-step reaction under the catalytic action of heating and an alkaline functionalized deep eutectic solvent. The specific steps are as follows:

[0009] At room temperature, first add a preset amount of reaction raw materials into a preset amount of alkaline functionalized low eutectic solvent, then mix evenly to form a reaction solution → heat the reaction solution to a preset temperature → keep warm for a preset time until the reaction ends → naturally cool to room temperature and then add ethanol → let stand, filter, wash the filter residue and then vacuum dry to obtain a 6-amino-2-thiocarbonyl-2H-thiopyran derivative.

[0010] Optionally, the chemical reaction formula involved in the above reaction is

[0011]

[0012] Optionally, mixing uniformly to form a reaction solution: adding monosubstituted acetophenone, malononitrile and carbon disulfide in a preset molar ratio into a reaction flask with a magnetic stirrer and a thermometer containing a preset volume of an alkaline functionalized deep eutectic solvent, and stirring uniformly at room temperature to form a reaction solution;

[0013] Heat the reaction solution to a preset temperature: Use oil bath heating to heat the reaction solution to 37-43°C;

[0014] Keep warm for a preset time until the reaction is finished: keep warm for 14 to 25 minutes at a temperature of 37 to 43°C with magnetic stirring, monitor the progress of the reaction by TLC, and stop heating and magnetic stirring immediately when the raw material point disappears, i.e. the reaction is complete, and remove the reaction flask from the oil bath;

[0015] After cooling naturally to room temperature, add ethanol: After the reaction solution is cooled naturally to room temperature, add ethanol and stir to mix evenly;

[0016] Allow to stand, filter, wash the filter residue and then dry in vacuum: allow to stand for 6 hours, filter and wash the filter residue with ethanol, and dry in vacuum at 85°C for 12 hours.

[0017] Optionally, the molar ratio of monosubstituted acetophenone, malononitrile and carbon disulfide in the reaction raw materials is 1:(1-1.2):1.

[0018] Optionally, the alkaline functionalized low eutectic solvent is a clear transparent solution obtained by heating a mixture of sodium hydroxide and ethylene glycol in a molar ratio of 1:(7-10) at 80° C. for 2 hours.

[0019] Optionally, the basic functionalized deep eutectic solvent is used in an amount in milliliters of volume that is 8 to 12 times the amount of the monosubstituted acetophenone substance in millimoles.

[0020] Optionally, the monosubstituted acetophenone is selected from any one of acetophenone, p-fluoroacetophenone, p-chloroacetophenone, p-bromoacetophenone, p-methylacetophenone and p-methoxyacetophenone.

[0021] Optionally, after the ethanol is evaporated off by rotary evaporation, the filtrate after suction filtration (the main component of which is the alkaline functionalized low eutectic solvent) can be directly added with monosubstituted acetophenone, malononitrile and carbon disulfide for recycling.

[0022] Optionally, if the purity of the product 6-amino-2-thiocarbonyl-2H-thiopyran derivative is lower than 98% or the yield is reduced by more than 5% compared with the first use during the recycling process of the filtrate, its recycling is stopped.

[0023] Beneficial effects of the present invention:

[0024] A method for synthesizing a drug intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative in one step of the present invention, using an alkaline functionalized low eutectic solvent as a catalyst and reaction solvent, and directly synthesizing a 6-amino-2-thiocarbonyl-2H-thiopyran derivative by a one-pot reaction of a monosubstituted acetophenone, malononitrile and carbon disulfide, the whole synthesis process operation steps are simple and convenient, the target product and production efficiency are high, and the economic benefit is good. In addition, the alkaline functionalized low eutectic solvent can be recycled, while improving the utilization rate of raw materials, it also reduces environmental pollution, and achieves the purpose of green synthesis of 6-amino-2-thiocarbonyl-2H-thiopyran derivatives. More importantly, due to the high selectivity of the alkaline functionalized low eutectic solvent, the purity of the target product is high, and there is no need to set up a purification process separately. Finally, since the present invention adopts a one-step synthesis process, it is easy to realize industrial large-scale and continuous production, and the universality is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to facilitate understanding by those skilled in the art, the present invention is further described below with reference to the accompanying drawings.

[0026] Figure 1 The 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile synthesized in Example 2 of the present invention 1 H NMR.

[0027] Figure 2 The 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile synthesized in Example 2 of the present invention 13 C NMR.

[0028] Figure 3 The 6-amino-4-p-methoxyphenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile synthesized in Example 6 of the present invention is 1 H NMR.

[0029] Figure 4 The 6-amino-4-p-methoxyphenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile synthesized in Example 6 of the present invention is 13 C NMR.

[0030] Figure 5 The purity and yield of 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile in Examples 7 to 12 of the present invention are changed.

[0031] Figure 6 The purity and yield of 6-amino-2-thiocarbonyl-4-p-tolyl-2H-thiopyran-5-carbonitrile in Examples 13 to 17 of the present invention are changed. DETAILED DESCRIPTION

[0032] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] In the following examples, the hydrogen and carbon spectra of the target product 6-amino-2-thiocarbonyl-2H-thiopyran derivative were characterized by using a nuclear magnetic resonance spectrometer of model AVANCE 400MHz from Bruker, Germany; the purity was characterized by using a high performance liquid chromatograph of model LC-2050 from Shimadzu, Japan; and the melting point was determined by a capillary method.

[0034] The preparation process of the basic functionalized deep eutectic solvent used in the present invention refers to the following data: Basic deepeutectic solvents as reactant, template and solvents for ultra-fast preparation of transition metal oxide nanomaterials [J], Chinese Chemical Letters, 2020, 31: 1584-1587.

[0035] The following is a specific embodiment and the attached Figures 1 to 6 The present invention is further described.

[0036] Example 1

[0037] Synthesis of 6-amino-4-phenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile

[0038] 1.0mmol acetophenone, 1.2mmol malononitrile and 1.0mmol carbon disulfide were added to a 50ml four-necked flask with a spherical condenser and a stirrer containing 12ml alkaline functionalized low eutectic solvent (the ratio of the amount of sodium hydroxide to ethylene glycol was 1:7), and stirred and mixed evenly at room temperature. The temperature was slowly raised to 43°C in an oil bath, and the reaction was maintained at this temperature under stirring. TLC (thin plate chromatography) was used to track the reaction. When the reaction time was 25min, the raw material point disappeared. At this time, the stirring was immediately stopped and the flask was removed from the oil bath. After cooling to room temperature naturally, 10ml ethanol was added, stirred and mixed, and then allowed to stand for 6h. A large amount of yellow solid was precipitated, and the residue was washed with ethanol and vacuum dried at 85°C for 12h, weighing 0.22g. The main substance was the target product 6-amino-4-phenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile, and its purity was 99.3%. The yield of the target product was calculated to be 91%. After the ethanol was evaporated at 85°C, acetophenone, malononitrile and carbon disulfide were directly added to the filtrate for the next round of reaction.

[0039] The structural formula of 6-amino-4-phenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile obtained in this example is:

[0040]

[0041] Its physical parameters and structural characterization data are: yellow solid; mp272~274℃; 1 H NMR (400MHz, DMSO-d6): δ = 6.68 (s, 1H, CH), 7.50 (s, 5H, ArH), 9.23 (s, 2H, NH2); 13 C NMR (100MHz, DMSO-d6): 198.5, 176.9, 158.6, 143.1, 135.6, 133.9, 133.2, 131.4, 120.8, 89.7.

[0042] Example 2

[0043] Synthesis of 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile

[0044] 1.0mmol of p-fluoroacetophenone, 1.2mmol of malononitrile and 1.0mmol of carbon disulfide were added to a 50ml four-necked flask with a spherical condenser and a stirrer containing 10ml of alkaline functionalized low eutectic solvent (the ratio of the amount of sodium hydroxide to ethylene glycol was 1:9), and stirred and mixed evenly at room temperature. The temperature was slowly raised to 41°C in an oil bath, and the reaction was maintained at this temperature under stirring. The reaction was tracked by TLC (thin plate chromatography). When the reaction time was 22min, the raw material point disappeared. At this time, the stirring was immediately stopped and the flask was removed from the oil bath. After cooling to room temperature naturally, 12ml of ethanol was added, stirred and mixed, and then allowed to stand for 6h. A large amount of yellow solid was precipitated, which was filtered, and the residue was washed with ethanol and vacuum dried at 85°C for 12h, weighing 0.25g. The main substance was identified by the retention value qualitative method of high performance liquid chromatography as the target product 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile, and its purity was 99.1%. The yield of the target product was calculated to be 94%. After the filtrate was evaporated at 85°C to remove the ethanol, p-fluoroacetophenone, malononitrile and carbon disulfide were directly added to carry out the next round of reaction.

[0045] The structural formula of 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile obtained in this example is:

[0046]

[0047] Its physical parameters and structural characterization data are: yellow solid; mp273~275℃; 1 H NMR (400MHz, DMSO-d6): δ=6.72 (s, 1H, CH), 7.32~7.36 (m, 2H, ArH), 7.60~7.63 (m, 2H, ArH), 9.25 (s, 2H, NH2); 13 C NMR (100MHz, DMSO-d6): 194.0, 172.1, 163.6, 152.6, 135.0, 131.1, 131.0, 126.5, 116.3, 84.9.

[0048] Example 3

[0049] Synthesis of 6-amino-4-(4-chlorophenyl)-2-thiocarbonyl-2H-thiopyran-5-carbonitrile

[0050] 1.0mmol p-chloroacetophenone, 1.1mmol malononitrile and 1.0mmol carbon disulfide were added to a 50ml four-necked flask with a spherical condenser and a stirrer containing 10ml alkaline functionalized low eutectic solvent (the ratio of the amount of sodium hydroxide to ethylene glycol was 1:10), and stirred and mixed evenly at room temperature. The temperature was slowly raised to 39°C in an oil bath, and the reaction was maintained at this temperature under stirring. TLC (thin plate chromatography) was used to track the reaction. When the reaction time was 20min, the raw material point disappeared. At this time, the stirring was immediately stopped and the flask was removed from the oil bath. After cooling to room temperature naturally, 12ml ethanol was added, stirred and mixed, and then allowed to stand for 6h. A large amount of yellow solid was precipitated, which was filtered, and the residue was washed with ethanol and vacuum dried at 85°C for 12h, weighing 0.26g. The main substance was identified by the retention value qualitative method of high performance liquid chromatography as the target product 6-amino-4-p-chlorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile, and its purity was 99.5%. The yield of the target product was calculated to be 92%. After the filtrate was evaporated at 85°C to remove the ethanol, p-chloroacetophenone, malononitrile and carbon disulfide were directly added to carry out the next round of reaction.

[0051] The structural formula of 6-amino-4-p-chlorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile obtained in this example is:

[0052]

[0053] Its physical parameters and structural characterization data are: yellow solid; mp262~264℃; 1 H NMR (400MHz, DMSO-d6): δ = 6.75 (s, 1H, CH), 7.61 (s, 4H, ArH), 9.28 (s, 2H, NH2); 13 C NMR (100MHz, DMSO-d6): 193.6, 171.4, 152.0, 136.9, 135.1, 129.9, 128.7, 125.8, 116.1, 84.7.

[0054] Example 4

[0055] Synthesis of 6-amino-4-(4-bromophenyl)-2-thiocarbonyl-2H-thiopyran-5-carbonitrile

[0056] 1.0mmol of p-bromoacetophenone, 1.0mmol of malononitrile and 1.0mmol of carbon disulfide were added to a 50ml four-necked flask with a spherical condenser and a stirrer containing 8ml of alkaline functionalized low eutectic solvent (the ratio of the amount of sodium hydroxide to ethylene glycol was 1:10), and stirred and mixed evenly at room temperature. The temperature was slowly raised to 37°C in an oil bath, and the reaction was maintained at this temperature under stirring. The reaction was tracked by TLC (thin plate chromatography). When the reaction time was 14min, the raw material point disappeared. At this time, the stirring was immediately stopped and the flask was removed from the oil bath. After cooling to room temperature naturally, 10ml of ethanol was added, stirred and mixed, and then allowed to stand for 6h. A large amount of yellow solid was precipitated, which was filtered, and the residue was washed with ethanol and vacuum dried at 85°C for 12h, weighing 0.31g. The main substance was identified by the retention value qualitative method of high performance liquid chromatography as the target product 6-amino-4-p-bromophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile, and its purity was 99.2%. The yield of the target product was calculated to be 96%. After the filtrate was evaporated at 85°C to remove the ethanol, p-bromoacetophenone, malononitrile and carbon disulfide were directly added to carry out the next round of reaction.

[0057] The structural formula of 6-amino-4-p-bromophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile obtained in this example is:

[0058]

[0059] Its physical parameters and structural characterization data are: yellow solid; mp277~279℃; 1 H NMR (400MHz, DMSO-d6): δ=6.73 (s, 1H, CH), 7.47 (d, J=8.2Hz, 2H, ArH), 7.68 (d, J=8.6Hz, 2H, ArH), 9.26 (s, 2H, NH2); 13 C NMR (100MHz, DMSO-d6): 193.7, 171.6, 152.3, 137.4, 132.1, 130.2, 125.7, 124.1, 115.9, 84.5.

[0060] Example 5

[0061] Synthesis of 6-amino-2-thiocarbonyl-4-p-tolyl-2H-thiopyran-5-carbonitrile

[0062] 1.0mmol p-methylacetophenone, 1.1mmol malononitrile and 1.0mmol carbon disulfide were added to a 50ml four-necked flask with a spherical condenser and a stirrer containing 10ml alkaline functionalized low eutectic solvent (the ratio of the amount of sodium hydroxide to ethylene glycol was 1:9), and stirred and mixed evenly at room temperature. The temperature was slowly raised to 39°C in an oil bath, and the reaction was maintained at this temperature under stirring. TLC (thin plate chromatography) was used to track the reaction. When the reaction time was 19min, the raw material point disappeared. At this time, the stirring was immediately stopped and the flask was removed from the oil bath. After cooling to room temperature naturally, 12ml ethanol was added, stirred and mixed, and then allowed to stand for 6h. A large amount of yellow solid was precipitated, which was filtered, and the residue was washed with ethanol and vacuum dried at 85°C for 12h, weighing 0.24g. The main substance was identified by the retention value qualitative method of high performance liquid chromatography as the target product 6-amino-2-thiocarbonyl-4-p-tolyl-2H-thiopyran-5-carbonitrile, and its purity was 99.3%. The yield of the target product was calculated to be 93%. After the filtrate was evaporated at 85°C to remove the ethanol, p-methylacetophenone, malononitrile and carbon disulfide were directly added to carry out the next round of reaction.

[0063] The structural formula of 6-amino-2-thiocarbonyl-4-p-tolyl-2H-thiopyran-5-carbonitrile obtained in this example is:

[0064]

[0065] Its physical parameters and structural characterization data are: yellow solid; mp227~229℃; 1 H NMR (400MHz, DMSO-d6): δ=2.35 (s, 3H, CH3), 6.68 (s, 1H, CH), 7.30 (d, J=8.2Hz, 2H, ArH), 7.42 (d, J=7.8Hz, 2H, ArH), 9.21 (s, 2H, NH2); 13 C NMR (100MHz, DMSO-d6): 198.4, 177.0, 158.5, 145.6, 140.4, 134.6, 133.1, 131.2, 121.3, 89.5, 26.3.

[0066] Example 6

[0067] Synthesis of 6-amino-4-p-methoxyphenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile

[0068] 1.0mmol p-methoxyacetophenone, 1.0mmol malononitrile and 1.0mmol carbon disulfide were added to a 50ml four-necked flask with a spherical condenser and a stirrer containing 8ml of alkaline functionalized low eutectic solvent (the ratio of the amount of sodium hydroxide to ethylene glycol was 1:8), and stirred and mixed evenly at room temperature. The temperature was slowly raised to 39°C in an oil bath, and the reaction was maintained at this temperature under stirring. TLC (thin plate chromatography) was used to track the reaction. When the reaction time was 16min, the raw material point disappeared. At this time, the stirring was immediately stopped and the flask was removed from the oil bath. After cooling to room temperature naturally, 15ml of ethanol was added, stirred and mixed, and then allowed to stand for 6h. A large amount of yellow solid was precipitated, which was filtered, and the filter residue was washed with ethanol and vacuum dried at 85°C for 12h, weighing 0.26g. The main substance was identified by the retention value qualitative method of high performance liquid chromatography as the target product 6-amino-4-p-methoxyphenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile, and its purity was 99.3%. The yield of the target product was calculated to be 95%. After the filtrate was evaporated at 85°C to remove the ethanol, p-methoxyacetophenone, malononitrile and carbon disulfide were directly added to carry out the next round of reaction.

[0069] The structural formula of 6-amino-4-p-methoxyphenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile obtained in this example is:

[0070]

[0071] Its physical parameters and structural characterization data are: yellow solid; mp255~257℃; 1 H NMR (400MHz, DMSO-d6): δ=3.81 (s, 3H, CH3O), 6.73 (s, 1H, CH), 7.03 (d, J=8.8Hz, 2H, ArH), 7.51 (d, J=8.8Hz, 2H, ArH), 9.16 (s, 2H, NH2); 13 C NMR (100MHz, DMSO-d6): 198.1, 177.3, 166.5, 158.4, 135.6, 135.4, 131.4, 121.7, 119.7, 89.8, 61.0.

[0072] Embodiments 7 to 12

[0073] Feasibility verification of recycling of alkaline functionalized deep eutectic solvents

[0074] Taking the reaction involved in Example 2 as an example, a recycling test of the alkaline functionalized low eutectic solvent was conducted to investigate the effect of the number of recycling times on the purity and yield of the target product 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile. The alkaline functionalized low eutectic solvent was used a total of 7 times, wherein the amount of the reaction raw materials, the alkaline functionalized low eutectic solvent, the reaction temperature, the reaction time and the operating procedure were the same as in Example 2. The purity and yield of 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile were shown in Table 1. Figure 5 .

[0075] Embodiments 13 to 17

[0076] Feasibility verification of recycling of alkaline functionalized deep eutectic solvents

[0077] Taking the reaction involved in Example 5 as an example, a recycling test of the alkaline functionalized low eutectic solvent was conducted to investigate the effect of the number of recycling times on the purity and yield of the target product 6-amino-2-thiocarbonyl-4-p-tolyl-2H-thiopyran-5-carbonitrile. The alkaline functionalized low eutectic solvent was used a total of 6 times, wherein the amount of the reaction raw materials, the amount of the alkaline functionalized low eutectic solvent, the reaction temperature, the reaction time and the operating procedure were the same as in Example 5, and the purity and yield of 6-amino-2-thiocarbonyl-4-p-tolyl-2H-thiopyran-5-carbonitrile were shown in Table 1. Figure 6 .

[0078] Depend on Figures 5-6 It can be seen that when the purity of the product 6-amino-2-thiocarbonyl-2H-thiopyran derivative is lower than 98% or the yield is reduced by more than 5% compared with the first use, the recycling of the filtrate (the main component is the basic functionalized deep eutectic solvent) is stopped. The basic functionalized deep eutectic solvent can be used 5 times in the process of synthesizing 6-amino-4-p-fluorophenyl-2-thiocarbonyl-2H-thiopyran-5-carbonitrile by reacting p-fluoroacetophenone, malononitrile and carbon disulfide as described in Example 2; the basic functionalized deep eutectic solvent can be used 4 times in the process of synthesizing 6-amino-2-thiocarbonyl-4-p-tolyl-2H-thiopyran-5-carbonitrile by reacting p-methylacetophenone, malononitrile and carbon disulfide as described in Example 5. The reason why the basic functionalized deep eutectic solvent cannot be recycled may be due to the accumulation of by-products in the reaction system.

[0079] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A one-step method for synthesizing a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative, characterized in that: The drug intermediate synthesis method uses monosubstituted acetophenone, malononitrile and carbon disulfide as reaction raw materials, and directly synthesizes 6-amino-2-thiocarbonyl-2H-thiopyran derivatives through a one-step reaction under the catalytic action of heating and alkaline functionalized deep eutectic solvent. The specific steps are as follows: At room temperature, first add a preset amount of reaction raw materials into a preset amount of alkaline functionalized low eutectic solvent, then mix evenly to form a reaction solution → heat the reaction solution to a preset temperature → keep warm for a preset time until the reaction ends → naturally cool to room temperature and then add ethanol → let stand, filter, wash the filter residue and then vacuum dry to obtain a 6-amino-2-thiocarbonyl-2H-thiopyran derivative.

2. A one-step synthesis method of a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative according to claim 1, characterized in that: The chemical reaction formula involved in the above reaction is 3. A one-step synthesis method of a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative according to claim 1, characterized in that: Mixing uniformly to form a reaction solution: adding monosubstituted acetophenone, malononitrile and carbon disulfide in a preset molar ratio into a reaction flask with a magnetic stirrer and a thermometer containing a preset volume of an alkaline functionalized deep eutectic solvent, and stirring uniformly at room temperature to form a reaction solution; Heat the reaction solution to a preset temperature: Use oil bath heating to heat the reaction solution to 37-43°C; Keep warm for a preset time until the reaction is finished: keep warm for 14 to 25 minutes at a temperature of 37 to 43°C with magnetic stirring, monitor the progress of the reaction by TLC, and stop heating and magnetic stirring immediately when the raw material point disappears, i.e. the reaction is complete, and remove the reaction flask from the oil bath; After cooling naturally to room temperature, add ethanol: After the reaction solution is cooled naturally to room temperature, add ethanol and stir to mix evenly; Allow to stand, filter, wash the filter residue and then dry in vacuum: allow to stand for 6 hours, filter and wash the filter residue with ethanol, and dry in vacuum at 85°C for 12 hours.

4. A one-step synthesis method of a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative according to claim 1, characterized in that: The molar ratio of monosubstituted acetophenone, malononitrile and carbon disulfide in the reaction raw materials is 1:(1-1.2):

1.

5. A one-step synthesis method of a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative according to claim 4, characterized in that: The alkaline functionalized low eutectic solvent is a clear and transparent solution obtained by heating a mixture of sodium hydroxide and ethylene glycol in a molar ratio of 1:(7-10) at 80° C. for 2 hours.

6. A one-step synthesis method of a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative according to claim 5, characterized in that: The basic functionalized deep eutectic solvent is used in an amount in milliliters of volume that is 8 to 12 times the amount of the monosubstituted acetophenone substance in millimoles.

7. A one-step synthesis method of a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative according to claim 1, characterized in that: The monosubstituted acetophenone is selected from any one of acetophenone, p-fluoroacetophenone, p-chloroacetophenone, p-bromoacetophenone, p-methylacetophenone and p-methoxyacetophenone.

8. A one-step synthesis method of a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative according to claim 1, characterized in that: After the ethanol is rotary distilled off, the filtrate after suction filtration can be directly added with monosubstituted acetophenone, malononitrile and carbon disulfide for recycling.

9. A one-step synthesis method of a pharmaceutical intermediate 6-amino-2-thiocarbonyl-2H-thiopyran derivative according to claim 8, characterized in that: If the purity of the product 6-amino-2-thiocarbonyl-2H-thiopyran derivative is lower than 98% or the yield is reduced by more than 5% compared with the first use during the recycling process of the filtrate, its recycling is stopped.

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