CN112500368A

CN112500368A - 1,3, 4-thiadiazole derivative and preparation method thereof

Info

Publication number: CN112500368A
Application number: CN202011203000.3A
Authority: CN
Inventors: 程斌; 李慧; 刘豆; 汪太民; 孙海燕; 翟宏斌
Original assignee: Shenzhen Polytechnic
Current assignee: Shenzhen Polytechnic
Priority date: 2020-11-02
Filing date: 2020-11-02
Publication date: 2021-03-16

Abstract

The invention relates to the field of chemical synthesis, in particular to a 1,3, 4-thiadiazole derivative and a preparation method thereof; the method uses alpha-enol dithioester and hydrazone compounds as initial raw materials, the raw materials are easy to prepare, dichloromethane is used as a reaction solvent for reaction, and the 1,3, 4-thiadiazole derivatives are prepared and synthesized under room temperature conditions. No noble metal catalyst is used in the reaction, the reaction condition is mild, the operation is simple, the post-treatment is convenient, the yield is high, and the inert gas protection is not needed in the preparation process.

Description

1,3, 4-thiadiazole derivative and preparation method thereof

Technical Field

The invention relates to the field of chemical synthesis, in particular to a 1,3, 4-thiadiazole derivative and a preparation method thereof.

Background

Organic sulfur compounds show increasingly wide application prospects in the aspects of medicines, pesticides, biology, organic functional materials and the like. As an important class of organic sulfur compounds, sulfur-containing heterocycles are important intermediates in the synthesis of many biologically and pharmaceutically active molecules, and in particular, have potential biological activity after being modified by functional groups. The thiadiazole compound is an important branch of a sulfur-containing heterocyclic compound, the thiadiazole and the derivative thereof are heterocyclic compounds with various biological activities, and the structural unit of the thiadiazole compound contains a basic structural framework of carbon, nitrogen and sulfur, and the thiadiazole and the derivative thereof are chemically modified to possibly obtain a compound with high biological activity. The 1,3, 4-thiadiazole is used as a drug synthesis intermediate, has biological activities of resisting bacteria, viruses, weeds, plant growth and plant verticillium wilt and the like, is widely applied, and particularly in the field of pesticide bactericides, various products such as ethaboxam, thifluzamide, thiabendazole and the like have been successfully developed. In 1997, the Labeish topic group catalyzed the 1, 2-dithiophthalimide and hydrazone compound by triethylamine under the condition of benzene as solvent to obtain benzothiophene spirothiadiazole derivatives (Heterocyclic chemicals and them in 1, 3-diol cyclic reactivity: I.reaction of 1, 2-dithiochemicals with nitriles, N.N.Labeish, D.A.Oparin, V.K.Bel' ski and V.A.Galishev, Russ.J.org.Chem.1997, 33, 381-387). In 2015, the Gomha project group synthesized cyanopyridylaminothiadiazole derivatives by reacting 1- (3-cyano-4, 6 diphenylpyridin-2-yl) -3-phenylthiourea with hydrazone chloride starting materials (Identification of Novel Aminothiozole and Aminothiozole Conjugated cyanohydrazines as Selective CHK1 Inhibitors, S.M.Gomha, M.M.Abdulla and S.M.Abou-series, Eur.J.Med.chem.,2015, 92459-.

In summary, most of the methods reported to date for the synthesis of thiadiazoles have disadvantages, such as long reaction time, strong solvent toxicity and cumbersome post-treatment, although the substrate universality is broad. Therefore, it is necessary to develop a simple and efficient method for synthesizing the thiadiazole compounds.

Disclosure of Invention

One of the purposes of the invention is to provide a 1,3, 4-thiadiazole derivative, the structural formula of which is shown as III,

wherein: r¹Is phenyl or alkyl substituent; r²Is phenyl or substituted phenyl, alkyl substituent; r³4-methyl and 3-chloro.

The substituted phenyl group includes: 4-methoxy, 4-methyl, 4-chloro, 4-nitro, 4-fluoro and 3-chloro.

Another object of the present invention is to provide a process for preparing 1,3, 4-thiadiazole derivatives, which comprises the following steps:

in the formula, the preparation method of the compound III comprises the following steps: dissolving a compound I and a compound II in a dichloromethane solvent, adding triethylamine for reaction, removing the dichloromethane solvent after a reactant I disappears completely, and eluting by column chromatography to obtain a target compound III.

The compound I and the compound II are dissolved in a dichloromethane solvent at room temperature, and the dichloromethane solvent is removed under reduced pressure.

When the compound III is prepared, the molar ratio of the compound I to the compound II is I: ii is 1:1, and the concentration of the dichloromethane solution is 0.1M.

The eluent used for silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the eluent to the ethyl acetate is V_{Petroleum ether}:V_{Ethyl acetate}＝10:1～3:1。

The invention also provides an application mode, and the 1,3, 4-thiadiazole derivative composition comprises the 1,3, 4-thiadiazole derivative.

The invention has the beneficial effects that: the method uses alpha-enol dithioester and hydrazone compounds as initial raw materials, the raw materials are easy to prepare, dichloromethane is used as a reaction solvent for reaction, and the 1,3, 4-thiadiazole derivatives are prepared and synthesized under room temperature conditions. No noble metal catalyst is used in the reaction, the reaction condition is mild, the operation is simple, the post-treatment is convenient, the yield is high, and the inert gas protection is not needed in the preparation process.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of a product III-1 obtained in an example of the present invention;

FIG. 2 is a nuclear magnetic carbon spectrum of a product III-1 obtained in an example of the present invention;

Detailed Description

The technical scheme of the invention is further explained by specific embodiments in the following with the accompanying drawings:

the preparation method comprises the steps of dissolving the compound I and the compound II in an organic solvent for reaction, removing the solvent after the reaction is finished, and then obtaining the target compound by using a column chromatography method. Experiments show that the preferable organic solvent is dichloromethane, the yield of the reaction product is generally high, and the molar ratio of the raw materials is that the molar ratio of the compound I to the compound II to the triethylamine is I: II: triethylamine ═ 1.0:1.0:1.5, and the optimum concentration of the solution was 0.1M. In all of the following examples, nuclear magnetic spectroscopy was performed by Bruker 400, JEOL 400 instrument in CDCl₃To obtain the compound. Delta values are internal standard relative values (CDCl)₃Scaling delta 7.26¹H NMR and 77.16¹³C NMR). High Resolution Mass Spectrometry (HRMS) was obtained using a 4G quadrupole time-of-flight (QTof) mass spectrometer.

Example 1

The reaction scheme of example 1, the structures of the compounds I-1, II-1 and the product III-1 used in particular are as follows

The specific experimental steps are as follows: 63mg (0.30mmol, 1.0 equivalent) of Compound I-1 and 73mg (0.3mmol, 1.0 equivalent) of Compound II-1 were dissolved in 3mL of methylene chloride, and triethylamine (0.45mmol, 1.5 equivalents) was added thereto and reacted at room temperature for 7 hours. After the reaction was completed, the solvent dichloromethane was removed by rotary evaporation of the reaction mixture under reduced pressure with a water pump. The residue was washed with 200-mesh 300-mesh silica gel and eluted with a volume ratio of V_{Petroleum ether}:V_{Ethyl acetate}Performing column chromatography at a ratio of 10: 1-3: 1) to obtain a compound shown in III-1, and performing nuclear magnetic (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry on the productAnd (5) identifying.

The product III-1 was a yellow solid with a yield of 99%.¹H NMR(400MHz,CDCl₃)δ7.95–7.86(m,4H),7.68–7.64(m,2H),7.61(t,J＝7.8Hz,2H),7.55–7.37(m,7H),6.74(s,1H)；¹³C NMR(100MHz,CDCl₃)δ183.9,160.2,154.8,139.6,139.0,131.2,130.9,129.9,129.8,129.2(2C),128.4,127.3,126.8,125.6,85.8；ESI-HRMS m/z calcd for C₂₂H₁₇N₂OS[M+H]⁺357.1056,found357.1058.

Example 2

The procedures used in the examples for preparing the other compounds of the present invention (compound III-2 to compound III-8) were the same as in example 1, and the reaction conditions were as follows: compound I (0.30mmol, 1.0 equiv.), Compound II (0.30mmol, 1.0 equiv.) were dissolved in 3mL of dichloromethane, and triethylamine (0.45mmol, 1.5 equiv.) was added thereto and reacted at room temperature for 7-10 hours.

The structures of the starting materials used for the preparation of compounds III-2 to III-8 are as follows:

the preparation method of the compound I-2 comprises the following steps: to a suspension of sodium hydride (58.8mmol) in tetrahydrofuran (20.0mL) was added dropwise a solution of imidazole (2.0g) in tetrahydrofuran (40.0mL) under ice-bath over about five minutes, the mixture becoming viscous with the addition of imidazole. Then a solution of carbon disulfide (11.0mmol, 2.7mL) in tetrahydrofuran (20.0mL) was added dropwise and the reaction mixture was stirred at 0-5 ℃ for 15 min. The reaction mixture became clear and dark yellow, to which was added dropwise a solution of methyl iodide (38.2mmol, 2.4mL) in tetrahydrofuran (20.0mL) over 2 minutes, and then the reaction mixture was stirred at 0-5 ℃ for 10 minutes. Distilled water was carefully added to quench the excess sodium hydride. The system was extracted with ethyl acetate (10.0mL) and dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure using a water pump to give a crude oil which was not purified.

A solution of acetone (5mmol) in N, N-dimethylformamide (10mL) was added to sodium hydride (12.5mmol) in DMF-hexane at 0 deg.CAfter 1 hour at 0 ℃ in a mixed solution of an alkane (4:1, 10mL), the yellow oily substance (5mmol) obtained above was slowly added to the system and reacted at room temperature for 10 hours, after the reaction was completed, 25mL of 0.1M HCl was added to quench the reaction, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was washed with 200-mesh 300-mesh silica gel and eluted with a volume ratio of V_{Petroleum ether}:V_{Ethyl acetate}And (2) carrying out column chromatography to obtain I-2, wherein the ratio of the I to the 50 to the 1) is 100: 1.

The preparation method of the compounds II-3 to II-7 comprises the following steps: pyridine (5mmol, 1eq.) was added slowly to a stirred solution of phenylhydrazine (5mmol) in dichloromethane (1M, 5mL) under ice-bath conditions. Then, a solution of the acid chloride (5mmol, 1eq.) in dichloromethane (4M, 1.25mL) was added dropwise to the reaction mixture. After addition was complete, the ice bath was removed and stirred at room temperature overnight. After the reaction, the layers were separated by extraction, and the organic phase was dried over sodium sulfate, concentrated and dried for direct use without additional purification. The corresponding hydrazide (2.5mmol,1eq.) was dissolved in CH₃CN (0.5M, 5mL), and triphenylphosphine (3mmol, 1.2eq.) and carbon tetrachloride (3mmol, 1.2eq.) were added. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (n-hexane/EtOAc ═ 30:1), and stored at 0 ℃ or lower.

The resulting product structures and data are characterized as follows:

the product III-2 was a yellow solid with a yield of 99%.¹H NMR(400MHz,CDCl₃)δ7.88(d,J＝6.4Hz,2H),7.78(d,J＝8.0Hz,2H),7.64(d,J＝7.2Hz,2H),7.59(t,J＝7.2Hz,2H),7.49(t,J＝7.2Hz,1H),7.45–7.35(m,3H),7.27(d,J＝8.0Hz,2H),6.71(s,1H),2.40(s,3H)；¹³C NMR(100MHz,CDCl₃)δ183.8,160.2,155.0,141.4,139.6,139.0,131.1,129.9(2C),129.1,128.4,127.3,127.0,126.7,125.6,85.7,21.6；ESI-HRMS m/z calcd for C₂₃H₁₉N₂OS[M+H]⁺371.1213,found 371.1216.

Product ofIII-3 is a yellow solid with a yield of 99%.¹H NMR(400MHz,CDCl₃)δ7.86(d,J＝7.6Hz,2H),7.77(d,J＝8.4Hz,2H),7.66–7.54(m,4H),7.50(t,J＝7.2Hz,1H),7.45–7.34(m,5H),6.71(s,1H)；¹³C NMR(100MHz,CDCl₃)δ183.7,159.8,153.4,139.4,138.7,136.8,131.1,129.8,129.4,129.1,128.3,128.2,127.8,127.2,125.4,85.9；ESI-HRMS m/z calcd for C₂₂H₁₆ClN₂OS[M+H]⁺391.0666,found 391.0669.

The product III-4 was a yellow solid with a yield of 97%.¹H NMR(400MHz,CDCl₃)δ7.88(d,J＝6.8Hz,2H),7.64(d,J＝7.6Hz,2H),7.59(t,J＝7.6Hz,2H),7.53–7.32(m,7H),7.00(d,J＝5.6Hz,1H),6.72(s,1H),3.83(s,3H)；¹³C NMR(100MHz,CDCl₃)δ183.7,160.1,160.0,154.6,139.5,138.8,131.0,130.8,130.2,129.8,129.1,128.3,127.2,125.5,119.3,117.3,111.2,85.7,55.4；ESI-HRMS m/z calcd for C₂₃H₁₉N₂O₂S[M+H]⁺387.1162,found387.1162.

The product III-5 was a yellow solid with a yield of 94%.¹H NMR(400MHz,CDCl₃)δ7.84(d,J＝6.8Hz,2H),7.63–7.51(m,5H),7.47–7.36(m,3H),6.71(s,1H),4.47(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ184.3,160.8,158.9,146.4,138.7,138.2,131.4,129.9,129.8,128.4,127.3,125.7,87.2,63.0,14.2；ESI-HRMS m/z calcd for C₁₉H₁₇N₂O₃S[M+H]⁺353.0954,found 353.0954.

The product III-6 was a yellow solid with a yield of 95%.¹H NMR(400MHz,CDCl₃)δ7.94–7.86(m,4H),7.51(d,J＝8.4Hz,2H),7.47–7.35(m,8H),6.70(s,1H),2.46(s,3H)；¹³C NMR(100MHz,CDCl₃)δ183.6,160.2,154.5,139.2,138.9,136.9,131.0,130.7,130.3,129.7,129.1,128.3,127.2,126.6,125.3,85.7,21.3；ESI-HRMS m/z calcd for C₂₃H₁₉N₂OS[M+H]⁺371.1213,found371.1216.

The product III-7 was a yellow solid with a yield of 97%.¹H NMR(400MHz,CDCl₃)δ7.91-7.84(m,4H),7.68(t,J＝2.0Hz,1H),7.57(dt,J＝8.0,1.6Hz,1H),7.51(t,J＝8.0Hz,1H),7.48–7.37(m,7H),6.74(s,1H)；¹³C NMR(100MHz,CDCl₃)δ184.0,159.6,155.0,140.5,138.7,135.5,131.2,131.0,130.7,129.4,129.2,129.1,128.4,127.3,126.7,125.8,123.4,86.0；ESI-HRMS m/z calcd for C₂₂H₁₆ClN₂OS[M+H]⁺391.0666,found 391.0668.

The product III-8 was a yellow solid in 76% yield.¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝7.6Hz,2H),7.59–7.52(m,4H),7.50–7.43(m,1H),7.25(d,J＝8.0Hz,2H),6.00(s,1H),2.39(s,3H),2.16(s,3H)；¹³C NMR(100MHz,CDCl₃)δ190.4,158.3,154.3,141.2,139.5,129.8,129.7,128.9,127.0,126.7,125.5,88.7,28.6,21.6；ESI-HRMS m/z calcd for C₁₈H₁₇N₂OS[M+H]⁺309.1056,found 309.1056.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims

1,3, 4-thiadiazole derivatives, which are characterized in that the structural formula is shown as III,

2. The 1,3, 4-thiadiazole derivative according to claim 1, wherein: the substituted phenyl group includes: 4-methoxy, 4-methyl, 4-chloro, 4-nitro, 4-fluoro and 3-chloro.

A process for producing a 1,3, 4-thiadiazole derivative, characterized in that the process comprises the following steps:

4. The process for producing a 1,3, 4-thiadiazole derivative according to claim 3, wherein: the compound I and the compound II are dissolved in a dichloromethane solvent at room temperature, and the dichloromethane solvent is removed under reduced pressure.

5. The process for producing a 1,3, 4-thiadiazole derivative according to claim 3, wherein: when the compound III is prepared, the molar ratio of the compound I to the compound II is I: ii is 1:1, and the concentration of the dichloromethane solution is 0.1M.

6. The process for producing a 1,3, 4-thiadiazole derivative according to claim 3, wherein: the eluent used for silica gel column chromatography is petroleumMixed solvent of ether and ethyl acetate, and volume ratio V_{Petroleum ether}:V_{Ethyl acetate}＝10:1～3:1。

7. A1, 3, 4-thiadiazole derivative composition, wherein the composition comprises a 1,3, 4-thiadiazole derivative.