P-toluenesulfonyl modified difluoroacetonitrile precursor compound as well as synthesis method and application thereof

Abstract

The invention discloses a p-toluenesulfonyl modified difluoroacetonitrile precursor compound as well as a synthesis method and application of the p-toluenesulfonyl modified difluoroacetonitrile precursor compound. According to the synthesis method of the p-toluenesulfonyl modified difluoroacetonitrile precursor compound, p-methylthiophenol, brominated ethyl difluoroacetate and 2, 4-dinitro hydroxylamine are used as raw materials, and the p-toluenesulfonyl modified difluoroacetonitrile precursor compound is prepared through mild reaction conditions and simple, convenient and safe operation. The precursor compound can be rapidly converted into toluenesulfonyl modified difluoroacetonitrile under mild conditions, and can be smoothly applied to synthesis of a difluoromethyl substituted 1, 2, 4-oxadiazole derivative with good anticancer activity. The synthesis method of the p-toluenesulfonyl modified difluoroacetonitrile precursor compound has the advantages of cheap and easily available raw materials, mild reaction conditions, simple and safe operation and the like, and has important application in organic synthesis and drug synthesis.

Description

Technical Field

[0001] The invention relates to a compound and a synthesis method thereof, and belongs to the fields of synthetic chemistry and medicinal chemistry, and in particular to the synthesis and application of a p-toluenesulfonyl-modified difluoroacetonitrile precursor. Background Art

[0002] As an important functional group, difluoromethyl can be regarded as an isostere of carbonyl, amide, alcohol and hydroxamic acid. It not only has good lipophilicity, but also can be used as a carrier of hydrogen bonds. It is commonly found in active molecules. In particular, difluoromethyl-substituted nitrogen-containing heterocyclic compounds are widely used in marketed drug molecules because of their good biological activity. For example, the ATP-competitive pan-class I PI3K inhibitor ZSTK474 developed by Kymera Therapeutics, the COX-2 selective inhibitor Deracoxib developed by Pharmacia & Upjohn, and the fungicide lsopyrazam developed by Syngenta are all difluoromethyl-substituted nitrogen-containing heterocyclic drug molecules.

[0003] The development and application of new difluoromethyl reaction building blocks is an important way to construct difluoromethyl-containing drug molecules. The p-toluenesulfonyl-modified difluoroacetonitrile precursor can generate p-toluenesulfonyl-modified difluoroacetonitrile in situ. This product has good reactivity and can efficiently participate in the reaction to generate p-toluenesulfonyl-modified difluoromethyl-substituted nitrogen-containing heterocyclic compounds. The modified p-toluenesulfonyl group can be removed under extremely mild conditions to obtain difluoromethyl-substituted nitrogen-containing heterocyclic molecules.

[0004]

[0005] At present, this type of difluoroacetonitrile precursor has never been reported as a new type of difluoromethyl reaction building block, so there is no related application transformation. The present invention has carried out pioneering research work in this regard. Summary of the invention

[0006] The invention provides a p-toluenesulfonyl-modified difluoroacetonitrile precursor compound and a synthesis method thereof, which fills the blank of difluoroacetonitrile application in organic synthesis; meanwhile, the p-toluenesulfonyl-modified difluoroacetonitrile precursor compound synthesized by the invention has stable properties, the required raw materials are cheap and easily available, and the synthesis can be scaled up to ten gram levels, thus having a high application prospect in drug research and development.

[0007] Technical solution adopted by the invention:

[0008] A p-toluenesulfonyl-modified difluoroacetonitrile precursor compound, the structure of which is shown in the following formula (1):

[0009]

[0010] The p-toluenesulfonyl-modified difluoroacetonitrile precursor compound described in the above formula (1) is prepared from p-methylthiophenol, ethyl bromodifluoroacetate, and 2,4-dinitrohydroxylamine as raw materials under mild reaction conditions through a few simple synthetic reactions:

[0011] The synthetic reaction route is shown in reaction formula (I):

[0012]

[0013] The synthetic preparation process includes the following steps:

[0014] 1) dissolving p-methylthiophenol in dimethyl sulfoxide with a solubility of 0.5-1.5 mol / L, adding 1.1-1.5 equivalents of sodium hydride, stirring at room temperature for 1-2 hours, adding 2.0-3.0 equivalents of ethyl bromodifluoroacetate, stirring at room temperature for 12-16 hours, washing, extracting, and concentrating to obtain a difluoroester-substituted thioether derivative;

[0015] 2) Dissolve the difluoroester-substituted sulfide in anhydrous ethanol at a concentration range of 0.5 to 1.5 mol / L, add 2.0 to 3.0 equivalents of sodium borohydride, and react at 0°C for 0.5 to 1.0 hours. After washing, extraction, and concentration, a difluorosulfide-substituted primary alcohol derivative is obtained;

[0016] 3) dissolving the difluorosulfide-substituted primary alcohol in a mixed solution of water and acetic acid in a concentration range of 0.5 to 1.5 mol / L, adding 2 to 4 equivalents of 30% hydrogen peroxide, heating and refluxing for 2 to 3 hours, washing, extracting, and concentrating to obtain an aromatic sulfonyl difluoromethyl-substituted primary alcohol derivative;

[0017] 4) The primary alcohol substituted with aromatic sulfonyldifluoromethyl is dissolved in dichloromethane, 1.2-1.5 equivalents of Dess-Martin oxidant is added in an ice-water bath and stirred for 0.5 hour, then the reaction is moved to room temperature and stirred for 0.5-1.0 hour, the organic phase is extracted with dichloromethane and saturated sodium carbonate aqueous solution, the organic phase is then washed with saturated brine, the combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the p-toluenesulfonyldifluoromethyl substituted aldehyde derivative is obtained by concentrating the solvent.

[0018] 5) Add 4 to 6 equivalents of concentrated hydrochloric acid to the above product, and then add 1.0 to 1.2 equivalents of 2,4-dinitrohydroxylamine, react at room temperature for 24 hours, and then recrystallize with anhydrous ethanol to obtain a pure target product.

[0019] Through the above reaction steps, a stable and safe p-toluenesulfonyl-modified difluoroacetonitrile precursor can be synthesized.

[0020] This type of precursor is dissolved in tetrahydrofuran or 1,2-dioxane at a concentration range of 0.1 to 0.5 mol / L. Under room temperature, it can be smoothly converted into p-toluenesulfonyl-modified difluoroacetonitrile by the action of 1.5 to 2.0 equivalents of base (sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or DBU). Under this condition, it can undergo cycloaddition with 1.0 equivalents of chlorinated aromatic or alkyl oxime to obtain p-toluenesulfonyl difluoromethyl-substituted 1,2,4-oxadiazole derivatives as shown in the following formula (2):

[0021]

[0022] The 1,2,4-oxadiazole derivative shown in formula (2) was dissolved in a mixed solution of equal volumes of DMF and acetic acid in a concentration range of 0.1 to 0.5 mol / L, and reacted with 10.0 equivalents of magnesium metal at -15°C for 6 hours to successfully remove Ts (p-methylbenzenesulfonyl) to obtain a difluoromethyl-substituted oxadiazole derivative shown in formula (3) in an equivalent yield:

[0023]

[0024] Through the MTT biological activity test, fluorouracil (5-Fu) was used as a positive control. This type of structure had a significant inhibitory effect on cervical cancer cells (HELA), colon cancer cells (HCT116) and lung cancer cells (A549) (inhibition rate at a concentration of 20 μM).

[0025]

[0026] In vitro cytotoxicity of difluoromethyl-substituted oxadiazole compounds (inhibition rate at 20 μM concentration)

[0027]

[0028] There is no related report on the synthesis method and application of this type of precursor compound. This is the first synthesis of the present invention (see the examples for detailed methods and data).

[0029] Beneficial effects of the invention:

[0030] 1. The present invention provides a method for synthesizing a p-toluenesulfonyl-modified difluoroacetonitrile precursor with mild reaction conditions, simple operation, high efficiency and safety. For the first time, the p-toluenesulfonyl-modified difluoroacetonitrile precursor was efficiently synthesized under mild reaction conditions using cheap and readily available raw materials, which reflects the convenience and safety of the method.

[0031] This type of precursor is stable and can be converted into difluoroacetonitrile modified with p-toluenesulfonyl under alkaline conditions.

[0032] 2. The p-toluenesulfonyl-modified difluoroacetonitrile precursor synthesized by the present invention is stable and easy to store. It can be quickly converted / in situ generated into p-toluenesulfonyl-modified difluoroacetonitrile under alkaline conditions. This type of difluoroacetonitrile has been confirmed by synthetic NMR characterization. This type of novel difluoromethyl synthetic building block can be used to efficiently construct difluoromethyl-substituted nitrogen-containing heterocyclic compounds, which reflects the practicality of the reaction precursor and can provide a strong boost for further construction of a difluoromethyl compound library.

[0033] 3. The difluoromethyl-substituted nitrogen-containing heterocyclic compound synthesized by the present invention has good anti-tumor activity and can be used to construct a lead compound with novel structure and potential drugability, which reflects that the reaction precursor has great application prospects in drug synthesis and drug research and development. After the p-toluenesulfonyl-modified difluoroacetonitrile precursor compound described or prepared by the present invention generates p-toluenesulfonyl-modified difluoroacetonitrile in situ, it can quickly undergo cycloaddition with chlorinated aromatic or alkyl oxime to obtain a series of p-toluenesulfonyl-modified difluoromethyl-substituted 1,2,4-oxadiazole derivatives. The product synthesized by the conversion application of the precursor compound is a new difluoromethyl nitrogen-containing heterocyclic structure, which can efficiently remove the p-toluenesulfonyl group and has good anti-tumor activity, such as significant inhibitory effects on cervical cancer cells (HELA), colon cancer cells (HCT116) and lung cancer cells (A549). BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1A , Figure 1B The NMR of the p-toluenesulfonyl-modified difluoroacetonitrile precursor obtained in Example 1 is shown. 1 HNMR Figure 1A ), 13 C NMR ( Figure 1B ) Spectrum;

[0035] Figure 2A , Figure 2B The NMR of the p-toluenesulfonyldifluoromethyl substituted oxadiazole derivative 2-a obtained in Example 2 is shown. 1 H NMR ( Figure 2A ), 13 C NMR ( Figure 2B ) Spectrum;

[0036] Figure 3A , Figure 3B The NMR of the p-toluenesulfonyldifluoromethyl substituted oxadiazole derivative 2-b in Example 3 is shown. 1 H NMR ( Figure 3A ), 13 C NMR ( Figure 3B ) Spectrum;

[0037] Figure 4A , Figure 4B The NMR of the p-toluenesulfonyldifluoromethyl substituted oxadiazole derivative 2-c in Example 4 is shown. 1 H NMR ( Figure 4A ), 13 C NMR ( Figure 4B ) Spectrum;

[0038] Figure 5A , Figure 5B The NMR of the p-toluenesulfonyldifluoromethyl substituted oxadiazole derivative 2-d in Example 5 is shown. 1 H NMR ( Figure 5A ), 13 C NMR ( Figure 5B )atlas.

[0039] Fig. 6A , Figure 6B The NMR of the p-toluenesulfonyldifluoromethyl substituted oxadiazole derivative 2-e is shown in Example 6. 1 H NMR ( Fig. 6A ), 13 C NMR ( Figure 6B )atlas.

[0040] Fig. 7A , Figure 7B The NMR of the p-toluenesulfonyldifluoromethyl substituted oxadiazole derivative 2-g is shown in Example 7. 1 H NMR ( Fig. 7A ), 13 C NMR ( Figure 7B )atlas.

[0041] Fig. 8A , Figure 8B The NMR of the difluoromethyl substituted oxadiazole derivative 3-f of Example 8 is shown. 1 H NMR ( Fig. 8A ), 13 C NMR ( Figure 8B )atlas. DETAILED DESCRIPTION

[0042] In order to make the technical concept and advantages of the present invention more clearly understood, the technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings. It should be understood that the following embodiments are only used to explain and illustrate the preferred implementation methods of the present invention, and should not be regarded as and do not constitute a limitation on the scope of patent protection claimed by the present invention.

[0043] The present invention provides a p-toluenesulfonyl-modified difluoroacetonitrile precursor, the structure of which is shown in the following formula:

[0044]

[0045] It is prepared by using p-methylthiophenol, ethyl bromodifluoroacetate and 2,4-dinitrohydroxylamine as raw materials and through several simple reactions under mild reaction conditions. The synthetic reaction process is shown in reaction formula (I):

[0046]

[0047] The specific synthesis preparation process includes the following steps:

[0048] 1) dissolving p-methylthiophenol in dimethyl sulfoxide with a solubility of 0.5-1.5 mol / L, adding 1.1-1.5 equivalents of sodium hydride, stirring at room temperature for 1-2 hours, adding 2.0-3.0 equivalents of ethyl bromodifluoroacetate, stirring at room temperature for 12-16 hours, washing, extracting, and concentrating to obtain a difluoroester-substituted thioether derivative;

[0049] 2) Dissolve the difluoroester-substituted sulfide in anhydrous ethanol at a concentration range of 0.5 to 1.5 mol / L, add 2.0 to 3.0 equivalents of sodium borohydride, and react at 0°C for 0.5 to 1.0 hours. After washing, extraction, and concentration, a difluorosulfide-substituted primary alcohol derivative is obtained;

[0050] 3) dissolving the difluorosulfide-substituted primary alcohol in a mixed solution of water and acetic acid in a concentration range of 0.5 to 1.5 mol / L, adding 2 to 4 equivalents of 30% hydrogen peroxide, heating and refluxing for 2 to 3 hours, washing, extracting, and concentrating to obtain an aromatic sulfonyl difluoromethyl-substituted primary alcohol derivative;

[0051] 4) The primary alcohol substituted with aromatic sulfonyldifluoromethyl is dissolved in dichloromethane, 1.2-1.5 equivalents of Dess-Martin oxidant is added in an ice-water bath and stirred for 0.5 hour, then the reaction is moved to room temperature and stirred for 0.5-1.0 hour, the organic phase is extracted with dichloromethane and saturated sodium carbonate aqueous solution, the organic phase is then washed with saturated brine, the combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the p-toluenesulfonyldifluoromethyl substituted aldehyde derivative is obtained by concentrating the solvent.

[0052] 5) Add 4 to 6 equivalents of concentrated hydrochloric acid to the above product, and then add 1.0 to 1.2 equivalents of 2,4-dinitrohydroxylamine, react at room temperature for 24 hours, and then recrystallize with anhydrous ethanol to obtain a pure target product.

[0053]

[0054] This type of precursor is dissolved in tetrahydrofuran or 1,2-dioxane at a concentration range of 0.1 to 0.5 mol / L. Under room temperature, it can be smoothly converted into p-toluenesulfonyl-modified difluoroacetonitrile by the action of 1.5 to 2.0 equivalents of base (sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or DBU). Under this condition, it can undergo cycloaddition with 1.0 equivalents of chlorinated aromatic or alkyl oxime to obtain p-toluenesulfonyl difluoromethyl-substituted 1,2,4-oxadiazole derivatives as shown in formula (2):

[0055]

[0056] The above process is as follows:

[0057]

[0058] The p-toluenesulfonyl difluoromethyl substituted 1,2,4-oxadiazole derivative was dissolved in a mixed solution of equal volumes of DMF and acetic acid at a concentration range of 0.1 to 0.5 mol / L, and reacted with 10.0 equivalents of magnesium at -15°C for 6 hours to successfully remove Ts (p-toluenesulfonyl) to obtain a difluoromethyl substituted oxadiazole derivative as shown in formula (3) in an equivalent yield:

[0059]

[0060] The product is a new difluoromethyl nitrogen-containing heterocyclic structure, which can efficiently remove p-toluenesulfonyl and has good anti-tumor activity, such as significant inhibitory effects on cervical cancer cells (HELA), colon cancer cells (HCT116) and lung cancer cells (A549). The technical solution of the present invention is further described in detail below with reference to the accompanying drawings through specific embodiments.

[0061] Example 1

[0062]

[0063] (1) 20 mmol of p-methylthiophenol was dissolved in 20 mL of dimethyl sulfoxide, 2.0 equivalents of sodium hydride (40 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then 48 mmol of ethyl bromodifluoroacetate was added, and the mixture was stirred at room temperature for 12 hours. The mixture was then washed, extracted, and concentrated. The mixture was directly used for the next step without further purification. (2) The above product was dissolved in 20 mL of ethanol, 2.0 equivalents of sodium borohydride (40 mmol) was added, and the mixture was reacted at 0°C for 0.5 hour. After washing, extraction, and concentration, a difluorosulfide-substituted primary alcohol derivative was obtained, which was directly used for the next step without purification. (3) The above product was dissolved in 40 mL of water and acetic acid. 4.0 equivalents of hydrogen peroxide were added to the mixed solution (volume ratio 1:1), heated to reflux for 2 hours, washed, extracted and concentrated to obtain a crude product, which was directly put into the next step without further purification; (4) The above product was dissolved in 20 mL of dichloromethane, 1.2 equivalents of Dess-Martin reagent were added, and the reaction was carried out at 0°C for 0.5 hours. Then 1.1 equivalents of p-toluenesulfonyl hydrazide were added to the reaction solution, and the reaction was carried out at 0°C for 1 hour. The organic phase was extracted with dichloromethane and saturated sodium carbonate aqueous solution, and the organic phase was washed with saturated brine. The organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The p-toluenesulfonyl difluoromethyl substituted aldehyde derivative was obtained by concentrating the solvent. 5 equivalents of concentrated hydrochloric acid were added to the above product, and then 1.1 equivalents of 2,4-dinitrohydroxylamine were added, and the reaction was carried out at room temperature for 24 hours. Then, it was recrystallized from anhydrous ethanol to obtain a pure light yellow solid target product. The overall yield was 60%.

[0064] The NMR of the p-toluenesulfonyl-modified difluoroacetonitrile precursor obtained in this example is 1 H NMR ( Figure 1A ), 13 CNMR( Figure 1B ) spectra are as follows Figure 1A , Figure 1B As shown, 1 H NMR(500MHz, CDCl3) δ8.88(d,J=2.7Hz,1H),8.47(dd,J=9.3,2.7Hz,1H),8.25(t,J =7.1Hz,1H),7.90(dd,J=13.8,8.7Hz,3H),7.48(d,J=8.1Hz,2H),2.52(s,3H)ppm; 13 C NMR (100MHz, CDCl3) δ155.4,148.3,145.7(t,J CF =26.3Hz),142.6,136.5,131.2,130.5,129.4,128.2,122.0,117.7,116.5(t,J CF =288.9Hz),22.1ppm.

[0065] Example 2

[0066]

[0067] 2 mmol of p-toluenesulfonyl-modified difluoroacetonitrile precursor was dissolved in 4 mL of tetrahydrofuran, and 1.5 equivalents of triethylamine were added. Under stirring at room temperature, 2 mmol of phenylchlorooxime was added, and the mixture was stirred at room temperature for 8 hours. The mixture was purified by column chromatography to obtain product 2-a in an equivalent yield. Figure 2A , Figure 2B The following are the NMR images of the aromatic sulfonyl-modified difluoromethyl reaction building blocks prepared in this example: 1 H NMR ( Figure 2A ), 13 C NMR ( Figure 2B )atlas. 1 H NMR (400MHz, CDCl3): δ8.15–8.08(m,2H),7.96–7.89(m,2H),7.60–7.44(m,5H),2.52(s,3H)ppm; 13 C NMR (100MHz, CDCl3): δ169.5,166.0(t,J CF =30.1Hz),148.5,132.2,131.3,130.5,129.1,128.0,127.8,125.1,114.7(t,J CF =291.1Hz),22.0ppm.

[0068] Example 3

[0069]

[0070] 2 mmol of p-toluenesulfonyl-modified difluoroacetonitrile precursor was dissolved in 4 mL of tetrahydrofuran, and 1.5 equivalents of sodium carbonate were added. Under stirring at room temperature, 2 mmol of benzyl chlorooxime was added, and the mixture was stirred at room temperature for 8 hours. The mixture was purified by column chromatography to obtain product 2-b in an equivalent yield. Figure 3A , Figure 3B The following are the NMR images of the aromatic sulfonyl-modified difluoromethyl reaction building blocks prepared in this example: 1 H NMR ( Figure 3A ), 13 C NMR ( Figure 3B ) spectrum. As shown in the figure, 1 H NMR (400MHz, CDCl3): δ7.86–7.74(m,2H),7.41–7.27(m,7H),4.17(s,2H),2.49(s,3H)ppm;13 CNMR (100MHz, CDCl3): δ170.7,166.1(t,J CF =30.3Hz),148.3,134.2,131.2,130.4,129.1,128.9,127.9,127.5,114.5(t,J CF =291.9Hz),32.1,22.0ppm.

[0071] Example 4

[0072]

[0073] 2 mmol of p-toluenesulfonyl-modified difluoroacetonitrile precursor was dissolved in 4 mL of tetrahydrofuran, and 1.5 equivalents of sodium carbonate were added. Under stirring at room temperature, 2 mmol of 2-thienyl chlorooxime was added, and the mixture was stirred at room temperature for 8 hours. The mixture was purified by column chromatography to obtain product 2-c in an equivalent yield. Figure 4A , Figure 4B The following are the NMR images of the aromatic sulfonyl-modified difluoromethyl reaction building blocks prepared in this example: 1 H NMR ( Figure 4A ), 13 C NMR ( Figure 4B ) spectrum. As shown in the figure, 1 H NMR (400MHz, CDCl3): δ7.92(d,J=8.2Hz,2H),7.88(dd,J=3.8,1.3Hz,1H),7.59(dd,J =5.0,1.3Hz,1H),7.47(d,J=8.1Hz,2H),7.19(dd,J=5.0,3.7Hz,1H),2.52(s,3H)ppm; 13 C NMR (100MHz, CDCl3): δ165.9(t,J CF =30.3Hz),165.5,148.5,131.3,131.3,130.8,130.5,128.3,128.0,126.2,114.6(t,J CF =291.9Hz),22.1ppm.

[0074] Example 5

[0075]

[0076] 2 mmol of p-toluenesulfonyl-modified difluoroacetonitrile precursor was dissolved in 4 mL of tetrahydrofuran, and 1.5 equivalents of sodium carbonate were added. Under stirring at room temperature, 2 mmol of 2-naphthylchlorooxime was added, and the mixture was stirred at room temperature for 8 hours. The mixture was purified by column chromatography to obtain product 2-d in an equivalent yield. Figure 5A , Figure 5B The following are the NMR images of the aromatic sulfonyl-modified difluoromethyl reaction building blocks prepared in this example: 1 H NMR ( Figure 5A ), 13 C NMR ( Figure 5B ) spectrum. As shown in the figure, 1 H NMR (400MHz, CDCl3): δ8.69(s,1H),8.16(dd,J=8.6,1.7Hz,1H),7.98(dd,J=8.5,2.1Hz,4 H),7.92(dd,J=7.3,1.9Hz,1H),7.67–7.56(m,2H),7.51(d,J=8.1Hz,2H),2.55(s,3H)ppm; 13 CNMR (100MHz, CDCl3): δ169.6,166.0(t,J CF =30.1Hz),148.5,135.0,132.9,131.4,130.5,129.1,129.0,128.9,128.1,128.1,128.0,127.07,123.6,122.3,114.7(t,J CF =291.1Hz),22.0ppm.

[0077] Example 6

[0078]

[0079] 2 mmol of p-toluenesulfonyl-modified difluoroacetonitrile precursor was dissolved in 4 mL of tetrahydrofuran, and 1.5 equivalents of potassium carbonate were added. Under stirring at room temperature, 2 mmol of 3-cyanophenyl chlorooxime was added, and the mixture was stirred at room temperature for 8 hours. The mixture was purified by column chromatography to obtain product 2-e in an equivalent yield. Fig. 6A , Figure 6B The following are the NMR images of the aromatic sulfonyl-modified difluoromethyl reaction building blocks prepared in this example: 1 H NMR ( Fig. 6A ), 13 C NMR ( Figure 6B ) spectrum. As shown in the figure, 1HNMR (400MHz, CDCl3): δ8.42(t,J=1.8Hz,1H),8.37(dt,J=7.9,1.5Hz,1H),7.94(d,J=8.1Hz,2 H),7.86(dt,J=7.7,1.5Hz,1H),7.67(t,J=7.8Hz,1H),7.50(d,J=8.1Hz,2H),2.54(s,3H)ppm; 13 C NMR (100MHz, CDCl3): δ167.9,166.7(t,J CF =30.1Hz),148.7,135.3,131.7,131.4,130.6,130.2,127.8,126.5,117.6,114.5(t,J CF =291.9Hz),113.8,22.1ppm.

[0080] Example 7

[0081]

[0082] 2 mmol of p-toluenesulfonyl-modified difluoroacetonitrile precursor was dissolved in 4 mL of tetrahydrofuran, and 1.5 equivalents of DBU were added. Under stirring at room temperature, 2 mmol of 4-trifluoromethylphenyl chlorooxime was added, and the mixture was stirred at room temperature for 8 hours. The mixture was purified by column chromatography to obtain product 2-g in an equivalent yield. Fig. 7A , Figure 7B The following are the NMR images of the aromatic sulfonyl-modified difluoromethyl reaction building blocks prepared in this example: 1 H NMR ( Fig. 7A ), 13 C NMR ( Figure 7B ) spectrum. As shown in the figure, 1 HNMR (400MHz, CDCl3): δ8.26(d,J=8.1Hz,2H),7.98–7.90(m,2H),7.79(d,J=8.2Hz,2H),7.49(d,J=8.1Hz,2H),2.53(s,3H)ppm; 13 C NMR (100MHz, CDCl3): δ168.5,166.5(t,J CF =30.3Hz),148.6,133.9(q,J CF =33.3Hz),131.4,130.6,128.4,128.2,127.9,126.1(q,J CF =4.0Hz),123.6(q,J CF =272.7Hz),114.6(t,JCF =292.9Hz),22.0ppm.

[0083] Example 8

[0084]

[0085] 2 mmol of 2-f product was dissolved in 4 mL of an equal volume of a mixed solution of DMF and acetic acid, stirred at -15°C, and then 10.0 equivalents of metallic magnesium were added. The reaction was continued at -15°C for 6 hours, and Ts (p-methylbenzenesulfonyl) was successfully removed to obtain 3-f in an equivalent yield. Fig. 8A , Figure 8B The following are the NMR images of the aromatic sulfonyl-modified difluoromethyl reaction building blocks prepared in this example: 1 H NMR ( Fig. 8A ), 13 C NMR ( Figure 8B ) spectrum. As shown in the figure, 1 H NMR (400MHz, CDCl3): δ8.27(t,J=1.8Hz,1H),8.05(dt,J=7.8,1.3Hz,1H),7.68(dt,J=8.0,1.4Hz,1H),7.39(t,J=7.9Hz,1H),6.88(t,J=52.1Hz,1H); 13 C NMR (100MHz, CDCl3): δ169.8(t,J CF =30.0Hz),167.7,135.0,130.7,130.6,127.3,126.2,123.2,105.6(t,J CF =242.0Hz)ppm.

[0086] Example 9

[0087]

[0088] The experimental method of this example is basically the same as that of Example 7. The chlorooxime used in this example is 3-bromophenyl chlorooxime. The obtained product is shown in the structural formula (2-f) with an equivalent yield.

[0089] Example 10

[0090]

[0091] The experimental method of this example is basically the same as that of Example 8. The chlorooxime used in this example is phenylchlorooxime. The obtained product is shown in the structural formula (3-a) with an equivalent yield.

[0092] Embodiment 11

[0093]

[0094] The experimental method of this example is basically the same as that of Example 8. The chlorooxime used in this example is benzyl chlorooxime. The obtained product is shown in the structural formula (3-b) with an equivalent yield.

[0095] Example 12

[0096]

[0097] The experimental method of this example is basically the same as that of Example 8. The chlorooxime used in this example is 2-thienylchlorooxime. The obtained product is shown in the structural formula (3-c) with an equivalent yield.

[0098] Example 13

[0099]

[0100] The experimental method of this example is basically the same as that of Example 8. The chlorooxime used in this example is 2-naphthylchlorooxime. The obtained product is shown in the structural formula (3-d) with an equivalent yield.

[0101] Embodiment 14

[0102]

[0103] The experimental method of this example is basically the same as that of Example 8. The chlorooxime used in this example is 3-cyanophenyl chlorooxime. The obtained product is shown in the structural formula (3-e) with an equivalent yield.

[0104] Example 10

[0105]

[0106] The experimental method of this example is basically the same as that of Example 8. The chlorooxime used in this example is 4-trifluoromethylphenyl chlorooxime, and the obtained product is shown in the structural formula (3-g).

[0107] The above description is only a preferred embodiment of the present invention and does not constitute and should not constitute a limitation of the invention. Under the guidance of the prior art, those skilled in the art can make other modifications to the implementation of the present invention without creative work. Any other modifications made within the spirit and principle of the invention or simple replacement or equivalent substitution using conventional technical means in the field should be included in the protection scope of the present invention.

Claims

1. A p-toluenesulfonyl-modified difluoroacetonitrile precursor compound, characterized in that: The compound structural formula is as follows:

2. A method for synthesizing the precursor compound as claimed in claim 1, characterized in that: It is prepared using p-methylthiophenol, ethyl bromodifluoroacetate and 2,4-dinitrohydroxylamine as raw materials. The synthetic route is as follows:

3. The synthesis method according to claim 2, characterized in that: Its synthetic preparation process includes the following steps: 1) using p-methylthiophenol and ethyl bromodifluoroacetate as starting materials to undergo a nucleophilic substitution reaction to obtain a difluoroester-substituted thioether derivative; 2) subjecting the difluoroester-substituted sulfide derivative to hydrogenation reduction to obtain a difluoromethyl sulfide-substituted primary alcohol derivative; 3) oxidizing the difluoromethyl sulfide-substituted primary alcohol to obtain a p-toluenesulfonyl difluoromethyl-substituted primary alcohol derivative; 4) dissolving the p-toluenesulfonyldifluoromethyl substituted primary alcohol derivative, adding an oxidant, and reacting at 0° C. for 0.5 to 1.0 hour. After the reaction is complete, extracting, washing, drying, and concentrating to obtain the p-toluenesulfonyldifluoromethyl substituted aldehyde derivative.

4. The synthesis method according to claim 3, characterized in that: In step 1), p-toluene thiophenol is dissolved in dimethyl sulfoxide (DMSO) with a solubility range of 0.5 to 1.5 mol / L, 1.1 to 1.5 equivalents of sodium hydride are added, and the mixture is stirred at room temperature for 1 to 2 hours. Then, 2.0 to 3.0 equivalents of ethyl bromodifluoroacetate are added, and the mixture is stirred at room temperature for 12 to 16 hours. After washing, extraction and concentration, a difluoroester-substituted thioether derivative is obtained.

5. The synthesis method according to claim 3, characterized in that: In step 2), a difluoroester-substituted sulfide derivative is dissolved in anhydrous ethanol at a concentration range of 0.5 to 1.5 mol / L, 2.0 to 3.0 equivalents of sodium borohydride are added, and the mixture is reacted at 0° C. for 0.5 to 1.0 hour; after washing, extraction and concentration, a difluoromethyl sulfide-substituted primary alcohol derivative is obtained.

6. The synthesis method according to claim 3, characterized in that: In step 3), the difluorosulfide-substituted primary alcohol derivative is dissolved in a mixed solution of water and acetic acid in a concentration range of 0.5 to 1.5 mol / L, 2 to 4 equivalents of 30% hydrogen peroxide are added, heated under reflux for 2 to 3 hours, and the p-toluenesulfonyldifluoromethyl-substituted primary alcohol derivative is obtained by washing, extraction and concentration.

7. The synthesis method according to claim 3, characterized in that: In step 4), a p-toluenesulfonyldifluoromethyl substituted primary alcohol derivative is dissolved in dichloromethane at a concentration range of 0.5 to 1.5 mol / L, and then 1.2 to 1.5 equivalents of Dess-Martin oxidant are added under ice-water bath conditions, and then the reaction is moved to room temperature and stirred for 0.5 to 1.0 hours. The organic phase is extracted with dichloromethane and a saturated sodium carbonate aqueous solution, and then washed with saturated brine. The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a p-toluenesulfonyldifluoromethyl substituted aldehyde derivative.

8. The synthesis method according to any one of claims 3 to 7, characterized in that: The method comprises the step 5) adding 4 to 6 equivalents of concentrated hydrochloric acid to the product obtained after drying and concentration, and then adding 1.0 to 1.2 equivalents of 2,4-dinitrohydroxylamine, reacting at room temperature for 24 hours, and then recrystallizing with anhydrous ethanol to obtain a pure target product.

9. The p-toluenesulfonyl-modified difluoroacetonitrile precursor compound prepared by the synthesis method according to claim 1 and any one of claims 2 to 8 in the preparation of 1,2,4-oxadiazole derivatives Application in.

10. The use according to claim 9, characterized in that: The conversion application process is as follows: 1) dissolving the precursor in an organic solvent at a concentration range of 0.1 to 0.5 mol / L, and converting it into p-toluenesulfonyl-modified difluoroacetonitrile under the action of 1.5 to 2.0 equivalents of base at room temperature; 2) Under the above conditions, the p-toluenesulfonyl (Ts)-modified difluoroacetonitrile is further subjected to a cycloaddition reaction with 1.0 equivalent of chloroaromatic or alkyl oxime to obtain a p-toluenesulfonyldifluoromethyl-substituted 1,2,4-oxadiazole derivative as shown in the following formula: The conversion reaction equation is as follows: The organic solvent used is any one of tetrahydrofuran and 1,2-dioxane or a mixed solvent; the base used is any one or more of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); the R substituent in the 1,2,4-oxadiazole derivative substituted with p-toluenesulfonyldifluoromethyl is any one of phenyl, benzyl, 2-thienyl, 2-naphthyl, 3-bromophenyl, 3-cyanophenyl, and 4-trifluoromethylphenyl.

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