Method for synthesizing sulfimide compound through N-triphenylmethyl-2-phenylethane-1-sulfinamide

Abstract

The invention belongs to the fields of organic synthesis, pesticides, medicines, material science and the like, and discloses a method for synthesizing a sulfimide compound from N-triphenylmethyl-2-phenylethane-1-sulfinamide. According to the invention, N-triphenylmethyl-2-phenylethane-1-sulfinamide is used as an initial raw material, tert-butyl hypochlorite is used for chlorination and oxidation, and then the product and a nucleophilic reagent are subjected to further derivatization application. In the invention, the N-triphenylmethyl-2-phenylethane-1-sulfinamide is a preorder research of a research group, and a new thought is provided for further derivatization application of the N-triphenylmethyl-2-phenylethane-1-sulfinamide to synthesize the sulfimide, so that the application of the N-triphenylmethyl-2-phenylethane-1-sulfinamide to the synthesis of the sulfimide is facilitated. The method has the characteristics of mild reaction conditions, convenient experimental operation, good nucleophilic reagent substrate compatibility and easy scale amplification, and has great application value and social and economic benefits.

Description

Technical Field

[0001] The present invention relates to a preparation method of pharmaceutical and chemical products, and relates to a method for preparing sulfimide compounds by using N-trityl-2-phenylethane-1-sulfinamide for chlorination oxidation with tert-butyl hypochlorite and further derivatization application with nucleophilic reagents. Background Art

[0002] Sulfimides are an important class of sulfur-containing compounds, which are widely used in the fields of organic synthesis, pesticides, pharmaceuticals, and materials science. Since their discovery in 1949 in organic synthesis, the sulfimide group has demonstrated its unique value in a variety of drug molecules. The functionalization activity of the nitrogen atom on the sulfimide still provides diverse possibilities for drug designers, and is very suitable for regulating the properties of compounds, as well as constructing new complex molecular structures and skeleton patterns.

[0003] The role of the sulfimide structure as a bioisostere of thiol and sulfur-free groups (such as alcohols and amines) has also been fully demonstrated in the literature. This structure is very suitable for regulating the druggability of active compounds, or enhancing the novelty of compound structures and avoiding patent restrictions.

[0004] Inspired by the exploration of sulfinamide compounds in our research group, the present invention synthesizes sulfimides to verify the applicability of N-trityl-2-phenylethane-1-sulfinamide in the derivatization synthesis of sulfimide compounds. The synthesis method of this sulfinamide uses widely sourced phenethyl alcohol as the starting material to synthesize xanthate compounds, which react with phosphine compounds under light conditions to generate alkyl radicals, and then the radicals are added to the sulfinimide reagent to produce sulfinamide. The present invention is a further derivatization application of this reaction.

[0005] The present invention proposes a method for synthesizing sulfimide compounds from tritylsulfinamide compounds and various derivatization routes.

[0006] Based on the above research, the present invention uses N-trityl-2-phenylethane-1-sulfinamide as the starting material, and uses tert-butyl hypochlorite for chlorination oxidation and further derivatization application with nucleophilic reagents. Summary of the Invention

[0007] The present invention provides a new method for synthesizing tritylsulfimide compounds from N-trityl-2-phenylethane-1-sulfinamide. First, N-trityl-2-phenylethane-1-sulfinamide is synthesized by a known sulfinamide synthesis method developed by our research group, and further exploration is carried out on the conditions of its derivatization application. The present invention has the advantages of mild reaction conditions, convenient experimental operation, good substrate compatibility, etc., laying a solid foundation for further industrial application and the creation of social and economic value.

[0008] Technical solution of the present invention:

[0009] A method for synthesizing a sulfimide compound through N-trityl-2-phenylethane-1-sulfinamide. First, at -50 °C, using the obtained sulfinamide compound as a reaction raw material, react with tert-butyl hypochlorite ( t BuOCl) as a chlorinating oxidant. In the second step, add a nucleophilic substitution reagent at -50 °C and react for 2 hours, and then react at room temperature. The synthesis route is as follows:

[0010]

[0011] The steps are as follows:

[0012] (1) Using phenethyl alcohol (1) and potassium tert-butoxide as starting materials, THF as a solvent, the molar ratio of alkyl alcohol, potassium tert-butoxide to CS2 is 1:1.2:3, and the reaction concentration is 0.1 M. Stir at room temperature for 30 minutes, then add CS2 and react at 0 °C for 2 - 3 hours to in-situ generate alkyl xanthate (1’) by a one-pot method;

[0013] (2) Under light conditions, alkyl xanthate (1’) reacts with a trivalent phosphorus compound and a sulfimide (2) to prepare a series of sulfinamide compounds (3);

[0014]

[0015] In the formula: Nu is a nucleophilic substitution reagent;

[0016] (3) Add N-trityl-2-phenylethane-1-sulfinamide (1.0 equivalent) to a dried 25 mL Schlenk tube, evacuate, fill with N2 three times, add a solvent, and cool to -50 °C. Then slowly add tert-butyl hypochlorite (1.0 equivalent) to the Schlenk tube, and after reacting for 1 hour, proceed to the next reaction.

[0017] (4) Under the condition of introducing N2, slowly add the mixture to another dry 10 mL reaction tube filled with N2 and a nucleophilic substitution reagent. Slowly warm the reaction mixture to room temperature for reaction, extract the mixture with ethyl acetate (10 mL), dry the combined organic phase (Na2SO4), filter and concentrate. Purify the product by silica gel chromatography.

[0018] The reaction solvent is selected from one of tetrahydrofuran, n-hexane, dichloromethane, acetone, acetonitrile, and toluene;

[0019] The reaction time for the second step ranges from 8 to 24 h, preferably 12 to 18 h;

[0020] The molar ratio of N-trityl-2-phenylethane-1-sulfinamide to tert-butyl hypochlorite is 1:1 to 1:2;

[0021] The molar ratio of N-trityl-2-phenylethane-1-sulfinamide to the nucleophilic substitution reagent is 1:1 to 1:3;

[0022] The concentration of N-trityl-2-phenylethane-1-sulfinamide in the organic solvent is 0.075 mmol / mL to 0.3 mmol / mL.

[0023] Advantages of the present invention: A new method for synthesizing the corresponding tritylamine sulfimide compound through N-trityl-2-phenylethane-1-sulfinamide. The method of the present invention has mild process conditions, a short process, simple steps, a wide substrate scope, can be scaled up, and has a yield as high as 70%, meeting the requirements of industrial production. On the other hand, the sulfimide generated by the reaction has broad application prospects in organic synthesis and drug research and development. Generally speaking, the present invention has important application value. Description of the Drawings

[0024] Figure 1 is the 1 1H-NMR spectrum of compound 3a.

[0025] Figure 2 is the 13 13C-NMR spectrum of compound 3a.

[0026] Figure 3 is the 1 1H-NMR spectrum of compound 4a.

[0027] Figure 4 is the 13 13C-NMR spectrum of compound 4a.

[0028] Figure 5 is the 1 1H-NMR spectrum of compound 4b.

[0029] Figure 6 is the 13 13C-NMR spectrum of compound 4b.

[0030] Figure 7 is the 1 1H-NMR spectrum of compound 4c.

[0031] Figure 8 is the 13 13C-NMR spectrum of compound 4c.

[0032] Figure 9 is the 1 1H-NMR spectrum of compound 4d.

[0033] Figure 10 13C-NMR spectrum of compound 4d 13 13C-NMR spectrum Detailed implementation manners

[0034] The following further describes the detailed implementation manners of the present invention in combination with the accompanying drawings and technical solutions.

[0035] Example 1: Synthesis of 2-phenyl-N-tritylethane-1-sulfinamide (3a)

[0036]

[0037] Weigh phenylethanol (36.7 mg, 0.3 mmol), KO t Bu (40.4 mg, 0.36 mmol) and dry THF (3.0 mL) in a glove box and stir at room temperature for 30 minutes. Then add CS2 (54.1 μL, 0.9 mmol) at 0 °C and react for 3 hours. After the reaction is completed, remove the solvent by distillation under reduced pressure to obtain xanthate. Then add sulfinimide, n-butyldi(1-adamantyl)phosphine and acetonitrile (3 mL) in sequence. Stir the obtained mixture under irradiation of a blue LED lamp (456 nm) at room temperature for 16 hours. After the reaction is completed, filter with diatomaceous earth, spin dry with a vacuum pump, and then use petroleum ether / ethyl acetate as the eluent for silica gel column separation. The yield of product 3a is 82%.

[0038] 1 1H NMR (400 MHz, CDCl3) δ 7.30 - 7.24 (m, 17H), 7.22 - 7.20 (m, 1H), 7.16 - 7.14 (m, 2H), 4.89 (s, 1H), 3.06 - 2.91 (m, 4H). 13 13C NMR (101 MHz, CDCl3) δ 144.74, 139.02, 129.11, 128.68, 128.49, 128.00, 127.33, 126.58, 72.83, 58.25, 29.14. This product is a known compound.

[0039] Example 2: Synthesis of 2-phenyl-N'-tritylethane-1-sulfonimidamide (4a)

[0040]

[0041] Take a 25 mL Schlenk tube dried in an oven and displace nitrogen three times. Add N-trityl-2-phenylethane-1-sulfinamide (123.3 mg, 0.3 mmol), dissolve it in 3 mL of THF solution, cool it to -50 °C, and then slowly add tert-butyl hypochlorite (42.3 mg, 0.39 mmol). The reaction is stirred at -50 °C for 1 h, add 1.5 mL of 25% aqueous ammonia solution, the reaction mixture is stirred at -50 °C for 2 h, then gradually warmed to room temperature and reacted for 12 h, and then add 6 M HCl solution to quench the reaction. Separate the organic layer, and extract the aqueous phase with dichloromethane (3 × 10 mL). Dry the organic phase with Na2SO4, filter, and remove the solvent. Purify the product by silica gel chromatography, eluent (PE:EA = 5:1, adding 5% Et3N), and product 4a is a white solid (66.5 mg, 52%). The 1H NMR data is 1 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.5 Hz, 5H), 7.38 - 6.98 (m, 15H), 3.35 - 3.05 (m, 4H), 2.86 (s, 2H). The 13C NMR data is 13 13C NMR (101 MHz, CDCl3) δ 147.14, 138.29, 128.79, 128.71, 128.51, 127.90, 127.78, 126.64, 71.79, 60.35, 30.68. The high-resolution mass spectrometry HRMS m / z (ESI) calculated value for C 27 H 26 N2OS (M + Na) + 449.1666, the measured value is 449.1654.

[0042] Example 3: Synthesis of 4-(2-phenyl-N-tritylethylsulfonimidoyl)morpholine (4b)

[0043]

[0044] Take a 25 mL Schlenk tube dried in an oven and displace nitrogen three times. Add N-trityl-2-phenylethane-1-sulfinamide (123.3 mg, 0.3 mmol), dissolve it in 3 mL of THF solution, cool it to -50 °C, and then slowly add tert-butyl hypochlorite (42.3 mg, 0.39 mmol). The reaction is stirred at -50 °C for 1 h, add morpholine (52.3 mg, 0.6 mmol), the reaction mixture is stirred at -50 °C for 2 h, then gradually warmed to room temperature and reacted for 16 h, and then add NH4Cl solution to quench the reaction. Separate the organic layer, and the aqueous phase is extracted with dichloromethane (3 × 10 mL). The organic phase is dried over Na2SO4, filtered, and the solvent is removed. The product is purified by silica gel chromatography, eluent (PE:EA = 10:1, adding 5% Et3N), and product 4b is a white solid (65.5 mg, 44%). The 1H NMR data is 1 1H NMR (400 MHz, CDCl3) δ 7.51 - 7.37 (m, 6H), 7.32 - 7.07 (m, 14H), 3.43 - 3.30 (m, 2H), 3.25 (dd, J = 13.6, 5.3 Hz, 1H), 3.17 - 3.07 (m, 2H), 3.05 - 2.89 (m, 3H), 2.87 - 2.71 (m, 4H). The 13C NMR data is 13 13C NMR (101 MHz, CDCl3) δ 147.88, 138.62, 129.12, 128.83, 128.53, 127.31, 126.80, 126.29, 71.37, 66.06, 53.15, 45.98, 29.89. The high-resolution mass spectrometry HRMS m / z (ESI) theoretical value is C 31 H 32 N2O2S (M+Na) + 519.2084, the measured value is 519.2079.

[0045] Example 4:

[0046] Synthesis of 8-chloro-11-(1-(2-phenyl-N-tritylethylsulfonimidoyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (4c)

[0047]

[0048] Take 25 mL of Schlenk tube dried in the oven and displace nitrogen three times. Add N-trityl-2-phenylethane-1-sulfonimidamide (82.3 mg, 0.2 mmol), dissolve it in 3 mL of THF solution, cool it to -50 °C, and then slowly add tert-butyl hypochlorite (28.2 mg, 0.26 mmol). The reaction is stirred at -50 °C for 1 h, add desloratadine (124.3 mg, 0.4 mmol), the reaction mixture is stirred at -50 °C for 2 h, then gradually warmed to room temperature and reacted for 14 h, and then add NH4Cl solution to quench the reaction. Separate the organic layer, and the aqueous phase is extracted with dichloromethane (3 × 10 mL). The organic phase is dried with Na2SO4, filtered, and the solvent is removed. The product is purified by silica gel chromatography, eluent (PE:EA = 5:1, adding 5% Et3N), and the product 4c is a white solid (77.5 mg, 54%). 1 H NMR (400 MHz, CDCl3) δ 8.26 (t, J = 5.1 Hz, 1H), 7.41 (d, J = 7.7 Hz, 6H), 7.33 - 6.88 (m, 19H), 3.44 - 3.06 (m, 7H), 2.94 (tt, J = 13.0, 3.8 Hz, 1H), 2.78 - 2.59 (m, 2H), 2.55 - 2.30 (m, 2H), 2.04 - 1.83 (m, 3H), 1.67 (t, J = 11.7 Hz, 1H). The carbon NMR data are 13 C NMR (101 MHz, CDCl3) δ 156.94, 156.87, 147.93, 146.53, 139.32, 138.77, 137.45, 137.35, 133.67, 133.23, 132.83, 130.45, 129.14, 129.13, 128.94, 128.86, 128.76, 128.52, 127.20, 126.67, 126.16, 126.07, 122.19, 71.29, 54.00, 47.22, 47.02, 31.60, 31.38, 30.46, 30.29, 30.10, 29.94. High-resolution mass spectrometry HRMS m / z (ESI) theoretical value C 46 H 42 ClN3OS (M + Na) + 742.2637, the measured value is 742.2628.

[0049] Example 5: Synthesis of Ethyl 2-phenyl-N-tritylethane-1-sulfonimidate (4d)

[0050]

[0051] Take a 25 mL Schlenk tube dried in an oven and displace nitrogen three times. Add N-trityl-2-phenylethane-1-sulfonimidamide (82.3 mg, 0.2 mmol), dissolve it in 3 mL of THF solution, cool it to -50 °C, and then slowly add tert-butyl hypochlorite (28.2 mg, 0.26 mmol). The reaction is stirred at -50 °C for 1 h, sodium ethoxide (27.2 mg, 0.4 mmol) is added, the reaction mixture is stirred at -50 °C for 2 h, then gradually warmed to room temperature and reacted for 16 h. Then, an NH4Cl solution is added to quench the reaction, the organic layer is separated, and the aqueous phase is extracted with dichloromethane (3 × 10 mL). The organic phase is dried over Na2SO4, filtered, and the solvent is removed. The product is purified by silica gel chromatography, the eluent (PE:EA = 50:1, with 5% Et3N added), and the product 4d is a white solid (66.5 mg, 73%). The 1H NMR data is 1 1H NMR (400 MHz, CDCl3) δ 7.51 - 7.33 (m, 6H), 7.29 - 7.06 (m, 14H), 3.53 - 3.40 (m, 2H), 3.37 - 3.09 (m, 4H), 0.81 (t, J = 7.1 Hz, 3H). The 13C NMR data is 13 13C NMR (101 MHz, CDCl3) δ 147.54, 138.13, 128.92, 128.74, 128.45, 127.39, 126.77, 126.39, 71.97, 65.38, 55.75, 30.52, 14.52. High-resolution mass spectrometry HRMS m / z (ESI) theoretical value for C 29 H 29 NO2S (M+Na) + 478.1819, the measured value is 478.1817.

[0052] Example 6: Scaled-up synthesis of Ethyl 2-phenyl-N-tritylethane-1-sulfonimidate (4d)

[0053]

[0054] Take a 100 mL Schlenk tube dried in an oven and displace nitrogen three times. Add N-trityl-2-phenylethane-1-sulfinamide (823 mg, 2 mmol), dissolve it in 30 mL of THF solution, cool it to -50 °C, and then slowly add tert-butyl hypochlorite (282 mg, 2.6 mmol). The reaction is stirred at -50 °C for 1 h, add sodium ethoxide (272 mg, 4 mmol), the reaction mixture is stirred at -50 °C for 2 h, then gradually warmed to room temperature and reacted for 16 h, and then add NH4Cl solution to quench the reaction, separate the organic layer, and the aqueous phase is extracted with dichloromethane (3 × 50 mL). The organic phase is dried over Na2SO4, filtered, and the solvent is removed. The product is purified by silica gel chromatography, the eluent (PE:EA = 50:1, adding 5% Et3N), and the product 4d is a white solid (637 mg, 70%).

Claims

1. A method for synthesizing a sulfonyl imide compound by N-trityl-2-phenylethane-1-sulfenamide, characterized in that: Here are the steps: (1) Using phenylethanol and potassium tert-butoxide as starting materials and THF as solvent, stirring at room temperature for 30 minutes, then adding CS2 and reacting at 0°C for 2-3 hours to generate alkyl xanthate in situ by a one-pot method; wherein the molar ratio of phenylethanol, potassium tert-butoxide and CS2 is 1:1.2:3, and the reaction concentration is 0.1M; (2) Under light conditions, alkyl xanthate reacts with a trivalent phosphine compound and sulfenyl imide to prepare N-trityl-2-phenylethane-1-sulfenamide; (3) adding 1.0 equivalent of N-trityl-2-phenylethane-1-sulfenamide into a dried Schlenk tube, evacuating the tube, filling the tube with N2 three times, adding a solvent, and cooling the tube to -50°C; then slowly adding 1.0 equivalent of tert-butyl hypochlorite into the Schlenk tube, reacting for 1 hour, and obtaining a mixture; (4) Under the condition of introducing N2, the mixture is slowly added to another dry reaction tube filled with N2 and a nucleophilic substitution reagent; the temperature is slowly raised to room temperature for reaction, the mixture is extracted with ethyl acetate, the combined organic phase is dried (Na2SO4), filtered and concentrated; and the sulfonimide compound is purified by silica gel chromatography.

2. The method according to claim 1, characterized in that The solvent is selected from tetrahydrofuran, n-hexane, dichloromethane, acetone, acetonitrile and toluene.

3. The method according to claim 1, characterized in that The molar ratio of the N-trityl-2-phenylethane-1-sulfenamide to tert-butyl hypochlorite is 1:1 to 1:

2.

4. The method according to claim 1, characterized in that: The molar ratio of the N-trityl-2-phenylethane-1-sulfenamide to the nucleophilic substitution reagent is 1:1 to 1:

3.

5. The method according to claim 1, characterized in that The concentration of the N-trityl-2-phenylethane-1-sulfenamide in the organic solvent is 0.075 mmol / mL to 0.3 mmol / mL.

6. The method according to claim 1, characterized in that The nucleophilic substitution reagent is selected from ammonia water, morpholine, desloratadine and sodium ethoxide.

7. The method according to claim 1, characterized in that The reaction time ranges from 8 to 24 hours.

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