A method for preparing sulfonic acid ester compounds based on a tertiary sulfonamide

Abstract

The application discloses a method for preparing sulfonic acid ester compounds based on tertiary sulfonamides, which uses economic and easily available tertiary sulfonamides and alcohol compounds as reaction substrates, uses cheap trichloroisocyanuric acid as an additive, uses trifluoromethanesulfonic anhydride as a Lewis acid, and uses acetonitrile as a solvent under mild conditions. Compared with the prior art, the application has the following advantages: the reaction system is simple, and the substrate range is extensive; the reaction yield is high; the reaction condition is mild; the operation is relatively simple; the raw materials are cheap and easily available; and the reaction system does not need a metal catalyst.

Description

Technical Field

[0001] This invention relates to a novel method for preparing sulfonate compounds, belonging to the field of organic synthesis technology. Background Technology

[0002] Sulfonate esters are an important class of structural skeletons, widely found in pharmaceuticals, agrochemicals, functional organic materials, and natural products. Many pharmaceutical and pesticide molecules contain sulfonate ester skeletons. For example, busulfan is an antitumor drug primarily used to treat the chronic phase of chronic myeloid leukemia, and can also be used to treat essential thrombocytosis and chronic myeloproliferative disorders such as polycythemia vera. Topiramate is mainly used as adjunctive therapy for other antiepileptic drugs, treating simple partial seizures, complex partial seizures, and generalized tonic-clonic seizures, with particularly good efficacy against Lennox-Gastaut syndrome and West syndrome (infantile spasms). Bupirimate is a systemic fungicide used to control powdery mildew in crops such as apples, greenhouse roses, and strawberries. Therefore, developing methods for synthesizing sulfonate esters is crucial. Literature review revealed several significant drawbacks in the synthesis of sulfonate esters, including the requirement for highly reactive sulfonyl chlorides, stringent reaction conditions, the use of saturated bases, and a limited range of reaction modes. For example, existing techniques utilize the reaction of sulfonyl chlorides and alcohols, with pyridine as a base, to synthesize sulfonate ester compounds at 0-5 °C. However, this reaction requires extremely stringent temperature conditions, and pyridine must be used in saturated amounts. Other techniques use sulfonyl chlorides and alcohols, with triethylamine as a base, to synthesize sulfonate esters at 0 °C. However, this reaction requires two hours at 0 °C, and triethylamine must be used in saturated amounts. Finally, existing techniques using sulfonyl chlorides and alcohols to synthesize sulfonate esters also require saturated amounts of triethylamine as a base, reacting in a sodium hydroxide solution, and maintaining an initial reaction temperature of 0 °C.

[0003] In summary, the currently reported methods for synthesizing sulfonates all require highly reactive substrates, sufficient base, stringent temperature conditions, and relatively limited reaction modes. Therefore, it is crucial to develop a novel, simple, widely applicable, green, mild, efficient, and environmentally friendly method for synthesizing sulfonates. Summary of the Invention

[0004] The purpose of this invention is to provide a novel, green, environmentally friendly, energy-efficient method for synthesizing sulfonate compounds.

[0005] To achieve the above-mentioned objectives, the technology employed in this invention is:

[0006] A method for preparing sulfonate compounds based on tertiary sulfonamides involves reacting tertiary sulfonamides and alcohols as raw materials in the presence of additives and Lewis acids to prepare sulfonate compounds.

[0007] In the above technical solution, the chemical structural formula of the tertiary sulfonamide is as follows:

[0008] ;

[0009] The chemical structural formula of the alcohol is as follows:

[0010] ;

[0011] The chemical structural formula of the sulfonate compound is as follows:

[0012] ;

[0013] In the above chemical structural formula, R 1 Selected from substituted or unsubstituted aryl groups; R 2 Selected from substituted or unsubstituted alkyl groups.

[0014] In the above technical solutions, the substituents in the substituted aryl and substituted alkyl groups are independently selected from methyl, tert-butyl, fluorine, chlorine, bromine, or aryl. Preferably, the substituent in the substituted aryl group is methyl or tert-butyl; and the substituent in the substituted alkyl group is selected from fluorine, chlorine, bromine, or aryl.

[0015] In the above technical solution, the temperature conditions are 25-40 ℃, with a preferred reaction temperature of 40 ℃; the reaction time is 12-48 hours, with a preferred reaction time of 24 hours.

[0016] In the above technical solution, the additive is trichloroisocyanuric acid, 1,3-dichloro-5,5-dimethylhydantoin, N -Chlorosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N - Bromosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin, N -Iodosuccinimide, in a preferred embodiment, the additive is trichloroisocyanuric acid.

[0017] In the above technical solution, the molar ratio of tertiary sulfonamide, trichloroisocyanuric acid, trifluoromethanesulfonic anhydride, and alcohol compound is 1: (1-2): (1-2): (1-2), and the preferred molar ratio is 1:1:1.9:2.

[0018] In the above technical solution, the reaction is carried out in a solvent; the solvent is one or more of acetonitrile, 1,4-dioxane, carbon tetrachloride, cyclohexane, n-hexane, and dimethyl carbonate.

[0019] As an example, the method for preparing sulfonate compounds disclosed in this invention is as follows: under conditions of 40 °C, sulfonamides and alcohols are used as raw materials, trichloroisocyanuric acid is used as an additive, trifluoromethanesulfonic anhydride is used as a Lewis acid, and acetonitrile is used as a solvent to prepare sulfonate compounds by reaction.

[0020] In this invention, the reaction substrates tertiary sulfonamides and alcohols, the solvent acetonitrile, and the additives trichloroisocyanuric acid and trifluoromethanesulfonic anhydride are all inexpensive commercial raw materials. The reaction is carried out at 40 °C. After the reaction is complete, the reaction is quenched with a saturated sodium carbonate aqueous solution, the reaction system is extracted with ethyl acetate (20 mL × 3), the organic phase is dried with anhydrous magnesium sulfate, the solvent and silica gel adsorption are removed by rotary evaporation, and the sulfonate compounds are obtained by simple column chromatography.

[0021] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0022] This invention uses tertiary sulfonamides and alcohols as raw materials, trichloroisocyanuric acid as an additive, and trifluoromethanesulfonic anhydride as a Lewis acid to prepare sulfonate esters in acetonitrile. This invention has the following significant advantages: the raw materials used, including the additive trichloroisocyanuric acid and trifluoromethanesulfonic anhydride, are all inexpensive commodities that can be purchased directly; it meets the requirements of green chemistry and sustainable development; compared with existing technologies, the reaction does not require the use of an equivalent amount of alkali, the conditions are mild, no low-temperature environment is needed, and the operation is very simple; it is practical. Attached Figure Description

[0023] Figure 1 This is the 1H NMR spectrum of compound 3a.

[0024] Figure 2 This is the carbon NMR spectrum of compound 3a. Detailed Implementation

[0025] The operation method of this invention is a conventional method in the field, and adopts a green, environmentally friendly, mild, efficient and energy-saving strategy. Using tertiary sulfonamides and alcohols as substrates, trichloroisocyanuric acid as additives, trifluoromethanesulfonic anhydride as Lewis acid, and organic solvents as reaction system, the reaction can be carried out at 40 °C in air to efficiently obtain sulfonate ester compounds, and the reaction does not require a metal catalyst.

[0026] The present invention will be further described below with reference to examples: the raw materials involved are existing products or can be conventionally obtained according to existing methods, the specific preparation operations and testing are conventional techniques, and the yield is a separation yield.

[0027] Example 1

[0028]

[0029] Sulfonamide 1a (0.5 mmol, 99.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2a (1.0 mmol, 74.1 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was completed, the system was quenched with saturated sodium carbonate aqueous solution. The reaction system was extracted with ethyl acetate (20 mL × 3), and the organic phase was dried over anhydrous magnesium sulfate. The solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product 3a was obtained by simple column chromatography with a separation yield of 90%. Figure 1 , Figure 2 The figures show the 1H NMR and 1C NMR spectra of compound 3a, respectively. The main test data for the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0030] 1 H NMR (400 MHz, Chloroform- d ) δ 7.79-7.77 (m, 2H), 7.34-7.32 (m,2H), 4.03-4.00 (t, J = 6.5 Hz, 2H), 2.44 (s, 3H), 1.66 – 1.58 (m, 2H), 1.36-1.30 (m, 2H), 0.87-0.83 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ144.6, 133.2, 129.8, 127.8, 70.3, 30.7, 21.6, 18.5, 13.3.

[0031] Extended Implementation Examples

[0032] Based on the examples, single-factor variations were performed, and the following results were obtained:

[0033]

[0034] Example 2

[0035]

[0036] Sulfonamide 1a (0.5 mmol, 99.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2b (1.0 mmol, 217.8 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was completed, the system was quenched with saturated sodium carbonate aqueous solution, and the reaction system was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product 3a was obtained by simple column chromatography with a separation yield of 90%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0037] 1 H NMR (400 MHz, Chloroform- d ) δ 7.82-7.80 (m, 2H), 7.38-7.36 (m,2H), 4.41 – 4.32 (m, 2H), 4.27 – 4.21 (m, 1H), 3.77 – 3.68 (m, 2H), 2.45 (s,3H). 13 C NMR (100 MHz, Chloroform- d ) δ 145.4, 132.1, 130.0, 128.1, 69.6, 45.4, 31.8, 21.7.

[0038] Example 3

[0039]

[0040] Sulfonamide 1a (0.5 mmol, 99.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2c (1.0 mmol, 138.9 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was completed, the system was quenched with saturated sodium carbonate aqueous solution, and the reaction system was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product 3a was obtained by simple column chromatography with a separation yield of 75%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0041] 1H NMR (400 MHz, Chloroform- d ) δ 7.81-7.79 (m, 2H), 7.37 – 7.34 (m,2H), 4.18-4.15 (t, J = 5.8 Hz, 2H), 3.42-3.39 (t, J = 6.3 Hz, 2H), 2.45 (s, 3H), 2.20-2.14 (m, 2H). 13 C NMR (100 MHz, Chloroform- d ) δ 145.0, 132.7, 129.9,127.9, 67.7, 31.7, 28.4, 21.6.

[0042] Example 4

[0043]

[0044] Sulfonamide 1a (0.5 mmol, 99.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2d (1.0 mmol, 60.1 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was completed, the system was quenched with saturated sodium carbonate aqueous solution, and the reaction system was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product 3a was obtained by simple column chromatography with a separation yield of 80%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0045] 1 H NMR (400 MHz, Chloroform- d ) δ 7.79-7.77 (m, 2H), 7.35-7.32 (m,2H), 3.99-3.96 (t, J = 6.6 Hz, 2H), 2.44 (s, 3H), 1.69-1.63 (m, 2H), 0.91-0.87(t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d) δ 144.6, 133.2, 129.8,127.8, 72.1, 22.2, 21.6, 9.9.

[0046] Example 5

[0047]

[0048] Sulfonamide 1a (0.5 mmol, 99.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2e (1.0 mmol, 198.0 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was complete, the system was quenched with saturated sodium carbonate aqueous solution, and the reaction system was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product 3a was obtained by simple column chromatography with a separation yield of 85%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0049] 1 H NMR (400 MHz, Chloroform- d ) δ 7.81-7.79 (m, 2H), 7.37-7.35 (m,2H), 5.13 (s, 2H), 2.46 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 145.4,132.4, 129.9, 128.0, 57.9, 21.6. 19 F NMR (376 MHz, Chloroform- d ) δ -140.96 – -141.04 (m, 2F), -150.59 – -150.71 (m, 1F), -160.96 – -161.09 (m, 2F).

[0050] Example 6

[0051]

[0052] Sulfonamide 1a (0.5 mmol, 99.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2e (1.0 mmol, 149.4 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was completed, the system was quenched with saturated sodium carbonate aqueous solution, and the reaction system was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product 3e was obtained by simple column chromatography with a separation yield of 74%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0053] 1 H NMR (400 MHz, Chloroform- d ) δ 7.85 – 7.83 (m, 2H), 7.40 – 7.36 (m, 2H), 4.54 (s, 2H), 2.46 (s, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 145.8,132.1, 130.0, 128.1, 93.2, 77.7, 21.7.

[0054] Example 7

[0055]

[0056] Sulfonamide 1a (0.5 mmol, 99.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2f (1.0 mmol, 153.14 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was completed, the system was quenched with saturated sodium carbonate aqueous solution, and the reaction system was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product 3f was obtained by simple column chromatography with a separation yield of 69%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0057] 1 H NMR (400 MHz, Chloroform- d) δ 8.18 – 8.16 (m, 2H), 7.81 – 7.79 (m,2H), 7.45 – 7.43 (m, 2H), 7.36 –7.34 (m, 2H), 5.14 (s, 2H), 2.45 (s, 3H). 13 CNMR (100 MHz, Chloroform- d ) δ 148.0, 145.4, 140.6, 132.7, 130.0, 128.6,127.9, 123.8, 69.7, 21.6.

[0058] Example 8

[0059]

[0060] Sulfonamide 1b (0.5 mmol, 120.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2a (1.0 mmol, 74.1 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was completed, the system was quenched with saturated sodium carbonate aqueous solution, and the reaction system was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product was obtained by simple column chromatography with a yield of 61%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis. 1 H NMR (400 MHz, Chloroform- d ) δ7.83-7.81 (m, 2H), 7.56-7.53 (m, 2H), 4.05-4.02 (t, J = 6.5 Hz, 2H), 1.66 –1.60 (m, 2H), 1.37 – 1.31 (m, 11H), 0.86-0.83 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 157.5, 133.1, 127.6, 126.1, 70.3, 35.2, 31.0, 30.7,18.5, 13.3.

[0061] Example 9

[0062]

[0063] Sulfonamide 1c (0.5 mmol, 92.5 mg), trichloroisocyanuric acid (0.5 mmol, 116.2 mg), acetonitrile (1.5 mL), alcohol 2a (1.0 mmol, 74.1 mg), and trifluoromethanesulfonic anhydride (0.96 mmol, 270.9 mg) were added sequentially to a test tube. The mixture was then stirred in air at 40 °C for 24 hours. After the reaction was complete, the system was quenched with saturated sodium carbonate aqueous solution, and the reaction system was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous magnesium sulfate, and the solvent and silica gel adsorption were removed by rotary evaporation. The sulfonate product 3i was obtained by simple column chromatography with a separation yield of 65%. The main test data of the obtained product are as follows. Analysis shows that the actual synthesized product is consistent with the theoretical analysis.

[0064] 1 H NMR (400 MHz, Chloroform- d ) δ 7.91 – 7.89 (m, 2H), 7.66 – 7.62 (m,1H), 7.56 – 7.52 (m, 2H), 4.06-4.03 (t, J = 6.5 Hz, 2H), 1.65 – 1.60 (m, 2H), 1.37 – 1.28 (m, 2H), 0.86-0.82 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 136.2, 133.6, 129.1, 127.7, 70.6, 30.7, 18.5, 13.3.

[0065] This invention uses tertiary sulfonamides and alcohols as raw materials, trichloroisocyanuric acid as an additive, and trifluoromethanesulfonic anhydride as a Lewis acid to prepare sulfonate esters in acetonitrile. This invention has the following significant advantages: the raw materials used, including the additive trichloroisocyanuric acid and trifluoromethanesulfonic anhydride, are all inexpensive commodities that can be purchased directly; it meets the requirements of green chemistry and sustainable development; compared with existing technologies, the reaction does not require the use of an equivalent amount of alkali, the conditions are mild, no low-temperature environment is needed, and the operation is very simple; it is practical.

Claims

1. A method for preparing sulfonate compounds based on tertiary sulfonamides, characterized in that, Sulfonate esters were prepared by reacting tertiary sulfonamides and alcohols in the presence of additives and Lewis acids. The chemical structural formula of the tertiary sulfonamide is as follows: ； The chemical structural formulas of the alcohol compounds are as follows: ； The chemical structural formula of the sulfonate compound is as follows: ； The reaction does not require a metal catalyst; the additive is trichloroisocyanuric acid; the Lewis acid is trifluoromethanesulfonic anhydride; and the solvent is one or more of acetonitrile, 1,4-dioxane, and n-hexane.

2. The method for preparing sulfonate compounds based on tertiary sulfonamides according to claim 1, characterized in that, The molar ratio of tertiary sulfonamide, additives, Lewis acid, and alcohol is 1:1:(1-2):

2.

3. The method for preparing sulfonate compounds based on tertiary sulfonamides according to claim 1, characterized in that, The reaction temperature is 25–40 °C, and the reaction time is 12–48 hours.

4. The method for preparing sulfonate compounds based on tertiary sulfonamides according to claim 1, characterized in that, The reaction takes place in air.

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