Process for the preparation of sulfonic acid derivatives by sulfonamide deamination

Abstract

The application discloses a method for synthesizing sulfonic acid derivatives, which comprises the following steps: mode one, first, sulfonamide compounds, tert-butyl nitrite, a chlorine source and a catalyst are subjected to a diazotization chlorination reaction in an organic solvent under nitrogen condition, or a nucleophile is additionally added for reaction, so that sulfonic acid derivatives are obtained; mode two, a two-step method is adopted, first, sulfonamide compounds, tert-butyl nitrite and a catalyst are subjected to a diazotization reaction in an organic solvent under nitrogen condition, and then a nucleophile is added for reaction, so that sulfonic acid derivatives are obtained. The method has the advantages of simple steps, low cost and simple operation, can overcome the shortcomings of high pre-functionalization of substrates, easy moisture absorption of reactants, metal catalysis of reaction and complicated steps in the prior art, and can play an important role in the research field of sulfonamide conversion and application.

Description

Technical Field

[0001] This invention relates to a method for synthesizing sulfonic acid derivatives from sulfonamide compounds. Specifically, it relates to a method for preparing sulfonic acid derivatives by reacting sulfonamide compounds, nitrosotert-butyl ester, and a catalyst. Method one involves adding a chlorine source, while method two involves reacting at low temperature without adding a chlorine source. Background Technology

[0002] Since Domagk, Mietzsch, and Klarer's pioneering work in 1932 at IG Farbenindustrie to report on the antibacterial activity of sulfonamides, sulfonamides have represented a turning point in medical history and become key to the treatment of major diseases. Taking Prontosil as an example, the sulfonamide bond remains a persistent structure in various biologically relevant compounds (Top.Curr.Chem.2018,376, 1-34).

[0003] Therefore, considerable effort has been devoted to developing efficient synthetic strategies and numerous methods. However, further analysis of these precedents indicates that the primary sulfonamide moiety has consistently been considered an endpoint, difficult to derivatize via SN bond activation. Given the importance of sulfur-containing motifs for drug discovery and their abundant presence in many medicinal chemistry libraries, there is a desire to directly construct new compounds via SN bond activation, thereby accelerating the drug development process.

[0004] In 2019, PSFier et al. reported a method for the reductive deamination of primary sulfonamides catalyzed by azacarbene (NHC) to achieve late-stage functionalization (J. Am. Chem. Soc., 2019, 141, 1441-1445). The reaction first forms a transient N-sulfonylimide, followed by the removal of benzonitrile to obtain a sulfinate, which is then used to achieve various transformations through sulfinate chemistry.

[0005] In the same year, J. Cornella et al. reported a method for promoting the deamination of primary sulfonamides and achieving later functionalization using pyranium salts (Pyry-BF4) (Angew. Chem. Int. Ed., 2019, 58, 18235-18239). This method uses pyranium salts to react with the less reactive amino group in sulfonamides to generate N-sulfonylpyridinium salts. In the presence of MgCl2, these generate sulfonyl chlorides, which are highly reactive and relatively stable electrophilic reagents in organic synthesis. Various transformations can then be achieved using sulfonyl chloride chemistry.

[0006] In 2021, H. Yorimitsu et al. reported a late-stage functionalization method for N-sulfonylpyrrole, obtained by prefunctionalization of sulfonamides with 2,5-dimethoxytetrahydrofuran, to sulfinate under visible light iridium catalytic reduction (Chem. Eur. J., 2021, 27, 15387-15391). This method uses 4 equivalents of diisopropylethylamine as a reducing agent.

[0007] In the same year, Luo, Xue, and Ding et al. reported a visible light-mediated method for sulfonylating arylboronic acids by breaking the N-S bond of sulfonamide derivatives (Chem Sci, 2021, 12, 9556-9560). This method first involves the sequential N-acylation and N-alkylation of primary sulfonamides to obtain further electron-deficient tertiary sulfonamides. Then, under photo-mediated iridium catalysis, sulfonyl radicals are coupled with arylboronic acids, thereby achieving the conversion of sulfonamides to sulfones. In 2022, the team further developed a visible light-mediated method for sulfonylating arylboronic acids by activating the SN-S bond of imines during sulfonamide conversion (ACS Catal., 2022, 12, 1986-1991). This method involves first condensing primary sulfonamides with 2,4,6-trimethoxybenzaldehyde to form an imine, promoted by the condensation of an equivalent amount of tri(2,2,2,-trifluoroethyl) borate, followed by solvent removal and further conversion.

[0008] A review of the literature reveals that current methods for activating sulfonamides either require expensive azacarbene reagents, or necessitate the preparation of pyranonium salts and excess inorganic salts with complex procedures, or require equivalent amounts of tri(2,2,2,-trifluoroethyl) borate, or generate equivalent amounts of highly toxic benzonitrile or malodorous pyridine or secondary amide byproducts, or require multiple steps for prefunctionalization. Therefore, providing a simple, low-cost, atom-efficient, and time-saving method for preparing sulfonamide derivatives is the technical problem this invention aims to solve. Summary of the Invention

[0009] The purpose of this invention is to provide a method for directly converting sulfonamide compounds into sulfonic acid derivatives.

[0010] The sulfonamide derivative to be prepared in this invention has the structural formula shown in Formula III:

[0011]

[0012] The method for preparing the compound shown in Formula III provided by the present invention is characterized by comprising the following steps: Method 1: firstly, sulfonamide compound, nitrosotert-butyl ester, magnesium chloride, and trifluoroacetic acid are subjected to a diazotization chlorination reaction in acetonitrile under nitrogen conditions, or an additional nucleophilic reagent is added to react and obtain the target compound.

[0013] Method 2: A diazotization reaction is carried out in acetonitrile with a sulfonamide compound, tert-nitrosobutyl ester, and trifluoroacetic acid under nitrogen atmosphere. A nucleophile is added to react and yield the target compound of Formula III. The structural formula of the sulfonamide compound is shown in Formula I; the structural formula of the tert-nitrosobutyl ester is shown in Formula II.

[0014]

[0015] Wherein, R is an alkyl, phenyl, hydrogen, alkoxy, ester, hydroxyl, nitro, halogen, or trifluoromethyl group.

[0016] More preferably, R is hydrogen, alkyl, phenyl, alkoxy, ester, hydroxyl, nitro, halogen, or trifluoromethyl; it may also be a straight-chain alkyl, naphthyl, or thiophene group.

[0017] More preferably, R is an alkyl or phenyl group.

[0018] More preferably, the additional nucleophile is an N-nucleophile or an O-nucleophile.

[0019] More preferably, the gas atmosphere is a nitrogen atmosphere.

[0020] More preferably, the reaction temperature is -20 to 100°C.

[0021] More preferably, the reaction temperatures of Method 1 and Method 2 are 50°C and 0-5°C, respectively.

[0022] More preferably, the reaction time of the first step is 7 hours and the reaction time of the second step is 40 minutes.

[0023] The features of this invention are: Method 1 adds chlorine source MgCl2, while Method 2 does not add chlorine source MgCl2. Both methods use sulfonamide compounds (the compound shown in Formula I) and nitrosotert-butyl ester (the compound shown in Formula II) as raw materials and trifluoroacetic acid as a catalyst to react with nucleophiles to obtain the target product (the compound shown in Formula III). This overcomes the disadvantages of the substrate needing to be highly prefunctionalized, the steps being cumbersome, and the difficulty in directly preparing sulfonic acid derivatives.

[0024] The invention will be further described in detail below with reference to specific examples. Detailed Implementation

[0025] Unless otherwise specified, all methods used in the following implementations are conventional methods. The result before the parentheses is the yield of method one, and the result inside the parentheses is the yield of method two.

[0026] Example 1

[0027] Method 1: Synthesizing sulfonyl chloride (the structural formula of which is shown in Formula III-1) using sulfonamide compounds, magnesium chloride, nitrosotert-butyl ester, and trifluoroacetic acid as catalysts, including the following steps:

[0028] 4-Methylbenzenesulfonamide (0.1 mmol) and magnesium chloride (0.1 mmol) were added sequentially to the reaction tube. Nitrogen gas was evacuated / filled using a double-row tube system and circulated three times. Acetonitrile (0.5 mL), trifluoroacetic acid (8 μL, 10 mol%), and nitrosotert-butyl ester (36 μL, 0.3 mmol) were injected sequentially via syringe. The tube was sealed with a rubber stopper and reacted at 50 °C for 7 hours. The product was purified by silica gel column chromatography (petroleum ether / EtOAc 10:1) to obtain the target compound of formula III-1 (17.9 mg) as a white solid, with a calculated yield of 94%.

[0029] Method 2: Using sulfonamide compounds, tert-butyl nitrosamine, and trifluoroacetic acid as catalysts, followed by the addition of magnesium chloride to synthesize sulfonyl chloride (the structural formula of this compound is shown in Formula III-1), including the following steps:

[0030] To a reaction tube, p-toluenesulfonamide (0.1 mmol) was added sequentially, and nitrogen gas was evacuated / filled using a double-row tube system and circulated three times. Acetonitrile (0.5 mL), trifluoroacetic acid (8 μL, 10 mol%), and nitrosotert-butyl ester (36 μL, 0.3 mmol) were injected sequentially via syringe. The tube was sealed with a rubber stopper and reacted at 0–5 °C for 7 hours. Then, magnesium chloride (6 μL, 0.15 mmol) was injected via syringe and reacted for 40 min. The product was purified by silica gel column chromatography (petroleum ether / EtOAc 5:1) to give the title compound (13.7 mg) as a white solid, with a calculated yield of 72%.

[0031]

[0032] White solid 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 2.49 (s, 3H).

[0033] Example 2

[0034] The compound shown in Formula III-2 was synthesized using Method 1, which replaced 4-methylbenzenesulfonamide in Example 1 with benzenesulfonamide. The reaction time was 10 h, and all other reaction conditions were the same as in Example 1. The yield was 88%.

[0035]

[0036] Colorless oily liquid 1H NMR (400MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 7.4 Hz, 3H), 7.63 (t, J = 7.6 Hz, 3H).

[0037] Example 3

[0038] The compound shown in Formula III-3 was synthesized using Method 1, in which 2-chlorobenzenesulfonamide was used instead of 4-methylbenzenesulfonamide in Example 1. The reaction time was 13 h, and all other reaction conditions were the same as in Example 1. The yield was 75%.

[0039]

[0040] Colorless oily liquid 1 HNMR(400MHz, CDCl3)δ8.18–8.17(m,1H),7.67-7.65(m,2H), 7.63(m,1H).

[0041] Example 4

[0042] The compound shown in Formula III-4 was synthesized using Method 1, in which 4-chlorobenzenesulfonamide was used instead of 4-methylbenzenesulfonamide in Example 1. The reaction time was 15 h, and all other reaction conditions were the same as in Example 1. The yield was 78%.

[0043]

[0044] White solid 1 H NMR (400MHz, CDCl3) δ7.99 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 4.0 Hz, 2H).

[0045] Example 5

[0046] The compound shown in Formula III-5 was synthesized using Method 1, which replaced 4-methylbenzenesulfonamide in Example 1 with naphthalene-2-sulfonamide. The reaction time was 15 h, and all other reaction conditions were the same as in Example 1. The yield was 80%.

[0047]

[0048] Light yellow powder, 1 HNMR (400MHz, CDCl3) δ8.61(s,1H),7.96–8.08(m,4H),7.77–7.68(m,2H).

[0049] Example 6

[0050] The compound shown in Formula III-6 was synthesized using Method 1, in which 2-thiophene sulfonamide was used instead of 4-methylbenzene sulfonamide in Example 1. The reaction time was 15 h, and all other reaction conditions were the same as in Example 1. The yield was 77%.

[0051]

[0052] White solid 1 H NMR (400MHz, CDCl3) δ7.90–7.89(m,1H),7.83–7.82(m,1H), 7.19–7.17(m,1H).

[0053] Example 7

[0054] The compound shown in Formula III-7 was synthesized using Method 1, in which ethylsulfonamide was used instead of 4-methylbenzenesulfonamide in Example 1. The reaction time was 11 h, and all other reaction conditions were the same as in Example 1. The yield was 95%.

[0055]

[0056] pale yellow liquid, 1 H NMR (400MHz, CDCl3) δ3.72–3.67 (q, J = 7.2Hz, 2H), 1.64 (t, J = 7.2Hz, 3H).

[0057] Example 8

[0058] Method 1: A methyl 4-toluenesulfonate (structural formula shown in Formula III-8) is synthesized from sulfonamide compounds, magnesium chloride, nitrosotert-butyl ester, trifluoroacetic acid as catalysts, and methanol, comprising the following steps:

[0059] To a reaction tube, p-toluenesulfonamide (0.1 mmol) and magnesium chloride (0.1 mmol) were added sequentially. Nitrogen gas was evacuated / filled using a double-row tube system and circulated three times. Acetonitrile (0.5 mL), trifluoroacetic acid (8 μL, 10 mol%), and nitrosotert-butyl ester (36 μL, 0.3 mmol) were injected sequentially via syringe. The tube was sealed with a rubber stopper and reacted at 50 °C for 7 hours. Then, a mixture of triethylamine (Et3N) (28 μL, 0.20 mmol) and methanol (6 μL, 0.15 mmol) was injected sequentially via syringe and reacted for 40 minutes. The product was purified by silica gel column chromatography (petroleum ether / EtOAc 5:1) to obtain the target compound of formula III-8 (13.6 mg), which was a colorless oily liquid. The calculated yield was 73%.

[0060] Method 2: Synthesizing methyl 4-toluenesulfonate (the structural formula of which is shown in Formula III-8) using sulfonamide compounds, nitrosotert-butyl ester, trifluoroacetic acid as a catalyst, and methanol, including the following steps:

[0061] p-Toluenesulfonamide (0.1 mmol) was added sequentially to the reaction tube, and nitrogen gas was evacuated / filled and circulated three times using a double-row tube system. Acetonitrile (0.5 mL), trifluoroacetic acid (8 μL, 10 mol%), and nitrosotert-butyl ester (36 μL, 0.3 mmol) were injected sequentially via syringe. The tube was sealed with a rubber stopper and reacted at 0–5 °C for 7 hours. Then, methanol (6 μL, 0.15 mmol) was injected via syringe and reacted for 40 min. The product was purified by silica gel column chromatography (petroleum ether / EtOAc 5:1) to give the title compound (13.4 mg) as a colorless oily liquid, with a calculated yield of 72%.

[0062]

[0063] White solid 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 2.49 (s, 3H).

[0064] Example 9

[0065] The compounds shown in Formula III-9 were synthesized by replacing methanol with ethanol in Example 8, with all other reaction conditions being the same as in Example 8. The yield of Method I was 80%, and the yield of Method II was 79%.

[0066]

[0067] Colorless oily liquid 1 H NMR (400MHz, CDCl3) δ7.79 (d, J = 8.0Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 4.13–4.08 (q, J = 6.8Hz, 2H), 2.45 (s, 3H), 1.30 (t, J = 7.0Hz, 3H).

[0068] Example 10

[0069] The compounds shown in Formula III-10 were synthesized by replacing methanol in Example 8 with isopropanol, and all other reaction conditions were the same as in Example 8. The yield of Method I was 62%, and the yield of Method II was 63%.

[0070]

[0071] Colorless oily liquid 1H NMR (400MHz, CDCl3) δ7.79 (d, J = 7.6Hz, 2H), 7.33 (d, J = 7.6Hz, 2H), 4.76–4.70 (m, 1H), 2.45 (s, 3H), 1.27 (d, J = 6.0Hz, 6H).

[0072] Example 11

[0073] The compounds shown in Formula III-11 were synthesized by replacing methanol in Example 8 with tetrahydropyrrole, and all other reaction conditions were the same as in Example 8. The yield of Method I was 99%, and the yield of Method II was 97%.

[0074]

[0075] White solid 1 H NMR (400MHz, CDCl3) δ7.72 (d, J = 7.2 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 3.32 (s, 4H), 2.43 (s, 3H), 1.75 (s, 4H).

[0076] Example 12

[0077] The compounds shown in Formula III-12 were synthesized by replacing methanol in Example 8 with benzylamine, and all other reaction conditions were the same as in Example 8. The yield of Method I was 73%, and the yield of Method II was 70%.

[0078]

[0079] White solid 1 H NMR (400MHz, CDCl3) δ7.76 (d, J = 7.6 Hz, 2H), 7.32–7.26 (m, 6H), 7.20 (d, J = 6.0 Hz, 2H), 4.69 (s, 1H), 4.12 (d, J = 6.0 Hz, 4H), 2.44 (s, 3H).

[0080] Example 13

[0081] The compounds shown in Formula III-13 were synthesized by replacing methanol in Example 8 with aniline, and all other reaction conditions were the same as in Example 8. The yield of Method I was 81%, and the yield of Method II was 80%.

[0082]

[0083] White solid 1H NMR (400MHz, CDCl3) δ7.66 (d, J = 8.4Hz, 2H), 7.25–7.21 (m, 4H), 7.12–7.06 (m, 3H), 6.88 (s, 1H), 2.31 (s, 3H).

[0084] Example 14

[0085] The compounds shown in Formula III-14 were synthesized by replacing methanol in Example 8 with p-toluidine, and all other reaction conditions were the same as in Example 8. The yield of Method I was 86%, and the yield of Method II was 84%.

[0086]

[0087] White solid 1 H NMR (400MHz, CDCl3) δ7.65(d,J=8.4Hz,2H),7.20(d,J=8.0Hz,2H),7.04–7.00(m,3H),7.97–7.95(m,2H),2.36(s,3H),2.25(s,3H).

[0088] Example 15

[0089] The compounds shown in Formula III-15 were synthesized by replacing methanol in Example 8 with p-chlorotoluene, and all other reaction conditions were the same as in Example 8. The yield of Method I was 84%, and the yield of Method II was 82%.

[0090]

[0091] White solid 1 H NMR (400MHz, CDCl3) δ7.66 (d, J = 8.4Hz, 2H), 7.25 (d, J = 8.0Hz, 2H), 7.21–7.17 (m, 2H), 7.11 (s, 1H), 7.04–7.00 (m, 2H), 2.38 (s, 3H).

[0092] Example 16

[0093] The compounds shown in Formula III-16 were synthesized by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 8 with 8-azabicyclo[3.2.1]octane-3-one. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 73%, and the yield of Method 2 was 72%.

[0094]

[0095] White solid, mp 165-166℃. 1 H NMR (400MHz, CDCl3) δ7.90 (d, J = 8.1Hz, 2H), 7.49(d,J=8.1Hz,2H),7.16(d,J=7.6Hz,2H),7.08(d,J=7.4Hz,2H),6.75(s,1 H),4.49(s,1H),2.79(d,J=15.6Hz,2H),2.39(d,J=10.3Hz,4H),1.76–1.59(m, 5H). 13 C NMR(101MHz,CDCl3)δ206.2,145.3,144.2(q, 2 J C-F =38.7Hz),142.8, 139.9,139.3,129.7,128.7,128.2,125.7,125.6,121.0(q, 1 J C-F =269.4Hz),106.4, 56.1,50.1,29.3,21.3. 19 F NMR (225MHz, CDCl3) δ-62.5 (s, 3F).

[0096] Example 17

[0097] The compound shown in Formula III-17 was synthesized by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 8 with thiomorpholine. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 85% and the yield of Method 2 was 85%.

[0098]

[0099] Light brown solid, mp 181–182℃. 1 HNMR (400MHz, CDCl3) δ7.73 (d, J=8.6Hz, 2H),7.50(d,J=8.6Hz,2H),7.18(d,J=7.9Hz,2H),7.10(d,J=8.1Hz,2H),6.75(s,1H),3.35–3.33(m,4H),2.71–2.68(m,4H),2.38(s,3H). 13 C NMR(101MHz, CDCl3)δ145.3,144.2(q, 2 J C-F=38.6Hz),142.7,139.8,136.5,129.8,128.7,128.3, 125.6,125.6,121.0(q, 1 J C-F =269.4Hz),106.3,47.8,27.3,21.3. 19 F NMR(225MHz, CDCl3)δ-62.5(s,3F).

[0100] Example 18

[0101] The compounds shown in Formula III-18 were synthesized by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 12 with tetrahydropyrrole. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 84% ​​and the yield of Method 2 was 83%.

[0102]

[0103] White solid, mp 133–134℃. 1 H NMR (400MHz, CDCl3) δ7.84 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.76 (s, 1H),3.24(t,J=6.7Hz,4H),2.39(s,3H),1.80–1.76(m,4H). 13 C NMR(101MHz, CDCl3)δ145.2,144.0(q, 2 J C-F =38.6Hz),142.4,139.7,129.6,128.6,128.3,125.5, 125.1,121.0(q, 1 J C-F =269.2Hz),106.1,47.9,25.2,21.2. 19 F NMR(225MHz, CDCl3)δ-62.4(s,3F).

[0104] Example 19

[0105] The synthesis of the compound shown in Formula III-19 was carried out by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 12 with methyl aziridine-3-carboxylate. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 77%, and the yield of Method 2 was 75%.

[0106]

[0107] White solid, mp 126-127℃. 1 H NMR (400MHz, CDCl3) δ7.83 (d, J = 7.9Hz, 2H), 7.55(d,J=7.9Hz,2H),7.19(d,J=7.4Hz,2H),7.13(d,J=7.5Hz,2H),6.76(s, 1H),4.01(t,J=8.4Hz,2H),3.93(t,J=7.2Hz,2H),3.67(s,3H),3.33–3.24(m, 1H),2.39(s,3H). 13 C NMR (101MHz, CDCl3) δ171.4,145.4,144.3(q, 2 J C-F =38.9 Hz),143.1,139.9,134.0,129.8,129.3,125.6,125.6,121.0(q, 1 J C-F =269.2Hz), 106.4,53.0,52.5,31.5,21.3. 19 F NMR (225MHz, CDCl3) δ-62.5 (s, 3F).

[0108] Example 20

[0109] The compounds shown in Formula III-20 were synthesized by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 12 with ethyl piperidine-4-carboxylate. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 83%, and the yield of Method 2 was 81%.

[0110]

[0111] White solid, mp 149–150℃. 1H NMR (400MHz, CDCl3) δ7.74 (d, J = 8.6Hz, 2H), 7.49(d,J=8.7Hz,2H),7.18(d,J=8.0Hz,2H),7.10(d,J=8.1Hz,2H),6.75(s,1 H),4.12(q,J=7.1Hz,2H),3.63–3.59(m,2H),2.54–2.47(m,2H),2.38(s,3H), 2.29–2.22(m,1H),1.99–1.95(m,2H),1.86–1.76(m,2H),1.23(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ173.58,145.28,144.12(q, 2 J C-F =38.6Hz),142.60, 139.82,135.89,129.72,128.66,128.53,125.57,125.55,121.00(q, 1 J C-F =269.1Hz), 106.23,60.71,45.32,39.87,27.35,21.29,14.11. 19 F NMR(225MHz,CDCl3)δ-62.5 (s,3F).

[0112] Example 21

[0113] The synthesis of the compound shown in Formula III-21 was carried out by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 12 with piperidine-3-carboxylic acid ester. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 81% and the yield of Method 2 was 80%.

[0114]

[0115] White solid, mp 151-152℃. 1HNMR (400MHz, CDCl3) δ7.76 (d, J = 7.9Hz, 2H), 7.50(d,J=7.9Hz,2H),7.18(d,J=7.4Hz,2H),7.11(d,J=7.4Hz,2H),6.75(s, 1H),4.14(m,2H),3.81(d,J=9.7Hz,1H),3.59(d,J=11.0Hz,1H),2.56(m,1H), 2.38(s,3H),2.07–1.97(m,1H),1.80(m,1H),1.68–1.58(m,1H),1.40(m,1H),1.27–1.32(m,4H). 13 C NMR(101MHz,)δ172.4,145.3,144.1(q, 2 J C-F =38.3Hz), 142.6,139.8,135.8,129.7,128.6,128.5,125.6,125.5,121.0(q, 1 J C-F =269.1Hz), 106.2,60.8,47.6,46.2,41.0,26.4,23.9,21.3,14.1. 19 F NMR(225MHz, CDCl3)δ -62.5(s,3F).

[0116] Example 22

[0117] The compound shown in Formula III-22 was synthesized by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 12 with isodihydroindole. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 72% and the yield of Method 2 was 70%.

[0118]

[0119] White solid, mp 200-201℃. 1 H NMR (400MHz, CDCl3) δ7.88 (d, J = 8.7Hz, 2H), 7.49(d,J=8.7Hz,2H),7.28–7.24(m,2H),7.20–7.13(m,4H),7.09(d,J=8.1Hz,2H),6.73(s,1H),4.64(s,4H),2.39(s,3H). 13 C NMR(101MHz,CDCl3)δ145.2, 144.1(q, 2 JC-F =38.4Hz),142.7,139.8,136.3,135.6,129.7,128.7,128.4,127.9, 125.6,123.8,123.2,122.6,121.0(q, 1 J C-F =269.3Hz), 106.2, 53.8, 21.3. 19 F NMR (225MHz, CDCl3)δ-62.5(s,3F).

[0120] Example 23

[0121] The compound shown in Formula III-23 was synthesized by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 12 with 4-iodo-1H-pyrazole. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 72%, and the yield of Method 2 was 70%.

[0122]

[0123] White solid, mp 114-115℃. 1 HNMR (400MHz, CDCl3) δ8.15(s,1H),8.00(d,J=7.5Hz,2H),7.73(s,1H),7.53(d,J=7.7Hz,2H),7.21(d,J=7.2Hz,2H),7.12(d,J =7.3Hz,2H),6.76(s,1H),2.42(s,3H). 13 C NMR (101MHz, CDCl3) δ150.1,145.4, 145.1,144.3(q, 2 J C-F =6.0Hz),140.1,135.4,134.9,129.9,129.4,128.7,125.5(q, 1 J C-F =7.3Hz),119.5,116.9,106.8,77.3,77.0,76.7,21.3. 19 F NMR(225MHz, CDCl3)δ-62.6(s,3F).

[0124] Example 24

[0125] The synthesis of the compound shown in Formula III-24 was performed by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 8 with 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol, with all other reaction conditions being the same as in Example 8. The yield of Method 1 was 78%, and the yield of Method 2 was 76%.

[0126]

[0127] White solid, mp 141–142℃. 1 HNMR(400MHz, CDCl3)δ8.37(s,1H),7.99(d, J=8.7Hz,2H),7.93(s,1H),7.49(d,J=8.7Hz,2H),7.27(s,1H),7.19(d,J= 8.1Hz,2H),7.10(d,J=8.1Hz,2H),6.73(s,1H),2.40(s,3H),1.32(s,12H). 13 C NMR (101MHz, CDCl3)δ150.1,145.31,144.29(q, 2 J C-F =38.4Hz),143.9,139.9,138.1, 135.9,129.8,129.2,128.6,125.4,125.3,120.8(q, 1 J C-F =269.2Hz),106.6,84.1,24.7, 21.2. 19 F NMR (225MHz, CDCl3) δ-62.6 (s, 3F).

[0128] Example 25

[0129] The compound shown in Formula III-25 was synthesized by replacing p-toluenesulfonamide in Example 8 with 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and methanol in Example 12 with ethanol. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 83% and the yield of Method 2 was 81%.

[0130]

[0131] White solid, mp 127–128℃. 1H NMR (400MHz, CDCl3) δ7.90 (d, J = 8.6Hz, 2H), 7.51(d,J=8.6Hz,2H),7.19(d,J=7.9Hz,2H),7.11(d,J=8.0Hz,2H),6.75(s,1H),4.14(q,J=7.1Hz,2H),2.39(s,3H),1.32(t,J=7.1Hz,3H). 13 C NMR (101 MHz, CDCl3) δ145.3,144.3(q, 2 J C-F =38.4Hz),143.4,139.9,135.7,129.8,128.9, 128.7,125.6,125.5,121.0(q, 1 J C-F =268.8Hz),106.5,67.5,21.3,14.7. 19 F NMR (225MHz, CDCl3)δ-62.5(s,3F).

[0132] Example 26

[0133] The compounds shown in Formula III-26 were synthesized by replacing p-toluenesulfonamide in Example 8 with 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide and methanol in Example 8 with thiomorpholine. All other reaction conditions were the same as in Example 8. The yield of Method 1 was 83%, and the yield of Method 2 was 82%.

[0134]

[0135] White solid, mp 173-174℃. 1 HNMR (400MHz, CDCl3) δ7.75 (d, J = 8.5Hz, 2H), 7.42–7.33 (m, 7H), 3.45–3.37 (m, 4H), 2.77–2.70 (m, 4H), 2.53 (s, 3H). 13 C NMR (101MHz, CDCl3) δ167.2,161.1,136.0,135.4,130.3,129.7,128.7,128.4,128.3, 127.7,114.3,47.8,27.2,11.8.

[0136] Example 27

[0137] The synthesis of 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonyl chloride (the structural formula of which is shown in Formula III-27) using sulfonamide compounds, magnesium chloride, nitrosotert-butyl ester, and trifluoroacetic acid as catalysts includes the following steps:

[0138] To a reaction tube, p-toluenesulfonamide (0.1 mmol) and magnesium chloride (0.1 mmol) were added sequentially. Nitrogen gas was evacuated / filled using a double-row tube system and circulated three times. Acetonitrile (0.5 mL), trifluoroacetic acid (8 μL, 10 mol%), and nitrosotert-butyl ester (36 μL, 0.3 mmol) were injected sequentially via syringe. The tube was sealed with a rubber stopper and reacted at 50 °C for 7 hours. The product was purified by silica gel column chromatography (petroleum ether / EtOAc 10:1) to obtain the target compound of formula III-27 (36.0 mg) as a white solid, with a calculated yield of 90%.

[0139]

[0140] White solid, mp 85-87℃. 1 HNMR (400MHz, CDCl3) δ8.03(d,J=8.9Hz,2H), 7.60(d,J=8.9Hz,2H), 7.23(d,J=8.0Hz,2H), 7.15(d,J=8.1Hz,2H), 6.77(s,1H), 2.42(s,3H). 13 CNMR(101MHz,CDCl3)δ145.5,144.7(q, 2 J C-F =38.8Hz), 144.4,143.0,140.2,130.0,128.7,128.1,125.5,125.5,120.9(q, 1 J C-F =269.2Hz), 107.0,21.3. 19 F NMR (225MHz, CDCl3) δ-62.6 (s, 3F).

[0141] Example 28

[0142] The compound shown in Formula III-28 was synthesized by replacing 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzenesulfonamide in Example 27 with 4-(5-methyl-3-phenylisoxazole-4-yl)benzenesulfonamide, with all other reaction conditions being the same as in Example 27, and the yield was 85%.

[0143]

[0144] White solid, mp113–114℃. 1 H NMR (400MHz, CDCl3) δ8.05 (d, J = 8.6Hz, 2H), 7.49–7.38 (m, 7H), 2.56 (s, 40min). 13 C NMR (101MHz, CDCl3) δ167.7,161.1, 143.2,138.1,130.6,130.0,128.9,128.5,128.2,127.4,114.0,11.9.

[0145] Example 29

[0146] The compound shown in Formula III-29 was synthesized by replacing 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzenesulfonamide in Example 27 with 4-(5-methyl-3-phenylisoxazole-4-yl)benzenesulfonamide and replacing magnesium chloride in Example 27 with sodium fluoride (2.0 equiv.). All other reaction conditions were the same as in Example 27, with a yield of 73%.

[0147]

[0148] White solid, mp119–121℃. 1 H NMR (400MHz, CDCl3) δ8.01 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 6.79 (s, 1H), 2.43 (s, 3H). 13 C NMR (101MHz, CDCl3) δ145.5,144.9,144.3(q, 2 J C-F =38.6 Hz),140.2,132.1,131.8,129.9,129.5,128.8,125.6,125.5,120.9(q, 1 J C-F =269.2 Hz), 107.0, 21.4. 19 F NMR (470MHz, CDCl3) δ66.5(s,F).,–62.5(s,3F).

Claims

1. A method for preparing sulfonic acid derivatives by deamination of sulfonamide, characterized in that, The method prepares sulfonic acid derivatives using any of the following methods: Method 1: Includes the following steps: mixing a sulfonamide compound with the structure shown in Formula I, nitrosotert-butyl ester with the structure shown in Formula II, MgCl2, and trifluoroacetic acid in an organic solvent, and carrying out a diazotization chlorination reaction at 20-70°C to obtain sulfonyl chloride; or, after the diazotization chlorination reaction, or simultaneously with the diazotization chlorination reaction, adding a nucleophilic reagent to the reaction system to carry out the reaction to obtain a sulfonate ester or sulfonamide; Method 2: Includes the following steps: sulfonamide compounds with structures as shown in Formula I, nitrosotert-butyl ester with structures as shown in Formula II, and trifluoroacetic acid are mixed in an organic solvent and subjected to a diazotization reaction at 0-5°C. Then, a nucleophile is added to the reaction system to carry out a nucleophilic reaction to obtain sulfonate esters or sulfonamides. The structures of Equations I and II are as follows: Wherein, R is alkyl, phenyl, or chlorine; The nucleophile is methanol, ethanol, isopropanol, aniline, 4-toluidine, 4-chloroaniline, benzylamine, tetrahydropyrrole, 8-azabicyclo[3.2.1]octane-3-one, thiomorpholine, methyl 3-azabicyclobutane-carboxylate, ethyl piperidine-4-carboxylate, ethyl piperidine-3-carboxylate, isodihydroindole, or 4-iodo-1H-pyrazole; The molar ratio of the nitrosotert-butyl ester to the sulfonamide compound is 3:

1.

2. The method as described in claim 1, characterized in that, In Method 1, the molar ratio of the sulfonamide compound to MgCl2 is 1:1 to 1:

2.

3. The method as described in claim 2, characterized in that, The molar ratio of the sulfonamide compound to MgCl2 is 1:

1.

4. The method as described in claim 1, characterized in that, In Method 1, the temperature for the diazotization-chlorination reaction is 50°C.

5. The method as described in claim 1, characterized in that, The organic solvent is acetonitrile.

6. The method as described in claim 1, characterized in that, In the second method, the nucleophilic reaction is carried out at room temperature.

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