Sulfonate synthesis method based on flowing photochemical technology

Abstract

The invention discloses a method for synthesizing a sulfonate compound based on a flowing photochemical technology, which comprises the following steps: (1) carrying out azidation reaction on a phenylacetate compound and p-toluenesulfonyl azide under the action of alkali to obtain an alpha-diazophenylacetate compound; and (2) respectively dissolving a sulfonic acid compound and the alpha-diazophenylacetate compound obtained in the step (1) in an organic solvent to form solutions, then continuously inputting the solutions into a microchannel reactor, carrying out an illumination reaction under an illumination condition, and after the reaction is finished, carrying out post-treatment to obtain the sulfonate compound. The preparation method can realize continuous reaction and is high in yield.

Description

Technical Field

[0001] This invention relates to a method for preparing symmetrical biphenyls involving aryl sulfinates catalyzed by sulfonyl-protected α-hydroxyaryl acetate based on flow photochemistry technology. Background Technology

[0002] Sulfonic acids and their derivatives are of great significance in the pharmaceutical industry and biomedical field. The extensive pharmacological value of sulfur in organic molecules makes it a preferred choice for constructing organic motifs. In addition, due to the ease of removal of sulfonate groups, it also plays a unique role in coupling reactions. Currently, there are more than 150 FDA-approved sulfur-containing drugs such as celecoxib, meloxicam, piroxicam, and sulfasalazine on the market (Rakesh KP, Wang SM, Leng J, et al. Recent development of sulfonyl or sulfonamide hybrids as potential anticancer agents: a key review[J]. Anti-Cancer Agents in MedicinalChemistry, 2018, 18(4): 488-505.). Sulfonate esters are widely used in many pharmaceuticals, dyes, pesticides and other bioactive compounds (Formula 1) and exhibit a wide range of biological activities, including antitumor, antimalarial, antimicrotubule, antiproliferative and monoamine oxidase (MAO) inhibitory activities (Pauff SM, Miller S C. Synthesis of near-IR fluorescentoxazine dyes with esterase-labile sulfonate esters[J]. Organic Letters, 2011,13(23): 6196-6199.).

[0003]

[0004] Formula 1 Bioactive compounds containing sulfonates

[0005] Typically, previously reported synthetic procedures for aryl sulfonates are based on the esterification reaction of appropriate sulfonyl chlorides with alcohols or phenols in the presence of a base (Nakamura K, Kumagai Y, Kobayashi A, et al. Facile synthesis of sulfinate esters from aryl iodides via direct oxidation of thioesters[J]. Organic & Biomolecular Chemistry, 2023, 2023(21): 6886-6891.), which requires the use of highly corrosive and carcinogenic thionyl chlorides (Equation 2). Furthermore, the high reactivity of thionyl chlorides also leads to poor functional group tolerance, as well as difficulties in storage and handling.

[0006]

[0007] Formula 2: Traditional method for synthesizing aryl sulfonates

[0008] Different synthetic methods for aryl sulfonates have been reported, but the synthesis of aryl sulfonates via diazo compounds is relatively rare. In 2017, Davies and colleagues reported the metal-free conversion of p-toluenesulfonylsulfonic acid to sulfonates using diazo esters (Jurberg ID, Davies HM L. Rhodium- and non-metal-catalyzed approaches for the conversion of isoxazol-5-ones to 2,3-dihydro-6H-1,3-oxazin-6-ones. Organic Letters, 2017, 19(19): 5158-5161.). Their method did not report any other sulfonates of sulfonates, but simply used the reaction product as a reaction intermediate to synthesize 1,3-oxazin-6-one (Formula 3).

[0009]

[0010] The reaction of formula 3 diazo ester with toluenesulfonylsulfonic acid

[0011] In 2022, Sivasankar and colleagues (Ahmad Khan H, Wotsa V, Sivasankar C. Functionalization of sulfonic acid to sulfonic ester using diazo compound under mild reaction conditions in the absence of additives[J]. Chemistry Select, 2022, 7(33): e202202440.) reported the use of vanadium to catalyze the insertion of carbene into the OH bond of aromatic sulfonic acid to generate sulfonate esters (Equation 4). This method exhibits high catalytic performance, good yield, no additives required, extremely high activity, and a shortened reaction time. However, the low-temperature conditions of this reaction limit its development.

[0012]

[0013] Formula 4: Vanadium-catalyzed OH bond insertion reaction between α-diazoate and sulfonic acid.

[0014] In this patent, we designed a reaction in which visible light promotes the OH bond insertion of α-diazo esters and sulfonic acids under continuous flow conditions. The reaction system passes through a visible light irradiation-microchannel module in a single pass, and the product is directly collected (Equation 5). Through optimization of conditions such as precise control of flow rate, concentration, and reactant ratio, the reaction achieves a high yield, and the reaction substrate exhibits good functional group tolerance.

[0015]

[0016] Equation 5: Visible light promotes the OH bond insertion reaction between α-diazo esters and sulfonic acids. Summary of the Invention

[0017] The purpose of this invention is to provide a method for preparing symmetrical biphenyls involving aryl sulfinates catalyzed by sulfonyl-protected α-hydroxyaryl acetate based on flow photochemistry technology. This method can achieve continuous reaction and has a high yield.

[0018] The technical solution of the present invention is as follows:

[0019] A method for synthesizing sulfonate compounds based on flow photochemistry technology includes the following steps:

[0020] (1) Phenylacetic acid esters and p-toluenesulfonyl azide undergo an azidization reaction under alkaline conditions to give α-diazophenylacetic acid esters;

[0021] The reaction formula is as follows:

[0022]

[0023] (2) The sulfonic acid compound and the α-diazophenylacetic acid ester compound obtained in step (1) are dissolved in an organic solvent to form a solution. The solution is then continuously fed into a microchannel reactor and subjected to a photo-reaction under light conditions. After the reaction is completed, the sulfonic acid ester compound is obtained through post-processing.

[0024] The reaction formula is as follows:

[0025]

[0026] Among them, R 1 H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -CF3, -NO2, R 2 It is a C1-C6 alkyl or benzyl group;

[0027] R 3 It is a C1-C6 alkyl, substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is one or more of a C1-C6 alkyl, C1-C6 alkoxy or hydroxyl group.

[0028] As a preferred option, R 1 -H, -Me, -OMe, halogen, -CF3, -NO2, R 2 For -Me, -Et, -CH2Ph, as a further preferred option, when R 1 =H,R 2 =-Me.

[0029] As a preferred option, R 3 The phenyl group is methyl, substituted or unsubstituted, wherein the substituent on the phenyl group is one or more of methyl, methoxy or hydroxyl groups.

[0030] Preferably, in step (1), the alkali is DBU.

[0031] Preferably, in step (1), the molar ratio of the phenylacetic acid ester compound, p-toluenesulfonyl azide, and base is 1:1.2~2:1.2~2.

[0032] Preferably, in step (1), the azide reaction is carried out in acetonitrile, THF, ethyl acetate or CH2Cl2.

[0033] Preferably, in step (1), the reaction temperature is 20~30℃ and the reaction time is 10~20h.

[0034] Preferably, in step (1), after the reaction is complete, the reaction mixture is quenched with a saturated sodium bicarbonate solution, then extracted with ethyl acetate, and after washing, drying and concentrating the organic phase, the product α-diazophenylacetic acid esters are obtained by column chromatography.

[0035] Preferably, in step (2), the organic solvent is acetonitrile.

[0036] Preferably, in step (2), the wavelength of the light is 440~460nm, preferably 450nm.

[0037] Preferably, in step (2), the reaction temperature is 20~30℃, the reaction flow rate is 1~5μL / min, and the microchannel reaction volume is 10~15 uL.

[0038] Preferably, in step (2), the molar ratio of the α-diazophenylacetic acid ester compound and the sulfonic acid compound is 1:1.2~2.

[0039] Preferably, in step (2), the post-processing is as follows: the organic solvent is removed by concentration, and then the product sulfonate compound is obtained by column chromatography.

[0040] The specific preparation method of this invention is as follows:

[0041] (1) Preparation of α-diazoarylacetic acid ester

[0042] Preparation of α-diazoaryl acetates (Formula 6). Crude phenylacetate products (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL). Then, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) was added to the mixture at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1–20:1) to obtain an orange-yellow oily α-diazophenylacetate compounds.

[0043]

[0044] Synthesis of Formula 6 α-diazoarylacetic acid ester

[0045] (2) Synthesis of α-Ms-arylacetic acid ester derivatives

[0046] The reaction was performed using a syringe pump-visible light irradiation apparatus. 0.1 mmol of α-aryl diazonate and 0.12 mmol of sulfonic acid compound were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the apparatus, placed on the syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was turned on, the temperature was set to room temperature, the specified flow rate was set, and the syringe pump was started (Equation 7). After the reaction was complete, the receiving bottle was removed, the solution was concentrated, and purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:8–1:1) to obtain the product.

[0047]

[0048] Formula 7 Synthesis of α-Ms-arylacetic acid ester derivatives

[0049] The method provided by this invention has the following characteristics:

[0050] This project achieved the insertion of the OH bond of sulfonic acid into α-aryl diazoate esters under blue light irradiation, providing a feasible route for the synthesis of Ms-protected α-hydroxycarboxylic acid ester derivatives. Regarding continuous flow, the direct-flow strategy employed, along with finer microchannels, improved visible light irradiation efficiency, thereby enhancing reaction efficiency and providing a green and efficient research method. Attached Figure Description

[0051] Figure 1 This is a schematic diagram of the injection pump-visible light irradiation reaction device used in the flow photochemical technology of the present invention. Detailed Implementation

[0052] The present invention will now be further described with reference to the accompanying drawings and specific embodiments.

[0053] Figure 1 This is a schematic diagram of the syringe pump-visible light irradiation reaction device used in the flow photochemical technology of the present invention. Figure 1 As can be seen, the reaction device of the present invention mainly includes an injection pump device, a microchannel-temperature controller, and a lighting device.

[0054] Injection pump device. Mainly includes an injection pump (3-0001) and a syringe. After the reactants are prepared into a solution, they are drawn into the syringe, placed in the injection pump, and the injection pump pushes the syringe into the microchannel, achieving a direct flow effect.

[0055] Microchannel-temperature controller. It mainly consists of a microchannel (T mixing reactor / 3024), a microreactor support, and a temperature controller (Labtrix Start main unit / A 3211). The microchannel reaction volume is 10 μL.

[0056] Lighting fixture. Consists of adjustable-power blue LED lights, and the light assembly can be replaced according to the required wavelength.

[0057] The following examples will help to understand the present invention, but are not limited to the content of the present invention:

[0058] Example 1

[0059] Synthesis of compound 1a. Methyl phenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazophenylacetate.

[0060] Synthesis of compound 3a. 0.1 mmol of methyl α-diazophenylacetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 8). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:8). The product was a known compound, and the yield was 97%.

[0061]

[0062] Synthesis of compound 3a of formula 8

[0063] Methyl 2-((methylsulfonyl)oxy)-2-phenylacetate (3a).

[0064]

[0065] Colorless liquid.

[0066] 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.40 (m, 5H), 5.94 (s, 1H), 3.78 (s,3H), 3.08 (s, 3H).

[0067] 13 C NMR (100 MHz, CDCl3) δ 168.2, 132.7, 130.0, 129.1, 127.8, 78.9,53.1, 39.4.

[0068] Example 2

[0069] Synthesis of Compound 1b. Methyl 4-methylphenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 50:1) to give an orange-yellow oily α-diazo-4-methylphenylacetate.

[0070] Synthesis of compound 3b. 0.1 mmol of methyl α-diazo-4-methylphenylacetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 9). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:8) in 86% yield.

[0071]

[0072] Synthesis of compound 3b (Formula 9)

[0073] Methyl 2-((methylsulfonyl)oxy)-2-(p-tolyl)acetate (3b).

[0074]

[0075] White solid; mp 76.3 – 77.2 ℃.

[0076] 1 H NMR (400 MHz, CDCl3) δ 7.3 (d, J = 8.0 Hz, 2H), 7.2 (d, J = 8.0 Hz, 2H), 5.1 (s, 1H), 3.8 (s, 3H), 2.3 (s, 3H), 1.3 (s, 3H).

[0077] 13 C NMR (100 MHz, CDCl3) δ 174.3, 138.4, 135.3, 129.3, 126.5, 72.8, 53.0, 29.7, 21.2.

[0078] HRMS(ESI) m / z: [M + Na] + Calcd for C 11 H 14 O5NaS + 281.0454; found 281.0453.

[0079] Example 3

[0080] Synthesis of compound 1c. Methyl 4-methoxyphenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 50:1) to give an orange-yellow oily methyl α-diazo-4-methoxyphenylacetate.

[0081] Synthesis of compound 3c. 0.1 mmol of methyl α-diazo-4-methoxyphenylacetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 10). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5). The product was a known compound, and the yield was 88%.

[0082]

[0083] Synthesis of compound 3c of formula 10

[0084] Methyl 2-(4-methoxyphenyl)-2-((methylsulfonyl)oxy)acetate (3c).

[0085]

[0086] Yellow liquid.

[0087] 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.6Hz, 1H), 6.99 – 6.92 (m, 2H), 5.90 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.07(s, 3H).

[0088] 13 C NMR (100 MHz, CDCl3) δ 168.1, 160.0, 134.0, 130.2, 120.0, 115.7,113.1, 78.8, 55.4, 53.1, 39.4.

[0089] Example 4

[0090] Synthesis of compound 1d. Methyl 4-fluorophenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazo-4-fluorophenylacetate.

[0091] Synthesis of compound 3d. 0.1 mmol of α-diazo-4-fluorophenylacetic acid methyl ester and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 11). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:8). The product was a known compound, and the yield was 78%.

[0092]

[0093] Synthesis of compound 3d (Formula 11)

[0094] Methyl 2-(4-fluorophenyl)-2-((methylsulfonyl)oxy)acetate (3d).

[0095]

[0096] Colorless liquid.

[0097] 1 H NMR (400 MHz, CDCl3) δ 7.46 – 7.42 (m, 2H), 7.12 – 7.07 (m, 2H), 5.92 (s, 1H), 3.77 (s, 3H), 3.10 (s, 3H).

[0098] 13C NMR (100 MHz, CDCl3) δ 168.1, 163.6 (d, J = 248.5 Hz), 129.8 (d, J= 8.7 Hz), 128.7 (d, J = 3.5 Hz), 116.2 (d, J = 21.9 Hz), 78.1, 53.2, 39.5.

[0099] 19 F NMR (376 MHz, CDCl3) δ -110.36.

[0100] Example 5

[0101] Synthesis of compound 1e. Methyl 4-chlorophenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 40:1) to give an orange-yellow oily methyl 4-diazo-4-chlorophenylacetate.

[0102] Synthesis of compound 3e. 0.1 mmol of methyl α-diazo-4-chlorophenylacetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 12). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5). The product was a known compound, and the yield was 83%.

[0103]

[0104] Synthesis of compound 3e (Formula 12)

[0105] Methyl 2-(4-chlorophenyl)-2-((methylsulfonyl)oxy)acetate (3e).

[0106]

[0107] White solid; mp 59.6 – 60.3 ℃.

[0108] 1 H NMR (400 MHz, CDCl3) δ 7.42 (s, 4H), 5.94 (s, 1H), 3.80 (s, 3H), 3.14 (s, 3H).

[0109] 13 C NMR (100 MHz, CDCl3) δ 167.9, 136.2, 131.3, 129.3, 129.0, 78.0,53.2, 39.5.

[0110] Example 6

[0111] Synthesis of compound 1f. Methyl 4-bromophenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 40:1) to give an orange-yellow oily methyl 4-bromo-α-diazophenylacetate.

[0112] Synthesis of compound 3f. 0.1 mmol of methyl 4-bromo-α-diazophenylacetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 13). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5). The product was a known compound, and the yield was 93%.

[0113]

[0114] Synthesis of compound 3f (Formula 13)

[0115] Methyl 2-(4-bromophenyl)-2-((methylsulfonyl)oxy)acetate (3f).

[0116]

[0117] White solid; mp 63.3 – 64.0 ℃.

[0118] 1 H NMR (400 MHz, CDCl3) δ 7.54 (dt, J = 8.8, 2.4 Hz, 2H), 7.33 (dt, J= 8.4, 2.4 Hz, 2H), 5.90 (s, 1H), 3.77 (s, 3H), 3.11 (s, 3H)

[0119] 13 C NMR (100 MHz, CDCl3) δ 167.8, 132.3, 131.8, 129.3, 124.4, 78.0,53.2, 39.5.

[0120] Example 7

[0121] Synthesis of 1 g of compound. Methyl 4-trifluoromethylphenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazo-4-trifluoromethylphenylacetate.

[0122] Synthesis of 3g of compound. 0.1 mmol of α-diazo-4-trifluoromethylphenylacetic acid methyl ester and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 14). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5). The product was a known compound, and the yield was 60%.

[0123]

[0124] Synthesis of 3g of compound 14

[0125] Methyl 2-((methylsulfonyl)oxy)-2-(4-(trifluoromethyl)phenyl)acetate(3g).

[0126]

[0127] White solid; mp 38.3 – 38.5 ℃.

[0128] 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.4Hz, 2H), 6.01 (s, 1H), 3.79 (s, 3H), 3.17 (s, 3H).

[0129] 13 C NMR (100 MHz, CDCl3) δ 167.7, 136.6, 127.9, 126.9, 126.0 (q, J =3.4 Hz), 125.5 (q, J = 3.7 Hz), 77.7, 53.3, 39.5.

[0130] 19 F NMR (376 MHz, CDCl3) δ -62.92.

[0131] Example 8

[0132] Synthesis of Compound 1h: Methyl 3-methylphenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazo-3-methylphenylacetate.

[0133] Synthesis of compound 3h. 0.1 mmol of α-diazo-3-methylphenylacetic acid methyl ester and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving flask was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 15). After the reaction was complete, the receiving flask was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:8). The product was a known compound, and the yield was 90%.

[0134]

[0135] Synthesis of compound 3h (Formula 15)

[0136] Methyl 2-((methylsulfonyl)oxy)-2-(m-tolyl)acetate (3h).

[0137]

[0138] Colorless liquid.

[0139] 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.21 (m, 4H), 5.90 (s, 1H), 3.77 (s, 3H), 3.07 (s, 3H), 2.37 (s, 3H).

[0140] 13C NMR (100 MHz, CDCl3) δ 168.3, 139.0, 132.6, 130.8, 129.0, 128.4,124.9, 79.0, 53.1, 39.4, 21.3.

[0141] Example 9

[0142] Synthesis of Compound 1i. Methyl 3-fluorophenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 50:1) to give an orange-yellow oily methyl α-diazo-3-fluorophenylacetate.

[0143] Synthesis of compound 3i. 0.1 mmol of methyl α-diazo-3-fluorophenylacetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 16). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:8) in 74% yield.

[0144]

[0145] Synthesis of Compound 3i (Formula 16)

[0146] Methyl 2-(3-fluorophenyl)-2-((methylsulfonyl)oxy)acetate (3i).

[0147]

[0148] Yellow liquid;

[0149] 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.34 (m, 1H), 7.25 (d, J = 8.0 Hz,1H), 7.18 (dt, J = 9.2, 2.4 Hz, 1H), 7.17 – 7.06 (m, 1H), 5.93 (s, 1H), 3.79(s, 3H), 3.14(s, 3H).

[0150] 13 C NMR (100 MHz, CDCl3) δ 167.8, 162.8 (d, J = 246.7 Hz), 134.9 (d, J= 7.6 Hz), 130.7 (d, J = 8.2 Hz), 123.4 (d, J = 2.6 Hz), 117.0 (d, J = 20.9Hz), 114.7 (d, J = 22.9 Hz), 77.9, 53.2, 39.5.

[0151] 19 F NMR (376 MHz, CDCl3) δ -116.55.

[0152] HRMS(ESI) m / z: [M + Na] + Calcd for C 10 H 11 FO5NaS + 285.0203; found 285.0213.

[0153] Example 10

[0154] Synthesis of Compound 1j. Methyl 2-fluorophenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily methyl 2-diazo-2-fluorophenylacetate.

[0155] Synthesis of compound 3j. 0.1 mmol of methyl α-diazo-2-fluorophenylacetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 17). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5). The product was a known compound, and the yield was 68%.

[0156]

[0157] Synthesis of compound 3j (Formula 17)

[0158] Methyl 2-(2-fluorophenyl)-2-((methylsulfonyl)oxy)acetate (3j).

[0159]

[0160] Yellow liquid;

[0161] 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.38 (m, 2H), 7.23 – 7.10 (m, 2H), 6.24 (s, 1H), 3.80 (s, 3H), 3.15 (s, 3H).

[0162] 13 C NMR (100 MHz, CDCl3) δ 167.8, 160.3 (d, J = 249.8 Hz), 132.1 (d, J= 8.3 Hz), 129.6, 124.8 (d, J = 3.4 Hz), 120.7 (d, J = 13.4 Hz), 116.1 (d, J = 21.0 Hz), 73.0 (d, J = 16.0 Hz), 53.3, 39.4.

[0163] 19 F NMR (376 MHz, CDCl3) δ -111.13.

[0164] Example 11

[0165] Synthesis of compound 1k. Methyl 2-chlorophenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 40:1) to give an orange-yellow oily methyl 2-diazo-2-chlorophenylacetate.

[0166] Synthesis of compound 3k. 0.1 mmol of methyl α-diazo-2-chlorophenylacetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 18). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5) in 53% yield.

[0167]

[0168] Synthesis of compound 3k (Formula 18)

[0169] Methyl 2-(2-chlorophenyl)-2-((methylsulfonyl)oxy)acetate (3k).

[0170]

[0171] Yellow liquid;

[0172] 1 H NMR (400 MHz, CDCl3) δ 7.48 – 7.43 (m, 2H), 7.40 – 7.30 (m, 2H), 6.40 (s, 1H), 3.80 (s, 3H), 3.15 (s, 3H).

[0173] 13C NMR (100 MHz, CDCl3) δ 168.0, 134.0, 131.3, 131.1, 130.2, 129.7,127.5, 75.9, 53.3, 39.4.

[0174] HRMS(ESI) m / z: [M + Na] + Calcd for C 10 H 11 ClO5NaS + 300.9908, found 300.9908.

[0175] Example 12

[0176] Synthesis of Compound 1l. Methyl 2-trifluoromethylphenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazo-2-trifluoromethylphenylacetate.

[0177] Synthesis of compound 3l. 0.1 mmol of α-diazo-2-trifluoromethylphenylacetic acid methyl ester and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 19). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5) in 53% yield.

[0178]

[0179] Synthesis of Compound 3l (Formula 19)

[0180] Methyl 2-((methylsulfonyl)oxy)-2-(2-(trifluoromethyl)phenyl)acetate(3l).

[0181]

[0182] Yellow solid; mp 37.5 – 37.9 ℃.

[0183] 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.67 – 7.60 (m,2H), 7.58 – 7.52 (m, 1H), 6.32 (s, 1H), 3.78 (s, 3H), 3.15 (s, 3H).

[0184] 13 C NMR (100 MHz, CDCl3) δ 167.7, 136.6, 127.9, 126.9, 126.0 (q, J =3.5 Hz), 125.5 (q, J = 3.4 Hz), 77.7, 53.3, 39.5.

[0185] HRMS(ESI) m / z: [M + Na] + Calcd for C 11 H 11 F3O5NaS + 335.0171; found 335.0177.

[0186] Example 13

[0187] Synthesis of compound 1m. Ethyl phenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 50:1) to give an orange-yellow oily α-diazophenylacetate.

[0188] Synthesis of compound 3m. 0.1 mmol of α-diazophenylethyl acetate and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump (Equation 20) was started. After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5). The product was a known compound, and the yield was 74%.

[0189]

[0190] Synthesis of compound 3m of formula 20

[0191] Ethyl 2-((methylsulfonyl)oxy)-2-phenylacetate (3m).

[0192]

[0193] Colorless liquid.

[0194] 1 H NMR (400 MHz, CDCl3) δ 7.48 – 7.39 (m, 5H), 5.92 (s, 1H), 4.33 –4.15 (m, 2H), 3.08 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0195] 13 C NMR (100 MHz, CDCl3) δ 167.7, 132.9, 130.0, 129.0, 127.7, 79.1,62.4, 39.5, 14.0.

[0196] Example 14

[0197] Synthesis of compound 1n. Benzyl phenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 30:1) to give an orange-yellow oily α-diazophenylacetate.

[0198] Synthesis of compound 3n. 0.1 mmol of α-diazophenylacetic acid benzyl ester and 0.12 mmol of methanesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 21). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:3) in 91% yield.

[0199]

[0200] Synthesis of compound 3n of formula 21

[0201] Benzyl 2-((methylsulfonyl)oxy)-2-phenylacetate (3n).

[0202]

[0203] White solid; mp 63.8 – 64.2 ℃.

[0204] 1 H NMR (400 MHz, CDCl3) δ 7.48 – 7.37 (m, 5H), 7.35 – 7.27 (m, 3H), 7.26 – 7.18 (m, 2H), 6.00 (s, 1H), 5.21 (d, J = 12.4 Hz, 2H), 3.05 (s, 3H).

[0205] 13C NMR (100 MHz, CDCl3) δ 167.6, 134.7, 132.6, 130.0, 129.1, 128.6,128.6, 128.1, 127.8, 79.0, 67.8, 39.4.

[0206] HRMS(ESI) m / z: [M + Na] + Calcd for C 16 H 16 O5NaS + 343.0611; found 343.0612.

[0207] Example 15

[0208] Synthesis of compound 1a. Methyl phenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 40:1) to give an orange-yellow oily α-diazophenylacetate.

[0209] Synthesis of compound 3o. 0.1 mmol of methyl α-diazophenylacetate and 0.12 mmol of phenylsulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 22). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:3). The product was a known compound, and the yield was 86%.

[0210]

[0211] Synthesis of compound 3o (Formula 22)

[0212] Methyl 2-phenyl-2-((phenylsulfonyl)oxy)acetate (3o).

[0213]

[0214] White solid; mp 65.2 – 65.8 ℃.

[0215] 1 H NMR (400 MHz, CDCl3) δ 7.90 – 7.83 (m, 2H), 7.65 – 7.56 (m, 1H), 7.53 – 7.43 (m, 2H), 7.35 – 7.28 (m, 5H), 5.82 (s, 1H), 3.67 (s, 3H).

[0216] 13 C NMR (100 MHz, CDCl3) δ 167.7, 136.4, 134.0, 132.6, 129.8, 129.1,128.8, 128.0, 127.5, 79.0, 52.9.

[0217] Example 16

[0218] Synthesis of compound 1a. Methyl phenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazophenylacetate.

[0219] Synthesis of compound 3p. 0.1 mmol of methyl α-diazophenylacetate and 0.12 mmol of p-toluenesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was aspirated using the syringe provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving flask was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 23). After the reaction was complete, the receiving flask was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:3). The product was a known compound, and the yield was 82%.

[0220]

[0221] Synthesis of compound 3p of formula 23

[0222] Methyl 2-phenyl-2-(tosyloxy)acetate (3p).

[0223]

[0224] White solid; mp 86.8 – 87.0 ℃.

[0225] 1 H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.4, 2.4 Hz, 2H), 7.34 – 7.29 (m, 5H), 7.27 (dd, J = 8.8, 0.8 Hz, 2H), 5.79 (s, 1H), 3.67 (s, 3H), 2.41 (s,3H).

[0226] 13 C NMR (100 MHz, CDCl3) δ 167.8, 145.1, 133.3, 132.7, 129.7, 129.7,128.8, 128.0, 127.5, 78.8, 52.9, 21.6.

[0227] Example 17

[0228] Synthesis of compound 1a. Methyl phenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazophenylacetate.

[0229] Synthesis of compound 3q. 0.1 mmol of methyl α-diazophenylacetate and 0.12 mmol of p-chlorobenzenesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 24). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5) in 77% yield.

[0230]

[0231] Synthesis of compound 3q of formula 24

[0232] Methyl 2-(((4-chlorophenyl)sulfonyl)oxy)-2-phenylacetate (3q).

[0233]

[0234] Yellow solid; mp 70.0 – 70.7 ℃.

[0235] 1 H NMR (400 MHz, CDCl3) δ 7.79 (dt, J = 8.8, 2.4 Hz, 1H), 7.44 (dt, J= 8.8, 2.4 Hz, 2H), 7.38 – 7.30 (m, 5H), 5.84 (s, 1H), 3.69 (s, 3H).

[0236] 13 C NMR (100 MHz, CDCl3) δ 167.6, 140.6, 135.0, 132.4, 129.9, 129.4,128.9, 127.6, 79.2, 53.0.

[0237] HRMS(ESI) m / z: [M + Na] + Calcd for C 15 H 13 ClO5NaS + 363.0064; found 363.0054.

[0238] Example 18

[0239] Synthesis of compound 1a. Methyl phenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazophenylacetate.

[0240] Synthesis of compound 3r. 0.1 mmol of methyl α-diazophenylacetate and 0.12 mmol of 2,4-dimethylbenzenesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 25). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:5) in 64% yield.

[0241]

[0242] Synthesis of compound 3r of formula 25

[0243] Methyl 2-(((2,4-dimethylphenyl)sulfonyl)oxy)-2-phenylacetate (3r).

[0244]

[0245] White solid. mp 62.0 – 62.7 ℃.

[0246] 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.35 – 7.29 (m,5H), 7.11 – 7.07 (m, 2H), 5.71 (s, 1H), 3.64 (s, 3H), 2.55 (s, 3H), 2.36 (s,3H).

[0247] 13 C NMR (100 MHz, CDCl3) δ 167.7, 145.0, 138.8, 133.3, 132.7, 131.7,130.0, 129.7, 128.8, 127.5, 126.6, 78.7, 52.8, 21.4, 20.1.

[0248] HRMS(ESI) m / z: [M + Na] + Calcd for C 17 H 18 O5NaS + 357.0767; found 357.0773.

[0249] Example 19

[0250] Synthesis of compound 1a. Methyl phenylacetate (10 mmol) and p-toluenesulfonyl azide (15 mmol) were added to acetonitrile (15 mL), followed by the addition of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 15 mmol) at 0 °C. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine, and dried over anhydrous sodium sulfate. The resulting organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate, v / v = 60:1) to give an orange-yellow oily α-diazophenylacetate.

[0251] Synthesis of compound 3S. 0.1 mmol of methyl α-diazophenylacetate and 0.12 mmol of p-hydroxybenzenesulfonic acid were weighed into conical flasks, and 1 mL of anhydrous acetonitrile was added to each to prepare a solution. The reaction solution was drawn up using the syringe needle provided with the reaction apparatus, placed on a syringe pump, and connected to the tubing. A clean receiving bottle was then placed at the outlet. The apparatus was turned on, the light source was set to 450 nm, the temperature was set to room temperature (25 °C), and the specified flow rate (4 μL / min) was set. The syringe pump was started (Equation 26). After the reaction was complete, the receiving bottle was removed, and the mixture was concentrated under vacuum. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as eluent (v / v, 1:8) in 83% yield.

[0252]

[0253] Synthesis of compound 3s (Formula 26)

[0254] Methyl 2-(((4-hydroxyphenyl)sulfonyl)oxy)-2-phenylacetate (3r).

[0255]

[0256] White solid; mp 72.0 – 72.7 °C.

[0257] 1 H NMR (400 MHz, CDCl3) δ 7.71 (dt, J = 8.8, 2.8 Hz, 2H), 7.36 – 7.29(m, 5H), 6.88 (s, 1H), 6.85 (dt, J = 8.8, 2.8 Hz, 2H), 5.80 (s, 1H), 3.70 (s,2H).

[0258] 13 C NMR (100 MHz, CDCl3) δ 168.5, 161.2, 132.5, 130.5, 129.9, 128.9,127.5, 126.9, 116.0, 78.6, 53.1.

[0259] HRMS(ESI) m / z: [M + Na] + Calcd for C 15 H 14 O6NaS + 345.0403; found 345.040。

Claims

1. A method for synthesizing sulfonate compounds based on flow photochemistry technology, characterized in that, Includes the following steps: (1) Phenylacetic acid esters and p-toluenesulfonyl azide undergo an azidization reaction under alkaline conditions to give α-diazophenylacetic acid esters; The reaction formula is as follows: ； (2) The sulfonic acid compound and the α-diazophenylacetic acid ester compound obtained in step (1) are dissolved in an organic solvent to form a solution. The solution is then continuously fed into a microchannel reactor and subjected to a photo-irradiation reaction under light conditions. After the reaction is completed, the sulfonic acid ester compound is obtained through post-treatment. The reaction formula is as follows: ； Among them, R 1 H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -CF3, -NO2, R 2 It is a C1-C6 alkyl or benzyl group; R 3 It is a C1-C6 alkyl, substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is one or more of a C1-C6 alkyl, C1-C6 alkoxy or hydroxyl group.

2. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, R 1 -H, -Me, -OMe, halogen, -CF3, -NO2, R 2 For -Me, -Et, -CH2Ph; R 3 The phenyl group is methyl, substituted or unsubstituted, wherein the substituent on the phenyl group is one or more of methyl, methoxy or hydroxyl groups.

3. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, In step (1), the alkali is DBU.

4. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, In step (1), the azide reaction is carried out in acetonitrile, THF, ethyl acetate or CH2Cl2.

5. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, In step (1), the reaction temperature is 20~30℃ and the reaction time is 10~20h.

6. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, In step (2), the organic solvent is acetonitrile.

7. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, In step (2), the wavelength of the light is 440~460nm, preferably 450nm.

8. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, In step (2), the reaction temperature is 20~30℃, the reaction flow rate is 1~5μL / min, and the microchannel reaction volume is 10~15 uL.

9. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, In step (2), the molar ratio of the α-diazophenylacetic acid ester compound and the sulfonic acid compound is 1:1.2~2.

10. The method for synthesizing sulfonate compounds according to claim 1, characterized in that, In step (2), the post-processing is as follows: the organic solvent is removed by concentration, and then the product sulfonate compounds are obtained by column chromatography.

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