CN-121974832-A - Sulfonate synthesis method based on flow photochemistry technology

Abstract

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

Inventors

• ZHAO BAOLI
• CHENG KAI
• HONG MINGZHE
• ZHANG ZIAO

Assignees

• 绍兴文理学院

Dates

Publication Date

20260505

Application Date

20260116

Claims (10)

1. 1. A method for synthesizing sulfonate compounds based on a flow photochemistry technology is characterized by comprising the following steps: (1) Performing an azide reaction on the phenylacetate compound and p-toluenesulfonyl azide in the presence of alkali to obtain an alpha-diazophenylacetate compound; The reaction formula is as follows: ; (2) Respectively dissolving a sulfonic acid compound and the alpha-diazophenylacetate compound obtained in the step (1) in an organic solvent to form a solution, continuously inputting the solution into a microchannel reactor, carrying out an illumination reaction under an illumination condition, and carrying out post-treatment after the reaction is finished to obtain the sulfonic acid ester compound; The reaction formula is as follows: ; Wherein R 1 is H, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, halogen, -CF 3 ,-NO 2 ,R 2 is C 1 ~C 6 alkyl or benzyl; r 3 is C 1 ~C 6 alkyl, substituted or unsubstituted phenyl, the substituents on the phenyl being one or more of C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy or hydroxy.
2. 2. The method for synthesizing a sulfonate compound according to claim 1, wherein R 1 is-H, -Me, -OMe, halogen, -CF 3 ,-NO 2 ,R 2 is-Me, -Et, -CH 2 Ph; R 3 is methyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is one or more of methyl, methoxy or hydroxy.
3. 3. The method for synthesizing a sulfonate compound according to claim 1, wherein in the step (1), the base is DBU.
4. 4. The method for synthesizing a sulfonate compound according to claim 1, wherein in the step (1), the azide is performed in acetonitrile, THF, ethyl acetate or CH 2 Cl 2 .
5. 5. The method for synthesizing a sulfonate compound according to claim 1, wherein in the step (1), the reaction temperature is 20 to 30 ℃ and the reaction time is 10 to 20 hours.
6. 6. The method for synthesizing a sulfonate compound according to claim 1, wherein in the step (2), the organic solvent is acetonitrile.
7. 7. The method for synthesizing a sulfonate compound according to claim 1, wherein in the step (2), the wavelength of light is 440 to 460nm, preferably 450nm.
8. 8. The method for synthesizing a sulfonate compound according to claim 1, wherein in the step (2), the reaction temperature is 20 to 30 ℃, the reaction flow rate is 1 to 5 μl/min, and the reaction volume of the microchannel is 10 to 15 μl.
9. 9. The method for synthesizing a sulfonate compound according to claim 1, wherein in the step (2), the molar ratio of the α -diazophenylacetate compound to the sulfonate compound is 1:1.2-2.
10. 10. The method for synthesizing the sulfonate compound according to claim 1, wherein in the step (2), the post-treatment process is as follows, the organic solvent is removed by concentration, and then the sulfonate compound is obtained by column chromatography.

Description

Sulfonate synthesis method based on flow photochemistry technology Technical Field The invention relates to a preparation method of symmetric biphenyl participated by sulfonyl-protected alpha-hydroxyaryl acetate catalyzed aryl sulfinate based on a flow photochemistry technology. Background Sulfonic acids and derivatives thereof are of great importance in the pharmaceutical industry and in the biomedical field. The broad pharmacological value of elemental sulfur in organic molecules makes it the first choice for building organic motifs. In addition, the sulfonate group plays a unique role in the coupling reaction because it is easily removed. Over 150 FDA approved sulfur-bearing drugs such as celecoxib, meloxicam, piroxicam, sulfasalazine, and the like, are currently commercially available （Rakesh K P, Wang S M, Leng J, et al. Recent development of sulfonyl or sulfonamide hybrids as potential anticancer agents: a key review[J]. Anti-Cancer Agents in Medicinal Chemistry, 2018, 18(4): 488-505.）. sulfonate esters widely used in a number of drugs, dyes, pesticides, and other biologically active compounds (formula 1) and exhibit a wide range of biological activities, including antitumor, antimalarial, antimicrotubular, antiproliferative, and monoamine oxidase (MAO) inhibitory activities (Pauff S M, Miller S C. Synthesis of near-IR fluorescent oxazine dyes with esterase-labile sulfonate esters[J]. Organic Letters, 2011, 13(23): 6196-6199.). Sulfonate containing bioactive compounds of formula 1 In general, the previously reported synthetic procedure for arylsulfonates is based on the esterification (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.), of the appropriate sulfonyl chloride with an alcohol or phenol in the presence of a base, which requires the use of highly corrosive and carcinogenic thionyl chloride (formula 2). In addition, the high reactivity of thionyl chloride also causes problems such as poor functional group tolerance, and difficulty in storage and handling. Method for traditionally synthesizing aryl sulfonate in formula 2 Different synthetic methods for aryl sulfonates have been reported successively, with few aryl sulfonates being synthesized by diazonium compounds. In 2017, davies and colleagues reported that metal-free conversion of p-toluenesulfonyl sulfonic acid to sulfonate (Jurberg I D, Davies H M 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.), using diazo esters did not report any other sulfonic acid sulfonate in their process, except that the reaction product was used as a reaction intermediate to synthesize 1, 3-oxazin-6-one (formula 3). Reaction of diazoates of formula 3 with tosyl sulfonic acid 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]. ChemistrySelect, 2022, 7(33): e202202440.) report that the use of vanadium to catalyze the insertion of carbenes into the O-H bond of aromatic sulfonic acids to form sulfonate esters (formula 4) has high catalytic performance, good yield, no additives, extremely high activity and shortened reaction time. But the conditions at low temperatures of the reaction limit its development. Formula 4 vanadium catalyzes the O-H bond insertion reaction of alpha-diazonium esters with sulfonic acids In this patent, we designed that under continuous flow conditions, visible light promotes the O-H bond insertion reaction of α -diazo esters with sulfonic acid, and the reaction system directly collects the product after a single pass through the visible light irradiation-microchannel module (formula 5). The reaction is optimized by precisely regulating and controlling the flow rate, regulating the concentration, the proportion of raw materials and other conditions, the yield is higher, and the reaction substrate has good functional group tolerance. Formula 5 visible light promotes the O-H bond insertion reaction of alpha-diazonium esters with sulfonic acids Disclosure of Invention The invention aims to provide a preparation method of sulfonyl-protected alpha-hydroxyaryl acetate catalyzed symmetrical biphenyl participated by aryl sulfinate based on a flow photochemistry technology, which can realize continuous reaction and has high yield. The technical scheme of the invention is as follows: a method for synthesizing sulfonate compounds based on a flow photochemistry technology comprises the following steps: (1) Performing an azide reaction on the phenylacetate compound and p-toluenesulfonyl azide in the presence of alkali to obtain an alpha-diazophenylacetate compound; The reaction formula is as follows: (2) Respectively dissolving a sulfonic aci