A method for deprotection of a thioacetal or thioketal

Abstract

The application belongs to the technical field of organic synthesis, and discloses a deprotection method of thioacetal or thioketals, which comprises the following steps: taking thioacetal or thioketals shown in formula-I as a reaction substrate, taking triiodine reagent shown in formula-II as an oxidant, adding into a mixed solvent of water and an organic solvent, and adding an acid as an activator to carry out a mixing reaction, so as to obtain aldehyde or ketone compounds shown in formula-III, and complete the removal of thioacetal or thioketals protective groups; wherein X in the thioacetal or thioketals is selected from S, O or N; R 1 , R 2 , R 3 are each independently selected from hydrogen, methyl, methoxy or halogen. Through the method of the application, the efficient removal of thioacetal or thioketals protective groups under mild conditions is realized by taking triiodine reagent as an oxidant. The reaction route of the method is as follows:

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field related to organic synthesis, and more particularly, relates to a method for deprotection of a thioacetal or a thioketals. BACKGROUND

[0002] The carbonyl of aldehyde (ketone) is a very important functional group in organic compounds, and many natural products, drug molecules have their presence. Because of the chemical properties of aldehyde (ketone) carbonyl is relatively active, it is easy to be attacked by nucleophiles in organic reactions, and it may also be converted into carboxyl or hydroxyl under oxidation or reduction conditions, so we often need to use a suitable protecting group to protect it in organic synthesis, and then remove the thioacetal or thioketals protecting group after completing the required transformation. The common protecting groups of aldehyde (ketone) carbonyl at present include O, O-acetal (ketone) and S, S-acetal (ketone), and O, S-acetal (ketone) and the like. Compared with O, O-acetal (ketone), the protection of thioacetal (ketone) is easier to form, which has obvious advantages in the protection of some large steric hindrance and low activity carbonyl functional groups, and it is more resistant to acidic conditions and relatively stable during the reaction. Therefore, it is particularly important to develop a mild method to efficiently remove the thioacetal or thioketals protecting group of aldehyde (ketone) carbonyl in organic synthesis.

[0003] Many methods have been developed for removing the thioacetal or thioketals protecting group, among which the more classical method is to use some heavy metals such as Hg 2+ , Ag 1+ , Fe 3+as an oxidizing agent. For example, the literature (Org. Process Res. Dev., 2023, 27, 2374-2384) reports that the use of mercury chloride in the synthesis of the drug midazolam can remove the dithioacetal protecting group with good yield. In the process of removing the dithioacetal or dithioacetal protecting group using heavy metal ions, the heavy metal compound as an oxidizing agent is usually stoichiometric or excessive, and the reaction conditions are usually harsh heating conditions, which reduces the economy of the reaction, and the heavy metal waste generated by the reaction needs complicated treatment steps and does not meet the requirements of green chemistry. In order to avoid the use of environmentally unfriendly heavy metal oxidizing agents, chemists have also developed many non-metal deprotection methods. In 1989, the high-valence iodine reagent bis-trifluoroacetyl iodobenzene (PIFA) was reported to be used for the removal of dithioacetal (ketone) protecting groups (Tetrahedron Lett., 1989, 30, 287-290). Sulfuryl iodide as a good oxidizing agent was also reported in 2021 for the removal of dithioacetal (ketone) protecting groups in anhydrous system (Arkivoc, 2021, vii, 48-65). But the above reaction system still needs to use equivalent amount of oxidizing agent to ensure the completion of the reaction. SUMMARY

[0004] In view of the above defects or improvement needs of the prior art, the present application provides a method for removing dithioacetal or dithioacetal, which uses dithioacetal or dithioacetal as a reaction substrate, trivalent iodine reagent as an oxidizing agent, and completes the removal of dithioacetal or dithioacetal structure under the joint action of acid catalyst and water, solving the problem that the existing technology requires the use of equivalent or excessive oxidizing agent, even the use of toxic metal oxidizing agent, achieving economic, green and efficient removal of dithioacetal (ketone).

[0005] To achieve the above-mentioned purpose, according to one aspect of the present application, a method for removing dithioacetal or dithioacetal is provided, and the reaction route of the method is as follows:

[0006]

[0007] Specifically, a cyclic dithioacetal or a cyclic dithioacetal with a structure as shown in formula-I is used as a reaction substrate, a trivalent iodine reagent with a structure as shown in formula-II is used as an oxidizing agent, is added to a mixed solvent of water and an organic solvent, and an acid is added as an activator, mixed reaction is carried out, an aldehyde or ketone compound with a structure as shown in formula-III is obtained, and the removal of the dithioacetal or dithioacetal protecting group is completed.

[0008] wherein, when the formula -I is a thioacetal, one of R' or R" is hydrogen, when the formula -I is a thiotone, neither R' nor R" is hydrogen, X is selected from S, O or N; R 1 , R 2 , R 3 are each independently selected from hydrogen, methyl, methoxy or halogen.

[0009] Preferably, when X is S, the molar ratio of the triiodine reagent to the thioacetal or thiotone is (0.5-1):1; when X is O or N, the molar ratio of the triiodine reagent to the thioacetal or thiotone is (0.25-1):1.

[0010] Preferably, R 1 , R 2 , R 3 in the triiodine reagent are each hydrogen.

[0011] Preferably, the acid is selected from trimethylsilyl triflate, trifluoromethanesulfonic acid, bistrifluoromethylsilyl imidazole, trifluoromethanesulfonic anhydride or boron trifluoride etherate; preferably trimethylsilyl triflate, bistrifluoromethylsilyl imidazole or trifluoromethanesulfonic anhydride.

[0012] Preferably, the molar ratio of the acid to the thioacetal is (5-100):100; the molar ratio of the acid to the thiotone is (5-100):100.

[0013] Preferably, the organic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane or toluene.

[0014] Preferably, the volume ratio of the water to the organic solvent is 1:(5-10).

[0015] Preferably, the organic solvent is dichloromethane, and the volume ratio of the water to the dichloromethane is 1:10.

[0016] Preferably, the aldehyde compound in the thioacetal is aliphatic aldehyde or aryl aldehyde; the ketone compound in the thiotone is aliphatic ketone, alicyclic ketone or aryl ketone.

[0017] Overall, compared with the prior art, the scheme provided by the present application has the following beneficial effects:

[0018] (1) The deprotection method of thioacetal or thiotone provided by the present application, which takes thioacetal or thiotone as a reaction substrate, takes triiodine reagent as an oxidant, and reacts in an acid-catalyzed, water and organic solvent mixed solvent, realizes efficient removal of the protecting group of thioacetal or thiotone under mild conditions.

[0019] (2) The oxidizing agent provided by the present application is a tri-valent iodine reagent, which is stable in chemical properties and easy to prepare and store efficiently. Compared with the stoichiometric or super-stoichiometric oxidizing agents in the prior art, the tri-valent iodine reagent as the oxidizing agent can complete the efficient removal of the thioacetal or thioacetonide protecting group at a sub-chemical dose.

[0020] (3) The present application has simple reaction operation and wide substrate application range, and has good application prospect.

[0021] (4) The present application does not need to use toxic metal reagents, compared with the existing deprotection method which needs to use heavy metal reagents. DETAILED DESCRIPTION

[0022] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application will be further described in detail below with examples. It should be understood that the specific examples described herein are only used to explain the present application, and are not used to limit the present application. In addition, the technical features involved in each embodiment of the present application described below can be combined with each other as long as they do not conflict with each other.

[0023] Unless otherwise specified, the raw materials or reagents used in the present application are commercially available. All reagents are of commercial grade and are used according to the received standard. The reaction is monitored by thin layer chromatography (TLC), detected by ultraviolet absorption (254 nm), and if necessary, sprayed with 10% phosphomolybdic acid ethanol solution and heated to develop color at 80-150℃. Flash column chromatography uses silica gel H. 1 H and 13 C nuclear magnetic resonance spectrum, deuterated chloroform (CDCl3) is used as deuterated reagent, recorded on Bruker AV 400, Bruker Av600. Chemical shift (δ) is expressed in ppm, with tetramethylsilane as internal standard. Coupling constant (J) is expressed in Hz.

[0024] Unless otherwise specified, the scientific and technical terms and abbreviations used in the present application have the meanings commonly understood by those skilled in the art. For example, "equivalent" in the present application refers to the ratio of the amount of substance of each substance participating in the reaction; for another example, the meanings of some abbreviations are as follows:

[0025] Abbreviations Chinese meaning Abbreviations Chinese meaning Tf trifluoromethylsulfonyl Ac acetyl Boc tert-butyloxycarbonyl TMS trimethylsilyl

[0026] In the present application, the tri-valent iodine reagent as shown in formula-Ⅱ can be prepared by the following examples:

[0027] Step S1, the o-iodobenzyl alcohol compound (I) and the periodic acid / periodate are placed in a reaction container, and a solvent (acetic acid aqueous solution) is injected to obtain a reaction raw material mixture system.

[0028] Step S2, the reaction raw material mixture of step S1 is heated and stirred for 4-12 hours.

[0029] Step S3, after the reaction of step S2 is completed, the reaction system is cooled and directly filtered. The filter cake is washed with water, acetonitrile and dichloromethane in sequence to obtain part of the target product. The mother liquor is concentrated and pulped to obtain part of the target product. The two parts of the target product are combined to obtain all the target products of the final reaction, i.e. the benzene iodosoxolane reagent (II).

[0030] The reaction formula involved in the reaction step (2) of the above-mentioned triiodine reagent is as follows:

[0031]

[0032] In the above-mentioned triiodine reagent reaction, R1 in step (2) is selected from methyl or trifluoromethyl, R2 is selected from hydrogen, halogen or methyl; R3 is selected from hydrogen or methyl; and the periodate is selected from sodium periodate, potassium periodate, potassium tetra-n-butylammonium periodate or lithium periodate. Sodium periodate is preferred.

[0033] In the above-mentioned triiodine reagent reaction, (I) in the reaction formula is selected from any one of the following compounds:

[0034]

[0035] In the above-mentioned triiodine reagent reaction, the molar ratio of the above-mentioned o-iodobenzyl alcohol compound to the above-mentioned periodate is 1.0: (1.0-2.0).

[0036] In the above-mentioned triiodine reagent reaction, the molar ratio of sodium periodate to the above-mentioned o-iodobenzyl alcohol compound is preferably 1.0:1.05.

[0037] In the above-mentioned triiodine reagent reaction, the solvent is an acetic acid aqueous solution, and the volume ratio of acetic acid to water is 1:9-1:1. Preferably, the volume ratio of acetic acid to water is preferably 3:7.

[0038] In the above-mentioned triiodine reagent reaction, the temperature in the above-mentioned oxidation reaction condition is 110°C, and the time is 4 hours.

[0039] The molecular structure formula of the target product obtained by the reaction based on the above-mentioned scheme is as follows:

[0040]

[0041] It should be noted that the labels such as R1, R2, R3, I and the like appearing in the preparation process of the above-mentioned triiodine reagent are only used to illustrate the preparation of the triiodine reagent. For example, when o-iodobenzyl alcohol represented by formula I-1 is used in the present application and sodium periodate is used in a solvent mixed with acetic acid and water in a volume ratio of 3:7, the product structure represented by formula II-a is obtained.

[0042] In the deprotection method of the present application, a thioacetal or a thioketale represented by formula I is used as a reaction substrate, a triiodine reagent represented by formula II is used as an oxidizing agent, and a catalytic amount of acid is used as an activator. The reaction substrate is in a mixed solvent of water and an organic solvent, and the thioacetal or thioketale protecting group is removed in a mild and efficient manner to obtain an aldehyde or ketone compound represented by formula III. The specific reaction formula is as follows:

[0043]

[0044] wherein, when the formula I is a thioacetal, one of R' or R" is hydrogen, when the formula I is a thioketale, neither R' nor R" is hydrogen, X is S or O or N, and when X is S, the reaction substrate is a cyclic dithioacetal or a cyclic dithioacetal ketone, when X is O, the reaction substrate is a cyclic thioacyl acetal or a cyclic thioacyl ketone, and when X is N, the reaction substrate is a cyclic thioamino acetal or a cyclic thioamino ketone; R 1 , R 2 , R 3 are each independently selected from hydrogen, methyl, methoxy or halogen.

[0045] Specifically, R' and R" in the acetal or ketale can be hydrogen, alkyl, alkenyl, aryl, ester, alicyclic hydrocarbon and the like common groups.

[0046] Preferably, when the triiodine reagent represented by formula II is used as an oxidizing agent, the amount of the oxidizing agent used is sub-chemical dose, the molar ratio of the oxidizing agent to the reaction substrate thioacetal / ketone compound is (0.5-1):1 when X is S, and the molar ratio of the oxidizing agent to the reaction substrate thioacetal / ketone compound is (0.25-1):1 when X is O or N.

[0047] Preferably, R 1 , R 2 , R 3 in the triiodine reagent are each selected from hydrogen. The structure in which R 1 , R 2 , R 3 are each selected from hydrogen is as follows:

[0048]

[0049] Preferably, the acid is selected from the group consisting of trifluoromethylsulfonic acid trimethylsilylester (TMSOTf), trifluoromethylsulfonic acid (TfOH), bistrifluoromethylsulfonimide trimethylsilylester (Tf2NTMS), trifluoromethylsulfonic anhydride (Tf20), boron trifluoride diethyl ether complex (BF3.Et20); more preferably TMSOTf, Tf2NTMS or Tf20;

[0050] Preferably, the molar ratio of acid to the thioacetal is (5-100): 100; the molar ratio of acid to the thioketals is (5-100): 100; preferably 5-20 mol%; more preferably 5-10 mol%.

[0051] Preferably, the organic solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane or toluene.

[0052] Preferably, the reaction system of the chemical reaction contains water in an amount of 1 equivalent of the thioacetal or the thioketals to one fifth of the amount of the solvent, preferably one tenth of the volume of the organic solvent. Preferably, dichloromethane, and the volume ratio of water to dichloromethane is 1:10.

[0053] Preferably, the reaction temperature of the chemical reaction is -20℃-40℃, preferably 0℃.

[0054] Preferably, the aldehyde compound in the thioacetal is aliphatic aldehyde or aryl aldehyde; the ketone compound in the thioketals is aliphatic ketone, alicyclic ketone or aryl ketone.

[0055] The thioacetal or the thioketals can be cyclic dithioacetal or dithioacetal ketone, such as 1,3-dithiopentane, can also be cyclic thiooxoacetal or thiooxoacetal ketone, such as 1,3-thiooxolane, and can also be cyclic thiooxoacetal or thiooxoacetal ketone.

[0056] The thioacetal / thioketals (Formula I) in the above-mentioned thioacetal / thioketals deprotection reaction are selected from the following structures:

[0057]

[0058] In specific operation, a scheme is provided: the reaction substrate thioacetal / thioketals compound, oxidant (0.2-0.6 eq) are sequentially added to a glass reaction vessel containing an appropriate amount of a mixture of dichloromethane and water, stirred uniformly at 0℃, then acid catalyst (0.05-0.1 eq) is added, the reaction mixture continues to stir for 30-60 min. TLC point plate monitoring reaction until completion, extracted with ethyl acetate, collect the organic phase, dry over anhydrous sodium sulfate, filter, reduce pressure concentration, silica gel column chromatography to obtain the target product.

[0059] The following are specific examples:

[0060] In the following specific examples, the oxidizing agent of choice for II is R 1 , R 2 , R 3 are hydrogen groups.

[0061] Examples 1-9:

[0062]

[0063] I-01 (0.04 mmol, 16.3 mg), II (0.02 mmol, 15.1 mg), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly, then a catalytic amount of acid was added to the mixture, and the stirring reaction was continued at the reaction temperature until the reaction was complete by TLC monitoring. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-01 (12.4 mg, 93%) corresponding to Example 6.

[0064] The compound characterization data are as follows: white solid, R f = 0.19 (petroleum ether-ethyl acetate 10:1). 1 H NMR (600 MHz, CDC13) 4.59 (t, J = 8.4 Hz, 1H), 2.37 (td, J = 15.6, 6.6 Hz, 1H), 2.32-2.23 (m, 2H), 2.16 (m, 1H), 2.08 (m, 1H), 2.03 (m, 4H), 1.73 (m, 2H), 1.66-1.42 (m, 5H), 1.39-1.26 (m, 5H), 1.16 (td, J = 13.2, 4.2 Hz, 1H), 1.05 (m, 1H), 1.01 (s, 3H), 0.91 (qd, J = 12.6, 4.8 Hz, 1H), 0.80 (s, 3H), 0.75 (m, 1H). HRMS (ESI-TOF) m / z: [M + Na] + calc. for C 21 H 32 O3Na 355.2244; found: 355.2240.

[0065] Example I (eq.) II (eq.) acid (eq.) temperature product yield 1 I-01(1.0) II (0.5) TMSOTf (0.2) 0℃-25℃ III-01 90％ 2 I-01(1.0) II (0.5) TMSOTf (0.1) 0℃-25℃ III-01 83％ 3 I-01(1.0) II (0.5) TMSOTf (0.2) 0℃ III-01 89％ 4 I-01(1.0) II (0.5) TMSOTf (0.2) 25℃ III-01 86％ 5 I-01(1.0) II (0.5) Tf20 (0.1) 0℃ III-01 92％ 6 I-01(1.0) II (0.5) Tf20 (0.05) 0℃ III-01 93％ 7 I-01(1.0) II (0.5) TfOH (0.2) 0℃ III-01 41％ 8 I-01(1.0) II (0.5) BF3»Et20 (0.2) 0℃ III-01 44％ 9 I-01(1.0) II (0.5) [ TMSNTf2 (0.2) ] 0℃ III-01 92％

[0066] As can be seen from the above examples, for substrates using a dithioacetal (such as 1,3-dithiopentane) as a protecting group, a half equivalent of benzoiodoxolane reagent (DBI) and a catalytic amount of acid can be used to obtain excellent deprotection yield.

[0067] Example 10:

[0068]

[0069] I-02 (0.06 mmol, 15.9 mg), II (0.03 mmol, 22.6 mg), dichloromethane, water were added into a 5 ml round-bottom flask in turn, and stirred uniformly at 0 °C, then Tf2O (0.003 mmol, 0.5 μL) was added into the mixture, and the reaction was continued to stir at 0 °C until the reaction was completed by TLC monitoring. The reaction mixture was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-02 (10.2 mg, 97%).

[0070] The compound characterization data are as follows: white crystalline solid, R f = 0.25 (n-hexane-ethyl acetate 20:1). 1 H NMR (600 MHz, CDCl3) 10.40 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H).

[0071] Example 11:

[0072]

[0073] I-03 (0.06 mmol, 14.9 mg), II (0.015 mmol, 11.3 mg), dichloromethane, water were added into a 5 ml round-bottom flask in turn, and stirred uniformly at 0 °C, then Tf2O (0.003 mmol, 0.5 μL) was added into the mixture, and the reaction was continued to stir at 0 °C until the reaction was completed by TLC monitoring. The reaction mixture was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-02 (10.2 mg, 97%).

[0074] The compound characterization data are as follows: white crystalline solid, R f = 0.25 (n-hexane-ethyl acetate 20:1). 1H NMR (600 MHz, CDC13) 10.40 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H).

[0075] Example 12:

[0076]

[0077] I-04 (0.06 mmol, 15.1 mg), II (0.03 mmol, 22.6 mg), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf20 (0.003 mmol, 0.5 μL) was added into the mixture, the reaction was continued to stir at 0 °C until the reaction was completed by TLC monitoring. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was purified by silica gel column chromatography, to obtain the target product III-02 (9.8 mg, 93%).

[0078] The compound characterization data are as follows: white crystalline solid, Rf = 0.25 (n-hexane-ethyl acetate 20:1). 1 H NMR (600 MHz, CDC13) 10.40 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H).

[0079] Example 13:

[0080]

[0081] I-05 (0.06 mmol, 13.3 mg), II (0.03 mmol, 22.6 mg), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf20 (0.003 mmol, 0.5 μL) was added into the mixture, the reaction was continued to stir at 0 °C until the reaction was completed by TLC monitoring. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was purified by silica gel column chromatography, to obtain the target product III-03 (7.6 mg, 96%).

[0082] The compound characterization data are as follows: yellow oil, Rf = 0.37 (petroleum ether-ethyl acetate 10:1). f = 0.37 (petroleum ether-ethyl acetate 10:1).1 H NMR (600 MHz, CDC13) 9.69 (d, J = 12.0 Hz, 1H), 7.57-7.54 (m, 2H), 7.49-7.40 (m, 4H), 6.71 (dd, J = 24.0, 12.0 Hz, 1H).

[0083] Example 14:

[0084]

[0085] I-06 (0.06 mmol, 15.9 mg), II (0.03 mmol, 22.6 mg), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf20 (0.003 mmol, 0.5 μL) was added to the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-04 (9.6 mg, 91%).

[0086] The compound characterization data are as follows: white solid, R f = 0.49 (petroleum ether-ethyl acetate 10:1). 1 H NMR (600 MHz, CDC13) 7.31 (m, 2H), 7.23 (m, 3H), 3.01 (tt, J = 12.0, 3.0 Hz, 1H), 2.49 (m, 4H), 2.21 (m, 2H), 1.94 (m, 2H).

[0087] Example 15:

[0088]

[0089] I-07 (0.06 mmol, 13.6 mg), II (0.03 mmol, 22.6 mg), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf20 (0.003 mmol, 0.5 μL) was added to the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-05 (7.8 mg, 95%).

[0090] The compound characterization data are as follows: colorless oil, Rf = 0.27 (petroleum ether-ethyl acetate 10:1). 1 H NMR (600 MHz, CDC13) 9.86 (s, 1H), 7.82 (m, 2H), 6.98 (m, 2H).

[0091] Example 16:

[0092]

[0093] I-08 (0.01672 mmol, 10.0 mg), II (0.008359 mmol, 6.3 mg), wet dichloromethane were added into a 5 ml round-bottom flask in turn, and stirred uniformly at 0°C, then TMSOTf (0.00334 mmol, 0.6 μL) was added into the mixture, and the reaction was continued to stir at 0°C until the reaction was completed by TLC monitoring. The reaction mixture was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-06 (8.1 mg, 93%).

[0094] The compound characterization data are as follows: orange-yellow foam solid, Rf f = 0.34 (petroleum ether-ethyl acetate 4:1). 1 H NMR (600 MHz, CDC13) 8.96 (d, J = 8.4 Hz, 1H), 7.50 (m, 1H), 7.38 (m, 1H), 7.29 (m, 1H), 7.26 (m, 1H), 7.18 (t, J = 9.0 Hz, 1H), 7.06 (d, J = 9.6 Hz, 1H), 5.27 (m, 1H), 3.80 (br s, 1H), 3.58 (m, 2H), 3.08 (m, 2H), 1.45 (s, 18H),. HRMS (ESI-TOF) m / z: [M+Na] + calc. for C 26 H 33 ClFN3O5Na 544.1985; found: 544.1975.

[0095] Example 17:

[0096]

[0097] I-09 (9.7 mg, 0.04 mmol), II (15.1 mg, 0.02 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf2O (0.002 mmol, 0.34 μL) was added to the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-07 (5.8 mg, 96%).

[0098] The compound characterization data are as follows: white solid, R f = 0.29 (petroleum ether-ethyl acetate 10:1). 1 H NMR (400 MHz, CDCl3) 8.00-7.94 (m, 4H), 7.40 (s, 2H), 2.59 (s, 3H).

[0099] Example 18:

[0100]

[0101] I-10 (15.3 mg, 0.06 mmol), II (22.6 mg, 0.03 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf2O (0.5 μL, 0.003 mmol) was added to the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-08 (8.8 mg, 90%).

[0102] The compound characterization data are as follows: white solid, R f = 0.14 (petroleum ether-ethyl acetate 2:1). 1 H NMR (400 MHz, CDCl3) 8.00-7.94 (m, 4H), 7.40 (s, 2H), 2.59 (s, 3H).

[0103] Example 19:

[0104]

[0105] I-11 (16.2 mg, 0.06 mmol), II (11.3 mg, 0.015 mmol), dichloromethane, and water were sequentially added to a 5 mL round-bottom flask and stirred at 0 °C until homogeneous. Then, Tf₂O (0.5 μL, 0.003 mmol) was added to the mixture, and the reaction was continued at 0 °C with stirring until complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed sequentially with water, saturated sodium bicarbonate solution, and saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was rapidly purified by silica gel column chromatography to give the target product III-09 (12.4 mg, 98%).

[0106] The characterization data for this compound are as follows: colorless oily substance, R f =0.46 (petroleum ether-ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3)7.32-7.23(m,6H),7.13(m,4H),3.7(s,4H).

[0107] Example 20:

[0108]

[0109] I-12 (13.7 mg, 0.06 mmol), II (22.6 mg, 0.03 mmol), dichloromethane, and water were sequentially added to a 5 mL round-bottom flask and stirred at 0 °C until homogeneous. Then, Tf₂O (0.5 μL, 0.003 mmol) was added to the mixture, and the reaction was continued at 0 °C with stirring until complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed sequentially with water, saturated sodium bicarbonate solution, and saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was rapidly purified by silica gel column chromatography to give the target product III-10 (8.8 mg, 97%).

[0110] The characterization data of this compound are as follows: white solid, R f =0.34 (petroleum ether-ethyl acetate 4:1). 1 H NMR (400MHz, CDCl) 3 )9.81(s,1H),7.42-7.39(m,2H),7.03-7.01(m,1H),6.19(s,1H),3.95(s,3H).

[0111] Example 21:

[0112]

[0113] I-13 (12.4 mg, 0.06 mmol), II (22.6 mg, 0.03 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf2O (0.5 μL, 0.003 mmol) was added into the mixture, the reaction was continued to stir at 0 °C until the reaction was completed by TLC monitoring. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-11 (6.5 mg, 93%).

[0114] The compound characterization data are as follows: white solid, R f = 0.28 (petroleum ether-ethyl acetate 10:1). 1 H NMR (600MHz, CDCl3) 2.96-2.94 (m, 4H), 2.70-2.68 (m, 4H).

[0115] Example 22:

[0116]

[0117] I-13 (12.4 mg, 0.06 mmol), II (22.6 mg, 0.03 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf2O (0.5 μL, 0.003 mmol) was added into the mixture, the reaction was continued to stir at 0 °C until the reaction was completed by TLC monitoring. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-11 (6.5 mg, 93%).

[0118] The compound characterization data are as follows: white solid, R f = 0.44 (petroleum ether-dichloromethane 2:1). 1 H NMR (600MHz, CDCl3) 2.96-2.94 (m, 4H), 2.70-2.68 (m, 4H).

[0119] Example 23:

[0120]

[0121] I-15 (9.1 mg, 0.04 mmol), II (15.1 mg, 0.02 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf2O (0.34 μL, 0.002 mmol) was added into the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-13 (5.5 mg, 92%).

[0122] The compound characterization data are as follows: colorless oil, Rf= 0.28 (petroleum ether-ethyl acetate 10:1). f 1 H NMR (400 MHz, CDCl3) 7.91 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.53 (s, 3H). Example 24:

[0123]

[0124] I-16 (13.7 mg, 0.06 mmol), II (11.3 mg, 0.015 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf2O (0.5 μL, 0.003 mmol) was added into the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-14 (9.5 mg, 94%).

[0125] The compound characterization data are as follows: colorless oil, Rf= 0.26 (petroleum ether-ethyl acetate 10:1). f 1 H NMR (600 MHz, CDCl3) 7.31 (m, 2H), 7.13 (m, 2H), 3.68 (s, 2H), 2.17 (s, 3H).

[0126] Example 24:

[0127]

[0128] ​​I-17 (16.9 mg, 0.06 mmol), II (22.6 mg, 0.03 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf2O (0.5 μL, 0.003 mmol) was added into the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-14 (10.0 mg, 95%).

[0129] Example 25:

[0130]

[0131] I-18 (14.1 mg, 0.06 mmol), II (11.3 mg, 0.015 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then Tf2O (0.5 μL, 0.003 mmol) was added into the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-14 (10.2 mg, 97%).

[0132] Example 26:

[0133]

[0134] I-19 (18.8 mg, 0.06 mmol), II (11.3 mg, 0.015 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, stirred uniformly at 0 °C, then TMSOTf (2.2 μL, 0.012 mmol) was added into the mixture, the reaction was continued to stir at 0 °C until TLC monitoring reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, saturated brine in turn, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated under reduced pressure in vacuum. The residue was quickly purified by silica gel column chromatography to obtain the target product III-14 (10.1 mg, 81%).

[0135] The compound characterization data are as follows: orange oil, Rf f = 0.53 (petroleum ether-ethyl acetate 10:1). 1H NMR (600 MHz, CDC13) 11.51 (s, 1H), 8.97 (d, J = 9.0 Hz, 2H), 8.68 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.66 (m, 2H), 7.54 (m, 2H).

[0136] Example 27:

[0137]

[0138] I-20 (16.9 mg, 0.06 mmol), II (11.3 mg, 0.015 mmol), dichloromethane, water were added into a 5 ml round-bottom flask in turn, and stirred uniformly at 0°C, then Tf20 (0.5 μL, 0.003 mmol) was added into the mixture, and the reaction was continued to stir at 0°C until the reaction was completed by TLC monitoring. The reaction mixture was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution, saturated brine solution in turn, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuum. The residue was purified by silica gel column chromatography, and the target product III-14 (8.7 mg, 83%) was obtained.

[0139] Although the present application has been described in detail with reference to the foregoing embodiments, the technical solutions recorded in the foregoing embodiments can be modified by those skilled in the art, or some technical features can be replaced by equivalent features, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for deprotection of a thioacetal or thioketal, characterized by, The reaction route of the method is as follows: ； Specifically, a cyclic thioacetal or a cyclic thioketal shown in a structural formula such as Formula-I is used as a reaction substrate, a triiodine reagent shown in a structural formula such as Formula-II is used as an oxidant, is added into a mixed solvent of water and an organic solvent, and an acid is used as an activator and is added for mixing reaction, to obtain an aldehyde or a ketone compound shown in a structural formula such as Formula-III, and removal of a thioacetal or thioketal protecting group is completed. wherein when said Formula -I is a thioacetal, one of R' or R" is hydrogen, when said Formula -I is a thioketale, neither R' nor R" is hydrogen, and X is selected from S, O, or N; R 1 , R 2 , R 3 are each independently selected from hydrogen, methyl, methoxy, or halogen; and said acid is selected from trimethylsilyl triflate, triflic acid, bistrifluoromethylsulfonimide trimethylsilyl ester, triflic anhydride, or boron trifluoride diethyl ether complex.

2. The deprotection method of a thioacetal or a thioketal according to claim 1, characterized in that, When X is S, the molar ratio of the triiodine reagent to the thioacetal or thioketal is (0.5-1): 1; when X is O or N, the molar ratio of the triiodine reagent to the thioacetal or thioketal is (0.25-1):

1.

3. The method for deprotection of a thioacetal or a thioketal according to claim 1, wherein, R in the triiodine reagent 1 , R 2 , R 3 are each a hydrogen group.

4. The method for deprotection of a thioacetal or thioketal according to claim 1, wherein, The acid is selected from trimethylsilyl trifluoromethanesulfonate, bistrifluoromethanesulfonylimide trimethylsilane or trifluoromethanesulfonic anhydride.

5. The method for deprotection of a thioacetal or thioketal according to claim 1, wherein, The molar ratio of the acid to the thioacetal is (5-100): 100; the molar ratio of the acid to the thioketal is (5-100):

100.

6. The method of deprotection of a thioacetal or thioketal according to claim 1, wherein, The organic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane or toluene.

7. The method of deprotection of a thioacetal or thioketal according to claim 1, wherein, The volume ratio of the water to the organic solvent is 1: (5-10).

8. The method for deprotection of a thioacetal or thioketal according to claim 1, wherein, The organic solvent is dichloromethane, and the volume ratio of the water to the dichloromethane is 1:

10.

9. The method of deprotection of a thioacetal or thioketal according to claim 1, wherein, The aldehyde compound in the thioacetal is a fatty aldehyde or an aryl aldehyde; the ketone compound in the thioketal is a fatty ketone, an alicyclic ketone or an aryl ketone.

10. The method of deprotection of a thioacetal or thioketal according to Claim 1, wherein, The reaction temperature of the chemical reaction is -20℃-40℃.

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