Deprotection method of thioacetal or thioketal

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a deprotection method of thioacetal or thioketal, which comprises the following steps: adding thioacetal or thioketal as shown in a formula-I as a reaction substrate and a trivalent iodine reagent as shown in a formula-II as an oxidizing agent into a mixed solvent of water and an organic solvent, adding an acid as an activating agent, and reacting to obtain the thioacetal or thioketal. Carrying out a mixed reaction to obtain an aldehyde or ketone compound as shown in a formula-III, and completing removal of the thioacetal or thioketal protecting group; wherein X in the thioacetal or the thioketal is selected from S, O or N; r1, R2 and R3 in the trivalent iodine reagent are independently selected from a hydrogen group, a methyl group, a methoxyl group or halogen. According to the method disclosed by the invention, the trivalent iodine reagent is used as the oxidizing agent, and efficient removal of the thioacetal or thioketal protecting group under a mild condition is realized. Specific reaction route of the method is as follows: # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field related to organic synthesis, and more specifically, relates to a deprotection method for thioacetal or thioketal. Background Art

[0002] The carbonyl group of aldehydes (ketones) is a very important functional group in organic compounds, and they are present in many natural products and drug molecules. Due to the relatively active chemical properties of the carbonyl group of aldehydes (ketones), it is easily attacked by nucleophiles in organic reactions, and may also be converted into carboxyl or hydroxyl groups under oxidation or reduction conditions. Therefore, in organic synthesis, we often need to use suitable protecting groups to protect it, and then remove the thioacetal or thioketal protecting group after completing the required transformation. Currently, common protecting groups for aldehyde (ketone) carbonyl groups include O, O-acetal (ketone) and S, S-acetal (ketone), as well as O, S-acetal (ketone). Compared with O, O-acetal (ketone), the protection of thioacetal (ketone) is easier to form, which has obvious advantages in the protection of some carbonyl functional groups with large steric hindrance and low activity, and it has stronger tolerance to acidic conditions and is relatively more stable during the reaction process. Therefore, developing a mild method to efficiently remove the thioacetal or thioketal protecting group of the carbonyl group of aldehyde (ketone) is particularly important in organic synthesis.

[0003] Many methods have been developed to remove the protective groups of thioacetal or thioketal. Among them, the more classic method is to use some heavy metals such as Hg 2+ 、Ag 1+ , Fe 3+Etc. as an oxidant for oxidative removal. For example, the document (Org.ProcessRes.Dev., 2023, 27, 2374-2384) reports that the use of mercuric chloride in the synthesis of the drug midazolam can remove the thioacetal protecting group with a good yield. In the process of removing the thioacetal or thioacetal protecting group using heavy metal ions, the heavy metal compound as an oxidant is usually stoichiometric or over-stoichiometric, and the reaction conditions are usually harsh heating conditions, which reduces the economy of the reaction. At the same time, the heavy metal waste generated by the reaction requires cumbersome processing steps, which does not meet the requirements of green chemistry. In order to avoid the use of environmentally unfriendly heavy metal oxidants, chemists have also developed many non-metallic deprotection methods. In 1989, the high-valent iodine reagent bistrifluoroacetyl iodobenzene (PIFA) was reported to be used for the removal of thioacetal (ketone) protecting groups (Tetrahedron Lett., 1989, 30, 287-290). As a good oxidant, iodophenyl was also reported in 2021 for the removal of thioacetal (ketone) protecting groups in anhydrous systems (Arkivoc, 2021, vii, 48-65). However, the above reaction system still requires the use of an equivalent amount of oxidizing agent to ensure the completeness of the reaction. Summary of the invention

[0004] In view of the above defects or improvement needs of the prior art, the present invention provides a deprotection method for thioacetal or thioketal, which uses thioacetal or thioketal as a reaction substrate, a trivalent iodine reagent as an oxidant, and completes the removal of the thioacetal or thioketal structure under the joint action of an acid catalyst and water, thereby solving the problem that the prior art method for removing the protecting group of thioacetal or thioketal requires the use of an equivalent or excess oxidant, or even a highly toxic metal oxidant, thereby achieving economical, green and efficient removal of thioacetal (ketone).

[0005] To achieve the above object, according to one aspect of the present invention, a deprotection method for thioacetal or thioketal is provided, and the reaction scheme of the method is as follows:

[0006]

[0007] Specifically, a cyclic thioacetal or cyclic thioketal as shown in the structural formula of Formula-Ⅰ is used as a reaction substrate, a trivalent iodine reagent as shown in the structural formula of Formula-Ⅱ is used as an oxidant, and is added to a mixed solvent of water and an organic solvent, and an acid is added as an activator to carry out a mixed reaction to obtain an aldehyde or ketone compound as shown in the structural formula of Formula-Ⅲ, thereby completing the removal of the thioacetal or thioketal protecting group;

[0008] Wherein, when the formula-I is a thioacetal, one of R' or R" is hydrogen, when the formula-I is a thioketal, R' and R" are not hydrogen, X is selected from S, O or N; R in the trivalent iodine reagent is 1 , R 2 , R 3 Each is independently selected from hydrogen, methyl, methoxy or halogen.

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

[0010] Preferably, R in the trivalent iodine reagent 1 , R 2 , R 3 All are hydrogen groups.

[0011] Preferably, the acid is selected from trimethylsilyl trifluoromethanesulfonate, trifluoromethanesulfonic acid, trimethylsilyl bis(trifluoromethanesulfonyl imide), trifluoromethanesulfonic anhydride or boron trifluoride etherate; preferably trimethylsilyl trifluoromethanesulfonate, trimethylsilyl bis(trifluoromethanesulfonyl imide) 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 thioketal 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 an aliphatic aldehyde or an aromatic aldehyde; and the ketone compound in the thioketal is an aliphatic ketone, an alicyclic ketone or an aromatic ketone.

[0017] In general, compared with the prior art, the above technical solution conceived by the present invention has the following beneficial effects:

[0018] (1) The deprotection method of thioacetal or thioketal provided by the present invention uses thioacetal or thioketal as a reaction substrate, a trivalent iodine reagent as an oxidant, and reacts in a mixed solvent of acid catalysis, water and an organic solvent, thereby achieving efficient removal of the thioacetal or thioketal protecting group under mild conditions.

[0019] (2) The oxidant provided by the present invention is a trivalent iodine reagent, which has stable chemical properties and is easy to prepare and store efficiently. Compared with the oxidant in the prior art that uses stoichiometric or over-stoichiometric amounts, the present invention uses a trivalent iodine reagent as the oxidant, which can efficiently remove the thioacetal or thioketal protecting group at a sub-stoichiometric amount.

[0020] (3) The reaction operation of the present invention is simple and the substrate has a wide range of applicability, and has good application prospects.

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

[0022] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention 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 invention are commercially available. All reagents are commercial grade and used according to the received standards. The reaction is monitored by thin layer chromatography (TLC) and detected by ultraviolet absorption (254nm). If necessary, it is sprayed with a 10% ethanol solution of phosphomolybdic acid by mass fraction and heated at 80-150°C for color development. Flash column chromatography uses silica gel H. 1 H and 13 C NMR spectra were recorded on Bruker AV 400 and Bruker Av 600 using deuterated chloroform (CDCl3) as the deuterated reagent. Chemical shifts (δ) are expressed in ppm with tetramethylsilane as the internal standard. Coupling constants (J) are expressed in Hz.

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

[0025] Abbreviations Chinese meaning Abbreviations Chinese meaning Tf Trifluoromethanesulfonyl Ac Acetyl Boc tert-Butyloxycarbonyl TMS Trimethylsilyl

[0026] In the present invention, the trivalent iodine reagent as shown in Formula-II can be prepared by the following exemplary method:

[0027] Step S1, placing an o-iodobenzyl alcohol compound (I) and periodic acid / periodate in a reaction container, injecting a solvent (acetic acid aqueous solution) to obtain a reaction raw material mixed system.

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

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

[0030] The specific reaction chemical formula involved in the reaction step (2) of the above trivalent iodine reagent is as follows:

[0031]

[0032] Specifically, in the above-mentioned trivalent iodine 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] Specifically, in the above-mentioned trivalent iodine reagent reaction, (I) in the reaction chemical formula is selected from a compound of any of the following structures:

[0034]

[0035] Specifically, in the above-mentioned trivalent iodine reagent reaction, the molar ratio of the above-mentioned o-iodobenzyl alcohol compound to the above-mentioned periodic acid or periodate is 1.0:(1.0-2.0).

[0036] Specifically, in the above-mentioned trivalent iodine reagent reaction, the molar ratio of the sodium periodate o-iodobenzyl alcohol compound to the above-mentioned periodic acid or periodate is preferably 1.0:1.05.

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

[0038] Specifically, in the above-mentioned trivalent iodine reagent reaction, the conditions of the above-mentioned oxidation reaction are as follows: the temperature is 110° C. and the time is 4 hours.

[0039] The molecular structure of the target product obtained by the reaction based on the above scheme is the following formula II-a and / or II-b:

[0040]

[0041] It should be noted that the marks in the preparation process of the above-mentioned trivalent iodine reagent, such as R1, R2, R3, Ⅰ, etc., are only used to illustrate the preparation of the trivalent iodine reagent. For example, in the present invention, when o-iodobenzyl alcohol as shown in Formula Ⅰ-1 and sodium periodate are used in a solvent in which acetic acid and water are mixed in a volume ratio of 3:7, a product structure as shown in Formula Ⅱ-a is obtained.

[0042] In the deprotection method of the present invention, a thioacetal or thioketal having a structural formula such as Formula-I is used as a reaction substrate, a trivalent iodine reagent having a structural formula such as Formula-II is used as an oxidant, and a catalytic amount of an acid is used as an activator. The reaction substrate is in a mixed solvent of water and an organic solvent to achieve mild and efficient removal of the thioacetal or thioketal protecting group to obtain an aldehyde or ketone compound such as Formula-III. The specific reaction chemical 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 thioketal, R' and R" are not 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 thiooxyacetal or a cyclic thiooxyketal; when X is N, the reaction substrate is a cyclic thionitrogen acetal or a cyclic thionitrogen ketal; R in the trivalent iodine reagent is 1 , R 2 , R 3 Each is independently selected from hydrogen, methyl, methoxy or halogen.

[0045] Specifically, R' and R" in the acetal or ketal may be common groups such as hydrogen, alkyl, alkenyl, aryl, ester, and alicyclic hydrocarbon.

[0046] Preferably, when the trivalent iodine reagent with the structural formula shown in Formula-II is used as the oxidant, the amount of the oxidant used is a substoichiometric dose, and when X is S, the molar ratio of the oxidant to the reaction substrate thioacetal / ketone compound is (0.5-1):1; when X is O or N, the molar ratio of the oxidant to the reaction substrate thioacetal / ketone compound is (0.25-1):1.

[0047] Preferably, R in the trivalent iodine reagent 1 , R 2 , R 3 are all selected from hydrogen. 1 , R 2 , R 3 All are selected from the structure of hydrogen:

[0048]

[0049] Preferably, the acid is selected from trimethylsilyl trifluoromethanesulfonate (TMSOTf), trifluoromethanesulfonic acid (TfOH), trimethylsilyl bis(trifluoromethanesulfonyl imide) (Tf2NTMS), trifluoromethanesulfonic anhydride (Tf2O), boron trifluoride ether complex (BF3·Et2O); more preferably TMSOTf, Tf2NTMS or Tf2O;

[0050] Preferably, 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; preferably 5-20 mol%; more preferably 5-10 mol%.

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

[0052] Preferably, the water content of the reaction system of the chemical reaction is 1 equivalent of thioacetal or thioketal to one fifth of the solvent volume, preferably one tenth of the volume of the organic solvent. Dichloromethane is preferred, and the volume ratio of water to dichloromethane is 1:10.

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

[0054] Preferably, the aldehyde compound in the thioacetal is an aliphatic aldehyde or an aromatic aldehyde; and the ketone compound in the thioketal is an aliphatic ketone, an alicyclic ketone or an aromatic ketone.

[0055] The thioacetal or thioketal can be a cyclic dithioacetal or dithioacetal ketone, such as 1,3-dithiapentane, or a cyclic thiooxyacetal or thiooxyketal, such as 1,3-thiooxapentane, or a cyclic thionitrogen acetal or thionitrogen acetal ketone.

[0056] In the above-mentioned thioacetal / ketone deprotection reaction, the thioacetal / ketone (Formula I) is selected from the following structures:

[0057]

[0058] In the specific operation, a scheme is provided: the reaction substrate thioacetal / ketone compound and the oxidant (0.2-0.6 eq) are sequentially added to a glass reaction container containing a mixed solution of an appropriate amount of dichloromethane and water, stirred evenly at 0°C, and then an acid catalyst (0.05-0.1 eq) is added, and the reaction mixture is stirred and reacted for 30-60 minutes. After the reaction is monitored by TLC spot plate until completion, it is extracted with ethyl acetate, the organic phase is collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the target product.

[0059] The following are specific embodiments:

[0060] In the following specific examples, the oxidants used in II are all R 1 , R 2 , R 3 All of them are hydrogen-based structures.

[0061] Embodiment 1-9:

[0062]

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

[0064] The characterization data of the compound are as follows: white solid, R f =0.19 (petroleum ether-ethyl acetate 10:1). 1 H NMR(600MHz, CDCl3)4.59(t,J=8.4Hz,1H),2.37(td,J=15.6,6.6Hz,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=13.2,4.2Hz,1H),1.05(m,1H),1.01(s,3H),0. 91(qd,J=12.6,4.8Hz,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) <![CDATA[Tf2O(0.1)]]> 0℃ III-01 92％ 6 I-01(1.0) II(0.5) <![CDATA[Tf2O(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) <![CDATA[BF3·Et2O(0.2)]]> 0℃ III-01 44％ 9 I-01(1.0) II(0.5) <![CDATA[TMSNTf2(0.2)]]> 0℃ III-01 92％

[0066] It can be seen from the above examples that for substrates using dithioketal (such as 1,3-dithiolane) as protecting groups, excellent deprotection yields can be obtained by using half an equivalent of benzoiodine oxolane reagent (DBI) and a catalytic amount of acid.

[0067] Embodiment 10:

[0068]

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

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

[0071] Embodiment 11:

[0072]

[0073] I-03 (0.06mmol, 14.9mg), II (0.015mmol, 11.3mg), dichloromethane and water were added to a 5ml round-bottom flask in sequence, stirred evenly at 0°C, and then Tf2O (0.003mmol, 0.5μL) was added to the mixture, and the reaction was continued to stir at 0°C until the reaction was complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and saturated brine in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuo. The residue was quickly purified by silica gel column chromatography to obtain the target product III-02 (10.1mg, 96%).

[0074] The characterization data of the compound are as follows: white crystalline solid, R f =0.25 (n-hexane-ethyl acetate 20:1). 1H NMR (600MHz, CDCl3) 10.40 (s, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.47 (d, J = 1.8Hz, 1H), 7.36 (d, J = 8.4Hz, 1H).

[0075] Embodiment 12:

[0076]

[0077] I-04 (0.06mmol, 15.1mg), II (0.03mmol, 22.6mg), dichloromethane and water were added to a 5ml round-bottom flask in sequence, stirred evenly at 0°C, and then Tf2O (0.003mmol, 0.5μL) was added to the mixture, and the reaction was continued to stir at 0°C until the reaction was complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and saturated brine in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuo. The residue was quickly purified by silica gel column chromatography to obtain the target product III-02 (9.8mg, 93%).

[0078] The characterization data of the compound are as follows: white crystalline solid, Rf=0.25 (n-hexane-ethyl acetate 20:1). 1 HNMR (600MHz, CDCl3) 10.40 (s, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.47 (d, J = 1.8Hz, 1H), 7.36 (d, J = 8.4Hz, 1H).

[0079] Embodiment 13:

[0080]

[0081] I-05 (0.06mmol, 13.3mg), II (0.03mmol, 22.6mg), dichloromethane and water were added to a 5ml round-bottom flask in sequence, stirred evenly at 0°C, and then Tf2O (0.003mmol, 0.5μL) was added to the mixture, and the reaction was continued to stir at 0°C until the reaction was complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and saturated brine in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuo. The residue was quickly purified by silica gel column chromatography to obtain the target product III-03 (7.6mg, 96%).

[0082] The characterization data of the compound are as follows: yellow oil, R f =0.37 (petroleum ether-ethyl acetate 10:1).1 H NMR (600MHz, CDCl3) 9.69 (d, J=12.0Hz, 1H), 7.57-7.54 (m, 2H), 7.49-7.40 (m, 4H), 6.71 (dd, J=24.0, 12.0Hz, 1H).

[0083] Embodiment 14:

[0084]

[0085] I-06 (0.06mmol, 15.9mg), II (0.03mmol, 22.6mg), dichloromethane and water were added to a 5ml round-bottom flask in sequence, stirred evenly at 0°C, and then Tf2O (0.003mmol, 0.5μL) was added to the mixture, and the reaction was continued to stir at 0°C until the reaction was complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and saturated brine in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuo. The residue was quickly purified by silica gel column chromatography to obtain the target product III-04 (9.6mg, 91%).

[0086] The characterization data of the compound are as follows: white solid, R f =0.49 (petroleum ether-ethyl acetate 10:1). 1 H NMR (600MHz, CDCl3)7.31(m,2H),7.23(m,3H),3.01(tt,J=12.0,3.0Hz,1H),2.49(m,4H),2.21(m,2H),1.94(m,2H).

[0087] Embodiment 15:

[0088]

[0089] I-07 (0.06mmol, 13.6mg), II (0.03mmol, 22.6mg), dichloromethane and water were added to a 5ml round-bottom flask in sequence, stirred evenly at 0°C, and then Tf2O (0.003mmol, 0.5μL) was added to the mixture, and the reaction was continued to stir at 0°C until the reaction was complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and saturated brine in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuo. The residue was quickly purified by silica gel column chromatography to obtain the target product III-05 (7.8mg, 95%).

[0090] The compound is characterized as follows: colorless oil, Rf =0.27 (petroleum ether-ethyl acetate 10:1). 1 H NMR (600MHz, CDCl3) 9.86 (s, 1H), 7.82 (m, 2H), 6.98 (m, 2H).

[0091] Embodiment 16:

[0092]

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

[0094] The characterization data of the compound are as follows: orange-yellow foamy solid, R f =0.34 (petroleum ether-ethyl acetate 4:1). 1 HNMR(600MHz, CDCl3)8.96(d,J=8.4Hz,1H),7.50(m,1H),7.38(m,1H),7.29(m,1H),7.26(m,1H),7.18(t,J=9.0Hz,1H), 7.06(d,J=9.6Hz,1H),5.27(m,1H),3.80(brs,1H),3.58(m,2H),3.08(m,2H),1.45(s,18H),.HRMS(ESI-TOF)m / z:[M+Na] + calc.forC 26 H 33 ClFN3O5Na544.1985; found:544.1975.

[0095] Embodiment 17:

[0096]

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

[0098] The characterization data of the compound are as follows: light yellow solid, R f =0.29 (petroleum ether-ethyl acetate 10:1). 1 H NMR (400MHz, CDCl3) 10.14 (s, 1H), 8.38 (d, J = 8.8Hz, 2H), 8.06 (d, J = 8.8Hz, 2H).

[0099] Embodiment 18:

[0100]

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

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

[0103] Embodiment 19:

[0104]

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

[0106] The characterization data of the compound are as follows: colorless oil, 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] Embodiment 20:

[0108]

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

[0110] The characterization data of the compound are as follows: white solid, R f =0.34 (petroleum ether-ethyl acetate 4:1). 1 H NMR (400 MHz, 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] Embodiment 21:

[0112]

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

[0114] The characterization data of the compound 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] Embodiment 22:

[0116]

[0117] I-13 (14.8 mg, 0.06 mmol), II (22.6 mg, 0.03 mmol), dichloromethane and water were added to a 5 ml round-bottom flask in sequence, stirred evenly at 0 ° C, and then Tf2O (0.5 μL, 0.003 mmol) was added to the mixture, and the reaction was continued to stir at 0 ° C until the reaction was complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, and saturated brine in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuo. The residue was quickly purified by silica gel column chromatography to obtain the target product III-12 (9.2 mg, 98%).

[0118] The characterization data of the compound are as follows: white solid, R f =0.44 (petroleum ether-dichloromethane 2:1). 1 H NMR (600MHz, CDCl3)10.17(s,1H),8.01(m,1H),7.97-7.91(m,3H),7.67-7.64(m,1H),7.61-7.58(m,1H).

[0119] Embodiment 23:

[0120]

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

[0122] The compound is characterized as follows: colorless oil, R f =0.28 (petroleum ether-ethyl acetate 10:1). 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 and water were added to a 5 ml round-bottom flask in sequence, stirred evenly at 0 ° C, and then Tf2O (0.5 μL, 0.003 mmol) was added to the mixture, and the reaction was continued to stir at 0 ° C until the reaction was complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, and saturated brine in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuo. The residue was quickly purified by silica gel column chromatography to obtain the target product III-14 (9.5 mg, 94%).

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

[0126] Embodiment 24:

[0127]

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

[0129] Embodiment 25:

[0130]

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

[0132] Embodiment 26:

[0133]

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

[0135] The characterization data of the compound are as follows: orange oil, R f =0.53 (petroleum ether-ethyl acetate 10:1). 1H NMR (600MHz, CDCl3) 11.51 (s, 1H), 8.97 (d, J = 9.0Hz, 2H), 8.68 (s, 1H), 8.05 (d, J = 8.4Hz, 2H), 7.66 (m, 2H), 7.54 (m, 2H).

[0136] Embodiment 27:

[0137]

[0138] I-20 (16.9 mg, 0.06 mmol), II (11.3 mg, 0.015 mmol), dichloromethane and water were added to a 5 ml round-bottom flask in sequence, stirred evenly at 0 ° C, and then Tf2O (0.5 μL, 0.003 mmol) was added to the mixture, and the reaction was continued to stir at 0 ° C until the reaction was complete as monitored by TLC. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, and saturated brine in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure in vacuo. The residue was quickly purified by silica gel column chromatography to obtain the target product III-14 (8.7 mg, 83%).

[0139] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A deprotection method for thioacetal or thioketal, characterized in that: The reaction route of this method is as follows: Specifically, a cyclic thioacetal or cyclic thioketal as shown in the structural formula of Formula-Ⅰ is used as a reaction substrate, a trivalent iodine reagent as shown in the structural formula of Formula-Ⅱ is used as an oxidant, and is added to a mixed solvent of water and an organic solvent, and an acid is added as an activator to carry out a mixed reaction to obtain an aldehyde or ketone compound as shown in the structural formula of Formula-Ⅲ, thereby completing the removal of the thioacetal or thioketal protecting group; Wherein, when the formula-I is a thioacetal, one of R' or R" is hydrogen, when the formula-I is a thioketal, R' and R" are not hydrogen, X is selected from S, O or N; R in the trivalent iodine reagent is 1 , R 2 , R 3 Each is independently selected from hydrogen, methyl, methoxy or halogen.

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

1.

3. The deprotection method of thioacetal or thioketal according to claim 1, characterized in that: The R 1 , R 2 , R 3 All are hydrogen groups.

4. The deprotection method of thioacetal or thioketal according to claim 1, characterized in that: The acid is selected from trimethylsilyl trifluoromethanesulfonate, trifluoromethanesulfonic acid, trimethylsilyl bis(trifluoromethanesulfonyl imide), trifluoromethanesulfonic anhydride or boron trifluoride ether complex; preferably trimethylsilyl trifluoromethanesulfonate, trimethylsilyl bis(trifluoromethanesulfonyl imide) or trifluoromethanesulfonic anhydride.

5. The deprotection method of thioacetal or thioketal according to claim 1, characterized in that: 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 deprotection method of thioacetal or thioketal according to claim 1, characterized in that: The organic solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane or toluene.

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

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

10.

9. The deprotection method of thioacetal or thioketal according to claim 1, characterized in that: The aldehyde compound in the thioacetal is aliphatic aldehyde or aromatic aldehyde; the ketone compound in the thioketal is aliphatic ketone, alicyclic ketone or aromatic ketone.

10. The deprotection method of thioacetal or thioketal according to claim 1, characterized in that: The reaction temperature of the chemical reaction is -20°C to 40°C, preferably 0°C.

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