Method for preparing chiral sulfinic acid thioester through asymmetric oxidation

Abstract

The invention provides a method for preparing chiral sulfinic acid thioester through asymmetric oxidation, which is characterized in that a disulfide compound is used as a raw material, a chiral aminoindanol-derived alloxan compound is used as a chiral catalyst, hydrogen peroxide or oxygen is used as an oxidant, and the chiral sulfinic acid thioester is prepared through asymmetric oxidation. Compared with a traditional chiral imine ligand matched with a vanadyl acetylacetonate catalyst, an aminoindanol-derived alloxan compound is used as a chiral small-molecule catalyst, so that the chiral small-molecule catalyst has higher catalytic stability and high optical purity of a product, is not influenced by factors such as the stirring speed, the shape and size of a reaction bottle and the like, and is convenient for engineering amplification; meanwhile, compared with a chiral resolution method, the method for synthesizing the chiral sulfinic acid thioester in one step by using a chiral small molecule catalysis method has higher step economy, and the method is simple to operate, high in raw material conversion rate, good in reaction enantioselectivity, high in product yield and high in optical purity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and relates to a chiral sulfoxide, in particular to a method for preparing a chiral sulfoxide by asymmetric oxidation. BACKGROUND

[0002] Sulfochiral compounds have a wide range of applications in the field of medicine. Many drug molecules contain sulfochiral centers, such as Armodafinil and Esomeprazole. These drugs play an important role in clinical treatment, and the unique structure of sulfochiral compounds makes them indispensable in drug design. In addition, there are also many natural products containing sulfochiral compounds in nature. For example, allicin, as a kind of sulfoxide, naturally exists in garlic and gives garlic a unique aroma and flavor. The discovery and application of this natural product further proves the wide existence and importance of sulfochiral compounds in nature. In addition, sulfochiral compounds also play an important role in the field of chemistry and are often used as chiral auxiliary reagents. For example, chiral sulfonamides, chiral sulfonamides, and chiral sulfoxides derived from menthol are widely used. In particular, chiral tert-butylsulfonamides play a key role in the synthesis of chiral amines and are widely used in the synthesis of various chiral amine compounds in organic synthesis and medicinal chemistry, such as antiallergic drug cetirizine hydrochloride, anti-Parkinson's disease drug rasagiline, and Alzheimer's disease treatment drug rivastigmine.

[0003] Currently, there are two methods for preparing chiral sulfoxides: the first method uses di-tert-butyl disulfide as a raw material, uses chiral imine ligands derived from indole amine alcohol and vanadyl acetylacetonate as catalysts, and uses hydrogen peroxide as oxidant to synthesize chiral di-tert-butyl sulfoxide by asymmetric oxidation, and the optical purity of the product is 86% (Org. Lett. 2003, 5, 1317). The disadvantages of this method are that the solvent, stirring speed, even the shape and size of the reaction bottle, etc. can affect the yield and optical purity of the product, and the optical purity of the product is not high; the second method uses optically pure binaphthol as a resolving agent to form a clathrate complex, and chiral di-tert-butyl sulfoxide is prepared by recrystallization, acid-base neutralization and extraction, etc. The optical purity of the product is ≥85% (Chem. Eur. J. 2003, 9, 2611). The disadvantages of this method are that the process steps are complicated, the optical purity of the product is not high, and the recovery and reuse efficiency of the resolving agent is low. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application aims to provide a method for preparing chiral sulfide of sulfinic acid by asymmetric oxidation, so as to solve the technical problem that the harshness of reaction conditions and the complexity of process cannot be reduced simultaneously in the prior art for preparing chiral sulfide of sulfinic acid.

[0005] In order to solve the above technical problems, the present application adopts the following technical solutions: The method for preparing chiral sulfide of sulfinic acid by asymmetric oxidation uses a disulfide compound as a raw material, a chiral amino indene alcohol derived tetraoxypyrimidine compound as a chiral catalyst, and hydrogen peroxide or oxygen as an oxidant, so as to prepare chiral sulfide of sulfinic acid by asymmetric oxidation, and the reaction formula is shown in formula I: ; In formula I, R includes methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl or allyl; and the temperature is -40℃ to 25℃.

[0006] The structural formula of the chiral catalyst is as follows: .

[0007] The present application also has the following technical features: Preferably, the method specifically comprises the following steps: dissolving the disulfide compound and the chiral catalyst in a solvent, adding the oxidant and stirring at a temperature less than or equal to room temperature for 1 to 6 hours, monitoring the reaction in gas phase, stopping the reaction when the conversion rate of the disulfide compound is greater than or equal to 95%, concentrating and purifying the obtained reaction liquid to obtain the product chiral sulfide of sulfinic acid.

[0008] Specifically, the method for purification comprises column chromatography or reduced pressure distillation.

[0009] Specifically, the solvent includes chloroform, dichloromethane, acetone or ethyl acetate.

[0010] Specifically, the molar ratio of the chiral catalyst to the disulfide compound is (0.1% to 5%): 1.

[0011] Specifically, the molar ratio of the oxidant to the disulfide compound is (0.9 to 1.1): 1.

[0012] Specifically, the disulfide compound is di-tert-butyl disulfide, dibenzyl disulfide, diphenyl disulfide or diallyl disulfide.

[0013] Specifically, the preparation method of the chiral catalyst specifically comprises the following steps: Step one, preparation of intermediate A: Aminoindol, tert-butyldimethylchlorosilane, imidazole, and solvent were added to a round-bottom flask and reacted at room temperature for 8–10 h to ensure complete conversion of the starting materials. The reaction was then stopped. The molar ratio of aminoindol, tert-butyldimethylchlorosilane, imidazole, and solvent was 1:1.05:1.1:(3–10). After the reaction was complete, the reaction solution was extracted 2–3 times with water and ethyl acetate. The combined organic phases were concentrated and recrystallized to obtain a white solid intermediate, A.

[0014] Step 2, Preparation of intermediate B: Intermediate A, bis(trichloromethyl) carbonate, and solvent were added to a round-bottom flask equipped with a reflux condenser and heated for 2–4 hours at a temperature of 110–120 °C. The reaction was monitored in the gas phase, and the reaction was stopped when the conversion rate of intermediate A was greater than or equal to 98%. The molar ratio of intermediate A, bis(trichloromethyl) carbonate, and solvent was 1:0.5:(3–10). After the reaction was completed, the reaction solution was extracted 2–3 times with water and ethyl acetate. The organic phases were combined, concentrated, and recrystallized to obtain a white solid product, intermediate B.

[0015] Step 3, Preparation of intermediate C: Malonic acid, benzotriazol-1-yl-oxytripyrrolidine phosphorus hexafluorophosphate, triethylamine, and solvent were added to a round-bottom flask and stirred at room temperature for 1 hour. Intermediate B was then added, and the reaction was continued at room temperature for 1–3 hours. The reaction was monitored in the gas phase, and the reaction was stopped when the conversion rate of intermediate B was greater than or equal to 98%. The molar ratio of intermediate B, malonic acid, benzotriazol-1-yl-oxytripyrrolidine phosphorus hexafluorophosphate, triethylamine, and solvent was 1:(1–1.2):(1–1.2):(1–1.2):(3–10). After the reaction was completed, the reaction solution was extracted 2–3 times with water and ethyl acetate. The organic phases were combined and washed sequentially with 10 wt.% dilute hydrochloric acid and 5 wt.%–8 wt.% saturated sodium bicarbonate solution to obtain the washed organic phase. The washed organic phase was then concentrated and recrystallized to obtain the white solid product intermediate C.

[0016] Step 4, Preparation of chiral catalyst: Tin dioxide was dissolved in a mixed solvent of dioxane and water to obtain a tin dioxide solution. Intermediate C was dissolved in dioxane at room temperature and then added dropwise to the tin dioxide solution. After the addition was complete, the reaction was heated for 3–5 h at a temperature of 60–80 °C. The reaction was monitored in the gas phase. The reaction was stopped when the conversion rate of intermediate C was greater than or equal to 98%. Trifluoroacetic acid was then added to the system, and the reaction was stopped after stirring at room temperature for 1–2 h. The molar ratio of intermediate C, tin dioxide, trifluoroacetic acid, and the mixed solvent of dioxane and water was 1:(1–1.5):(1–2):(3–10). After the reaction was completed, a 10 wt.% NaOH aqueous solution was added to adjust the pH of the reaction system to 7. The reaction solution was filtered, and the filtrate was collected, concentrated, and recrystallized to obtain a pink solid chiral catalyst.

[0017] This invention also protects the use of a chiral sulfinic acid thioester prepared by the method described above for the preparation of chiral tert-butyl sulfinamide.

[0018] Compared with the prior art, the present invention has the following technical effects: (I) This invention uses chiral aminoindanol-derived tetraoxazine compounds as catalysts to generate chiral sulfinic acid thioesters from disulfide compounds under low-temperature conditions through asymmetric oxidation. The advantages of this method are that using aminoindanol-derived tetraoxazine compounds as chiral small-molecule catalysts provides higher catalytic stability compared to traditional chiral imine ligands combined with acetylacetone vanadium oxide catalysts, resulting in higher product optical purity. Furthermore, it is unaffected by factors such as stirring speed, reaction flask shape, and size, facilitating large-scale engineering. Simultaneously, compared to chiral resolution methods, the one-step synthesis of chiral sulfinic acid thioesters using chiral small-molecule catalysis offers greater step economy.

[0019] (II) The preparation method of the chiral sulfinic acid thioester in this invention is simple to operate, has a high raw material conversion rate and good enantioselectivity, high product yield and high optical purity, and generates little waste in the preparation process. It is suitable for large-scale preparation and can be applied to organic synthesis methodology and the synthesis of pharmaceutical and pesticide intermediates. Attached Figure Description

[0020] Figure 1(a) is the optical purity test spectrum of the racemic form of chiral di-tert-butylsulfinic acid thioester 2a in Example 2 of the present invention.

[0021] Figure 1(b) is the optical purity test spectrum of the enantiomeric chiral di-tert-butylsulfinic acid thioester 2a in Example 2 of the present invention.

[0022] The specific content of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Detailed Implementation

[0023] It should be noted that, unless otherwise specified, all raw materials, methods, and equipment used in this work are those commonly known in the art in the prior art. For example, disulfide compounds are known disulfide compounds, oxygen is known oxygen, chloroform is known chloroform, dichloromethane is known dichloromethane, acetone is known acetone, n-hexane is known n-hexane, isopropanol is known isopropanol, asymmetric oxidation methods are known asymmetric oxidation methods, chromatographic methods are known chromatographic methods, vacuum distillation methods are known vacuum distillation methods, and the Chiralcel AS-H chromatographic column is a known Chiralcel AS-H chromatographic column.

[0024] In this invention, room temperature refers to the ambient temperature during the production process, which is typically within the range of 20±10℃.

[0025] Following the above technical solution, specific embodiments of the present invention are given below. It should be noted that the present invention is not limited to the following specific embodiments, and all equivalent modifications made on the basis of the technical solution of the present invention fall within the protection scope of the present invention.

[0026] Example 1: This embodiment provides a method for preparing chiral sulfinic acid thioesters by asymmetric oxidation. The prepared chiral sulfinic acid thioesters are in the gram range. The chiral sulfinic acid thioesters obtained by this method are abbreviated as 2a. The method specifically includes the following steps: 1.78 g of di-tert-butyl disulfide and 42.4 mg of chiral catalyst were dissolved in 6 mL of chloroform. 1.1 mL of 30 wt.% hydrogen peroxide was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h, and the reaction was monitored by gas phase. The reaction was stopped when the di-tert-butyl disulfide was completely converted. The resulting reaction solution was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain 1.84 g of colorless liquid product, chiral di-tert-butyl sulfinic acid sulfate 2a.

[0027] In this embodiment, the di-tert-butyl disulfide used is a commonly known di-tert-butyl disulfide in the art.

[0028] The structural formula of the product, chiral di-tert-butylsulfinic acid thioester 2a, is as follows: .

[0029] The reaction formula for preparing chiral di-tert-butylsulfinic acid thioester 2a by this method is shown in Formula I: ; In Formula I: R is tert-butyl.

[0030] The structural formula of the chiral catalyst is: .

[0031] The preparation method of chiral catalysts specifically includes the following steps: Step 1, Preparation of intermediate A: 4.5 g of aminoindanol, 4.7 g of tert-butyldimethylchlorosilane (TBSCl), 2.2 g of imidazole, and 45 mL of N,N-dimethylformamide (DMF) were added to a round-bottom flask and reacted at room temperature for 8 h to ensure complete conversion of the starting materials. The reaction was then stopped. After the reaction was completed, the reaction solution was extracted 2-3 times with water and ethyl acetate. The combined organic phases were concentrated and recrystallized to obtain 7.5 g of white solid intermediate A, with a yield of 95%.

[0032] In this embodiment, aminoindanol is the commonly known aminoindanol in the art, tert-butyldimethylchlorosilane is the commonly known tert-butyldimethylchlorosilane in the art, imidazole is the commonly known imidazole in the art, N,N-dimethylformamide is the commonly known N,N-dimethylformamide in the art, water is the commonly known deionized water in the art, and ethyl acetate is the commonly known ethyl acetate in the art.

[0033] In this embodiment, the concentration and recrystallization methods are both commonly known in the art.

[0034] The structural formula of intermediate A is .

[0035] The NMR data for intermediate A of the product were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.36 (m, 1H), 7.25 – 7.16 (m, 3H), 4.44 (q, 1H), 4.12 (d, 1H), 3.01 (dd, 1H), 2.88 (dd, 1H), 1.48 (s, 2H), 0.90(s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 144.4, 140.1, 127.6, 126.7, 124.8, 124.6, 75.3, 59.5, 39.2, 25.8, 18.2, -4.6, -4.8.

[0036] Step 2, Preparation of intermediate B: 6.6 g of intermediate A, 3.7 g of bis(trichloromethyl) carbonate, and 35 mL of xylene were added to a round-bottom flask equipped with a reflux condenser and the mixture was heated to 120 °C for 2 h. The reaction was monitored by gas phase, and the reaction was stopped when the conversion rate of intermediate A reached 95%. After the reaction was completed, the reaction solution was extracted 2-3 times with water and ethyl acetate. The organic phases were combined, concentrated, and recrystallized to obtain 12.6 g of white solid intermediate B, with a yield of 91%.

[0037] In this embodiment, the bis(trichloromethyl) carbonate is a commonly known bis(trichloromethyl) carbonate in the art, the xylene is a commonly known xylene in the art, the reflux condenser is a commonly known reflux condenser in the art, and the gas phase monitoring reaction method is a commonly known gas phase monitoring reaction method in the art.

[0038] The structural formula of intermediate B is .

[0039] The NMR data for intermediate B of the product were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.30 – 7.20 (m, 4H), 7.14 – 7.04 (m, 4H), 6.48 (s, 2H), 5.01 (d, 2H), 4.76 (m, 2H), 3.23 (dd, 2H), 2.98 (dd, 2H), 0.96(s, 18H), 0.13 (s, 6H), 0.12 (s, 6H); 13 C NMR (101 MHz, DMSO-d6) δ 157.6, 143.4, 139.9, 128.2, 126.1, 124.5, 76.1, 68.8, 37.9, 30.8, 25.9, -2.6, -2.8.

[0040] Step 3, Preparation of intermediate C: 2.3 g of malonic acid, 11.4 g of benzotriazol-1-yl-oxytripyrrolidinephosphide (PyBOP), 2.22 g of triethylamine, and 50 mL of acetonitrile were added to a round-bottom flask and stirred at room temperature for 1 h. Then, 11.6 g of intermediate B was added, and the reaction was continued at room temperature for 1.5 h. The reaction was monitored by gas phase, and the reaction was stopped when the conversion rate of intermediate B reached 98%. After the reaction was completed, the reaction solution was extracted 2-3 times with water and ethyl acetate. The organic phases were combined and washed successively with 10 wt.% dilute hydrochloric acid and 5 wt.%-8 wt.% saturated sodium bicarbonate solution to obtain the washed organic phase. The washed organic phase was then concentrated and recrystallized to obtain 11.7 g of white solid intermediate C, with a yield of 90%.

[0041] In this embodiment, the malonic acid used is malonic acid commonly known in the art; the benzotriazol-1-yl-oxytripyrrolidine phosphorus hexafluorophosphate used is benzotriazol-1-yl-oxytripyrrolidine phosphorus commonly known in the art; the triethylamine used is triethylamine commonly known in the art; the acetonitrile used is acetonitrile commonly known in the art; the 10 wt.% dilute hydrochloric acid used is dilute hydrochloric acid commonly known in the art; and the 5 wt.% to 8 wt.% saturated sodium bicarbonate solution used is saturated sodium bicarbonate solution commonly known in the art.

[0042] The structural formula of intermediate C is .

[0043] The NMR data for intermediate C of the product were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.28 – 7.21 (m, 4H), 7.16 – 7.05 (m, 4H), 5.52 (d, 2H), 4.81 (m, 2H), 3.75 (s, 2H), 3.25 (dd, 2H), 2.96 (dd, 2H), 0.98(s, 18H), 0.21(s, 6H), 0.20(s, 6H); 13 C NMR (101 MHz, CDCl3) δ 165.5, 150.7, 144.2, 139.1, 129.0, 126.5, 124.3, 73.4, 69.3, 41.1, 37.8, 30.9, 25.8, -2.1, -2.0.

[0044] Step 4, Preparation of chiral catalyst: 2.1 g of tin dioxide was dissolved in 10 mL of a mixed solvent of dioxane and water (volume ratio of dioxane to water: 15:1) to obtain a tin dioxide solution. At room temperature, 10.8 g of intermediate C was dissolved in 15 mL of dioxane and then added dropwise to the tin dioxide solution. After the addition was complete, the reaction was heated for 3 h at 75 °C. The reaction was monitored in the gas phase. The reaction was stopped when the conversion rate of intermediate C reached 98%. Then, 2.9 g of trifluoroacetic acid was added to the system, and the reaction was stopped after stirring at room temperature for 1 h. After the reaction was completed, 10 mL of a 10 wt.% NaOH aqueous solution was added to adjust the pH of the reaction system to 7. The reaction solution was filtered, and the filtrate was collected, concentrated, and recrystallized to obtain 5.8 g of pink solid chiral catalyst, with a yield of 80% and a purity of 98%.

[0045] In this embodiment, tin dioxide is tin dioxide commonly known in the art, dioxane is dioxane commonly known in the art, and trifluoroacetic acid is trifluoroacetic acid commonly known in the art.

[0046] The structural formula of the chiral catalyst is: .

[0047] The overall synthetic route for chiral catalysts is as follows: ; The NMR data for the product chiral catalyst are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.27 – 7.12 (m, 8H), 5.36 (s, 2H), 4.98 – 4.91 (m, 2H), 4.72 – 4.63 (m, 2H), 3.91 (s, 2H), 2.83 – 2.75 (m, 2H), 2.62 –2.48 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 164.62, 150.59, 137.89, 135.26, 129.36126.63, 126.18, 124.30, 53.28, 40.94, 29.46; Specific rotation [α] D 25 = +106° (c 1.0, CHCl3).

[0048] The yield of chiral di-tert-butylsulfinic acid sulfonate 2a prepared by the method in this embodiment was 95%; the optical purity ee was 96%. The high performance liquid chromatography (HPLC) chromatograms are shown in Figure 1(a) and Figure 1(b) (HPLC chromatogram test conditions: Chiralcel AS-H column; mobile phase, n-hexane and isopropanol (n-hexane:isopropanol volume ratio of 97:3), flow rate of 1.0 mL / min; detection wavelength of 254 nm, retention time of 19.73 min and 26.46 min).

[0049] The NMR data for product chiral di-tert-butylsulfinate thioester 2a are as follows: 1 H NMR (400MHz, CDCl3): δppm 1.56 (s, 9H), 1.38 (s, 9H); 13 C NMR (101MHz, CDCl3): δ 59.3, 48.5, 32.2, 24.1.

[0050] Specific rotation [α] D 25 = +7.8° (c 1.0, CHCl3).

[0051] Example 2: This embodiment provides a method for preparing chiral sulfinic acid thioesters by asymmetric oxidation. The chiral sulfinic acid thioesters prepared are in the hundreds of grams range. The chiral sulfinic acid thioesters obtained by this method are abbreviated as 2a. The method specifically includes the following steps: 101.7 g of di-tert-butyl disulfide and 2.4 g of chiral catalyst were dissolved in 300 mL of chloroform. 5 mL of 30 wt.% hydrogen peroxide was added dropwise at 0 °C. The mixture was stirred at 0 °C for 3 h, and the reaction was monitored in the gas phase. The reaction was stopped when the di-tert-butyl disulfide was completely converted. The resulting reaction solution was concentrated to obtain a crude product. The crude product was purified by vacuum distillation to obtain 102 g of the colorless liquid product, chiral di-tert-butyl sulfinic acid sulfate 2a.

[0052] In this embodiment, the structural formula of the product chiral di-tert-butyl sulfinic acid sulfide 2a, the reaction formula for preparing chiral di-tert-butyl sulfinic acid sulfide 2a, the chiral catalyst, the preparation method of the chiral catalyst, and the test conditions for optical purity ee are all the same as in Example 1.

[0053] The yield of chiral di-tert-butylsulfinic acid sulfonate 2a prepared by the method in this embodiment was 92% and the optical purity ee was 96%.

[0054] Example 3: This embodiment provides a method for preparing chiral sulfinic acid thioesters by asymmetric oxidation. The chiral sulfinic acid thioesters prepared are in the gram range, and the chiral sulfinic acid thioesters obtained by this method are abbreviated as 2b.

[0055] The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation in this embodiment is basically the same as that in Example 1, except that the raw material in this embodiment is changed from "1.78g di-tert-butyl disulfide" to "2.46g dibenzyl disulfide".

[0056] In this embodiment, the dibenzyl disulfide used is a commonly known dibenzyl disulfide in the art.

[0057] The structural formula of the product chiral dibenzyl sulfinate 2b is as follows: .

[0058] In this embodiment, the reaction formula for preparing chiral di-tert-butylsulfinic acid thioester 2b is basically the same as that in Example 1, the only difference being that R is benzyl.

[0059] In this embodiment, the chiral catalyst, the preparation method of the chiral catalyst, and the test conditions for optical purity ee are the same as in Example 1.

[0060] The preparation method in this embodiment yielded 2.54 g of the colorless liquid product chiral dibenzylsulfinic acid thioester 2b.

[0061] The yield of chiral dibenzyl sulfinic acid thioester 2b prepared by the method in this embodiment was 97%, and the optical purity ee was 93%.

[0062] The NMR data for the product chiral dibenzylsulfinate thioester 2b are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.44 – 7.28 (m, 10H), 4.39 – 4.21 (m, 4H); 13 C NMR (101MHz, CDCl3): δ 139.6, 133.2, 130.8, 128.7, 128.5, 127.7, 127.1, 125.7, 59.8, 36.2.

[0063] Specific rotation [α] D 25 = +9.6° (c 1.0, CHCl3).

[0064] Example 4: This embodiment provides a method for preparing chiral sulfinic acid thioesters by asymmetric oxidation. The chiral sulfinic acid thioesters prepared are in the gram range, and the chiral sulfinic acid thioesters obtained by this method are abbreviated as 2c.

[0065] The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation in this embodiment is basically the same as that in Example 1, except that the raw material is changed from "1.78g di-tert-butyl disulfide" to "2.18g diphenyl disulfide"; and the reaction time is changed from "stopping the reaction when the raw material di-tert-butyl disulfide is completely converted" to "stopping the reaction when the conversion rate of the raw material diphenyl disulfide is 95%".

[0066] In this embodiment, the diphenyl disulfide used is a commonly known diphenyl disulfide in the art.

[0067] The structural formula of the product chiral diphenylsulfinic acid thioester 2c is as follows: .

[0068] In this embodiment, the reaction formula for preparing chiral diphenylsulfinic acid thioester 2c is basically the same as that in Example 1, the only difference being that R is phenyl.

[0069] In this embodiment, the chiral catalyst, the preparation method of the chiral catalyst, and the test conditions for optical purity ee are the same as in Example 1.

[0070] The preparation method in this embodiment yielded 2.11 g of the colorless liquid product chiral diphenylsulfinic acid thioester 2c.

[0071] The yield of chiral diphenylsulfinic acid thioester 2c prepared by the method in this embodiment was 90%, and the optical purity ee was 88%.

[0072] The NMR data for the product, chiral diphenylsulfinic acid thioester 2c, are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.65 (m, 2H), 7.54 – 7.37 (m, 8H); 13 C NMR (101MHz, CDCl3): δ 144.6, 135.2, 131.9, 130.7, 130.0, 129.6, 129.3, 124.6.

[0073] Specific rotation [α] D 25 = +7.3° (c 1.0, CHCl3).

[0074] Example 5: This embodiment provides a method for preparing chiral sulfinic acid thioesters by asymmetric oxidation. The chiral sulfinic acid thioesters prepared are in the gram range, and the chiral sulfinic acid thioesters obtained by this method are abbreviated as 2d.

[0075] The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation in this embodiment is basically the same as that in Example 1, except that: the raw material in this embodiment is changed from "1.78g di-tert-butyl disulfide" to "1.46g diallyl disulfide"; and the reaction time is changed from "stopping the reaction when the raw material di-tert-butyl disulfide is completely converted" to "stopping the reaction when the conversion rate of the raw material diallyl disulfide is 98%".

[0076] In this embodiment, diallyl disulfide is a commonly used diallyl disulfide known in the art.

[0077] The structural formula of the product chiral diallyl sulfinic acid thioester 2d is as follows: .

[0078] In this embodiment, the reaction formula for preparing chiral diallyl sulfinic acid thioester 2d is basically the same as that in Example 1, the only difference being that R is allyl.

[0079] In this embodiment, the chiral catalyst, the preparation method of the chiral catalyst, and the test conditions for optical purity ee are the same as in Example 1.

[0080] The preparation method in this embodiment yielded 1.49 g of the colorless liquid product chiral diallyl sulfinic acid thioester 2d.

[0081] The yield of chiral diallyl sulfinic acid thioester 2d prepared by the method in this embodiment was 92%, and the optical purity ee was 91%.

[0082] The 2-day NMR data for the product, chiral diallyl sulfinate thioester, are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.07 – 5.78 (m, 1H), 5.56 – 5.03 (m, 2H), 4.04 – 3.71 (m, 2H); 13 C NMR (101MHz, CDCl3): δ 133.0, 125.9, 124.2, 119.2, 60.0, 35.2.

[0083] Specific rotation [α] D 25 = +6.9° (c 1.0, CHCl3).

[0084] Example 6: This embodiment provides an application of a chiral sulfinic acid thioester in the preparation of a chiral tert-butyl sulfinamide. The preparation method of the chiral tert-butyl sulfinamide (3) in this embodiment specifically includes the following steps: Add 80 mL of liquid ammonia to a 200 mL Shrek tube, slowly add 1.4 g of lithium sheet, and simultaneously cool the reaction system with a -78 °C cold bath to keep the reaction system at a gentle boil. After adding the lithium sheet, keep the reaction system at -78 °C and continue stirring for 10 minutes to obtain an aminolithium solution. 15.5 g of the chiral di-tert-butylsulfinic acid thioester 2a obtained by the method in Example 1 was dissolved in 20 mL of tetrahydrofuran (THF) and then slowly added dropwise to a freshly prepared aminolithium solution. After the addition was completed, the mixture was stirred for 10 minutes. Then, 12.8 g of ammonium chloride was slowly added. The cold bath was removed, and the reaction system was stirred until it returned to room temperature. The reaction was then stopped.

[0085] Most of the solvent was removed by vacuum distillation. The remaining liquid was extracted 2-3 times with water and ethyl acetate. The organic phase was collected and concentrated to obtain a pale yellow crude solid product. 40 mL of n-hexane was added for recrystallization to obtain 8.5 g of white solid product, chiral tert-butylsulfinamide.

[0086] In this embodiment, the Shrek tube is a Shrek tube commonly known in the art, the liquid ammonia is liquid ammonia commonly known in the art, the lithium sheet is lithium sheet commonly known in the art, the tetrahydrofuran is tetrahydrofuran commonly known in the art, the ammonium chloride is ammonium chloride commonly known in the art, and the n-hexane is n-hexane commonly known in the art.

[0087] The reaction formula for preparing chiral tert-butylsulfinamide in this embodiment is as follows: ; The yield of chiral tert-butyl sulfinamide prepared by the method in this embodiment was 88%; the optical purity ee was 99.5%.

[0088] In this embodiment, the test conditions for optical purity ee are the same as those for optical purity ee in Example 1.

[0089] The NMR data for the product, chiral tert-butyl sulfinamide, are as follows: 1 H NMR (400MHz, CDCl3): δppm 1.18(s, 9H), 3.82(s, 2H); 13 C NMR (101MHz, CDCl3): δ 55.3, 22.1.

[0090] Specific rotation [α] D 25= +4.9°(c 1.0, CHCl3)。

Claims

1. A method for preparing chiral sulfinic acid thioesters by asymmetric oxidation, characterized in that, This method uses disulfide compounds as raw materials, chiral aminoindanol-derived tetraoxazine compounds as chiral catalysts, and hydrogen peroxide or oxygen as oxidants to prepare chiral sulfinic acid thioesters through asymmetric oxidation. The temperature for preparing chiral sulfinic acid thioesters is -40℃ to 25℃; The structural formula of the chiral catalyst is: .

2. The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation as described in claim 1, characterized in that, The method specifically includes the following steps: dissolving disulfide compounds and chiral catalysts in a solvent, adding an oxidant and stirring for 1 to 6 hours at room temperature or below, monitoring the reaction in the gas phase, stopping the reaction when the conversion rate of disulfide compounds is greater than or equal to 95%, concentrating and purifying the obtained reaction solution to obtain the product chiral sulfinic acid thioester.

3. The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation as described in claim 2, characterized in that, The purification methods include column chromatography or vacuum distillation.

4. The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation as described in claim 2, characterized in that, The solvents include chloroform, dichloromethane, acetone, or ethyl acetate.

5. The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation as described in claim 1, characterized in that, The molar ratio of the chiral catalyst to the disulfide compound is (0.1% to 5%):

1.

6. The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation as described in claim 1, characterized in that, The molar ratio of the oxidant to the disulfide compound is (0.9–1.1):

1.

7. The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation as described in claim 1, characterized in that, The disulfide compounds mentioned are di-tert-butyl disulfide, dibenzyl disulfide, diphenyl disulfide, or diallyl disulfide.

8. The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation as described in claim 1, characterized in that, The preparation method of the chiral catalyst specifically includes the following steps: Step 1, Preparation of intermediate A: Aminoindol, tert-butyldimethylchlorosilane, imidazole, and solvent were added to a round-bottom flask and reacted at room temperature for 8–10 h to ensure complete conversion of the starting materials. The reaction was then stopped. The molar ratio of aminoindol, tert-butyldimethylchlorosilane, imidazole, and solvent was 1:1.05:1.1:(3–10). After the reaction was complete, the reaction solution was extracted 2–3 times with water and ethyl acetate. The combined organic phases were concentrated and recrystallized to obtain a white solid intermediate, A. Step 2, Preparation of intermediate B: Intermediate A, bis(trichloromethyl) carbonate, and solvent were added to a round-bottom flask equipped with a reflux condenser and heated for 2–4 hours at a temperature of 110–120°C. The reaction was monitored in the gas phase, and the reaction was stopped when the conversion rate of intermediate A was greater than or equal to 98%. The molar ratio of intermediate A, bis(trichloromethyl) carbonate, and solvent was 1:0.5:(3–10). After the reaction was completed, the reaction solution was extracted 2–3 times with water and ethyl acetate. The combined organic phases were concentrated and recrystallized to obtain a white solid product, intermediate B. Step 3, Preparation of intermediate C: Malonic acid, benzotriazol-1-yl-oxytripyrrolidine phosphorus hexafluorophosphate, triethylamine, and solvent were added to a round-bottom flask and stirred at room temperature for 1 hour. Intermediate B was then added, and the reaction was continued at room temperature for 1–3 hours. The reaction was monitored in the gas phase, and the reaction was stopped when the conversion rate of intermediate B was greater than or equal to 98%. The molar ratio of intermediate B, malonic acid, benzotriazol-1-yl-oxytripyrrolidine phosphorus hexafluorophosphate, triethylamine, and solvent was 1:(1–1.2):(1–1.2):(1–1.2):(3–10). After the reaction was completed, the reaction solution was extracted 2–3 times with water and ethyl acetate. The organic phases were combined and washed sequentially with 10 wt.% dilute hydrochloric acid and 5 wt.%–8 wt.% saturated sodium bicarbonate solution to obtain the washed organic phase. The washed organic phase was then concentrated and recrystallized to obtain the white solid product intermediate C. Step 4, Preparation of chiral catalyst: Tin dioxide was dissolved in a mixed solvent of dioxane and water to obtain a tin dioxide solution. Intermediate C was dissolved in dioxane at room temperature and then added dropwise to the tin dioxide solution. After the addition was complete, the reaction was heated for 3–5 h at a temperature of 60–80 °C. The reaction was monitored in the gas phase. The reaction was stopped when the conversion rate of intermediate C was greater than or equal to 98%. Trifluoroacetic acid was then added to the system, and the reaction was stopped after stirring at room temperature for 1–2 h. The molar ratio of intermediate C, tin dioxide, trifluoroacetic acid, and the mixed solvent of dioxane and water was 1:(1–1.5):(1–2):(3–10). After the reaction was completed, a 10 wt.% NaOH aqueous solution was added to adjust the pH of the reaction system to 7. The reaction solution was filtered, and the filtrate was collected, concentrated, and recrystallized to obtain a pink solid chiral catalyst.

9. The method for preparing chiral sulfinic acid thioesters by asymmetric oxidation according to any one of claims 1 to 8, characterized in that, The chiral sulfinic acid thioester prepared by this method is used in the preparation of chiral tert-butyl sulfinamide.

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