Chiral selenium oxidation catalyst and application thereof in preparation of voglibose key intermediate validalanolamine

Abstract

The invention discloses a chiral selenium oxidation catalyst and application of the chiral selenium oxidation catalyst in preparation of a voglibose key intermediate validalanolamine. The high polymer loaded hexavalent chiral selenium catalyst (III) provided by the invention has relatively strong catalytic oxidation capacity and stereoselectivity, and can be used for precise stereooxidation of validamine exoalkene (IV) to prepare a 1, 2-diol compound validamine (VI) with a specific stereostructure; according to the oxidation method, hydrogen peroxide can be used as an oxidizing agent, the method is cheap, clean and safe, and the hexavalent chiral selenium catalyst (III) is simple in separation mode, can be recycled, has huge industrial application potential and is suitable for technical popularization; # imgabs0 #

Description

Technical Field

[0001] The invention relates to a chiral selenium oxidation catalyst and application thereof in the preparation of voglibose key intermediate virucamide. Background Art

[0002] Diabetes is a metabolic disorder characterized by chronic hyperglycemia caused by a variety of causes, accompanied by abnormal sugar, fat and protein metabolism caused by defects in insulin secretion or action. The main clinical symptoms of the disease are "three mores and one less", namely, drinking more, eating more, urinating more, and losing weight. Type II diabetes, also known as adult-onset diabetes, mostly develops after the age of 35-40, accounting for more than 90% of diabetic patients. Since diabetes can lead to a variety of serious complications, such as cardiovascular and cerebrovascular complications, kidney complications, eye diseases, neuropathy, diabetic foot lesions, diabetic skin lesions, etc., which can endanger the patient's life in critical cases, diabetes is listed as one of the four major difficult diseases in the world.

[0003] Voglibose (Voglibose, X) is the earliest oral hypoglycemic drug developed by Takeda Corporation of Japan. It was first launched in Japan under the trade name Basen. Later, it was launched in China as another new α-glucosidase inhibitor after acarbose. After oral administration, it can inhibit the degradation of disaccharides into monosaccharides in the last step of carbohydrate digestion, reduce the formation of D-glucose, and thus play a role in inhibiting the increase of blood sugar after meals. It is used to treat diabetes, especially type 2 diabetes. Compared with acarbose, voglibose has a series of advantages: first, voglibose has high activity, small dosage, high selectivity for α-glucosidase, and low intestinal side effects; second, its mechanism of action is to delay the formation and absorption of glucose, and the hypoglycemic effect is more stable, and it does not stimulate the secretion of insulin. Therefore, there is no hyperinsulinemia after meals, and hypoglycemia is not easy to occur; and it is equally effective when used alone or in combination with other hypoglycemic drugs. When used in combination, it can also make medication and hypoglycemic effects more synchronized.

[0004] Voglibose has become the first choice drug for the treatment of diabetes due to its good blood sugar lowering effect and low side effects, and the market demand is very huge. The chemical name is: (1S)-[1-(hydroxy),2,4,5 / 1,3]-[2-hydroxy-1-(hydroxymethyl)ethyl]amino-1-carbon-(hydroxymethyl)-1,2,3,4-cyclohexanetetraol, white to off-white crystalline powder, chemical structure X:

[0005]

[0006] The preparation method of voglibose reported earlier is to prepare it from glucose through more than ten steps of chemical reactions, with low yield, many hazardous chemical raw materials, high pollution, low yield, and it is difficult to produce it industrially. The current classic preparation method is to prepare evalidamine by fermentation, and then synthesize evalidamine (IV), the key intermediate of voglibose, valiolamine (VI) through multi-step chemical synthesis, dehydration condensation with 1,3-dihydroxyacetone, and then hydrogenation reduction to obtain voglibose. The reaction formula is as follows:

[0007]

[0008] However, in the existing production process of the intermediate virgin aminophenol (VI), due to the poor stereoselectivity of the key step of virgin aminophenol exocyclic olefin (IV) oxidation to prepare diol, the oxidation product is a 1:1 mixture, 50% of the by-product (VII) isomer is generated, and the separation cost is increased, which ultimately leads to the high price of voglibose.

[0009]

[0010] Hydrogen peroxide oxidation is one of the important directions for the development of catalytic oxidation reactions towards green chemistry. The selective oxidation of olefins is challenging in the field of catalysis. Organic selenium compounds have unique chemical reaction properties and biological activity and have been widely used in many fields such as biology, medicine, chemistry and materials. Due to the excellent oxygen atom transfer ability of selenium, low-valent selenium can be quickly oxidized and high-valent selenium can be quickly reduced. Compared with traditional transition metal catalysts, organic selenium catalysts have the following advantages:

[0011] (1) No metal residue, eco-friendly: Selenium can be metabolized by organisms and is an essential trace element. An appropriate amount of selenium in the environment is beneficial. Organic selenium-catalyzed oxidation reactions usually use clean oxidants such as hydrogen peroxide and oxygen, do not produce harmful waste, and have high atom economy.

[0012] (2) The price is low. China’s selenium resources are extremely abundant. The selenium reserves in Enshi, Hubei alone rank first in the world.

[0013] (3) The reaction system is simple and does not require ligands or additives.

[0014] Therefore, in recent years, organic selenium-catalyzed oxidation reactions have developed rapidly (Jacek M et al. Molecules, 2015, 20, 10205-10243.), for example, Baeyer-Villiger oxidation of aldehydes and ketones, oxidation of vicinal diketo carbon-carbon bonds, oxidative ring expansion reactions [, olefin dihydroxylation, hydroxyl oxidation, amino oxidation, oxidation of allylic carbon-hydrogen bonds, and oxidation of oximes to synthesize aldehydes and ketones (Zhang X. et al., Adv. Synth. Catal. 2015, 357, 955-960; Yu L. et al., Green Chem. 2014, 16, 287-293; Yu L., et al., Catal. Sci. Technol., 2016, 6, 1804-1809; Yu L. et al., Catal. Sci. Technol., 2015, 5, 4830-4838; Yu L. et al., ChemCatChem, 2016, 8, 1033-1037; Yu L. et al., Appl. Organometal. Chem. 2014, 28, 652-656.).

[0015] The catalysts used in the above reactions are zero-valent or tetravalent selenium, which still have disadvantages such as low catalytic efficiency, large catalyst dosage, and slow reaction speed. Since hexavalent selenium cannot exist stably in small molecule compounds, it will quickly react with low-valent selenium to generate relatively stable tetravalent selenium ("small molecule effect"). The present invention immobilizes chiral selenium compounds on polystyrene resins, thereby avoiding the "small molecule effect", developing high-performance hexavalent chiral selenium catalysts, and using hydrogen peroxide as an oxidant to achieve efficient, highly selective clean oxidation of jinggangmycinamine exocyclic olefins (IV) to prepare jinggangmycinolamine (VI), a 1,2-diol compound with a specific stereostructure. Summary of the invention

[0016] The present invention aims to provide a chiral selenium oxidation catalyst and its application in the preparation of voglibose key intermediate virucamide.

[0017] The technical solution of the present invention is as follows:

[0018] A chiral selenium oxidation catalyst, as shown in formula (III):

[0019]

[0020] In formula (III), It represents 1% cross-linked polystyrene resin (those skilled in the art should understand that, in fact, PS (polystyrene) is composed of evenly distributed phenyl groups, and only one is drawn in the structural formula as a schematic diagram).

[0021] The preparation method of the chiral selenium oxidation catalyst of the present invention is as follows:

[0022] S1, 1% cross-linked polystyrene resin (I) is lithiationed with n-butyl lithium, and then undergoes selenization reaction with chiral selenium reagent D to obtain chiral selenoether resin (II);

[0023] S2, the chiral selenoether resin (II) is oxidized with hydrogen peroxide to obtain a chiral selenium oxidation catalyst (III);

[0024] The reaction formula is as follows:

[0025]

[0026] The structural formula of chiral selenium reagent D is as follows:

[0027]

[0028] Specifically, the S1 operation method is as follows:

[0029] Under nitrogen protection, 1% cross-linked polystyrene resin (I) is soaked in cyclohexane for 8-12 hours, then tetramethylethylenediamine (TMEDA) and n-butyl lithium are added at room temperature with stirring, the temperature is raised to 65-70°C for reaction for 4 hours, cooled to room temperature, filtered under nitrogen protection, the filtered resin is mixed with anhydrous tetrahydrofuran, cooled to 0°C, chiral selenium reagent D is added under stirring, the temperature is maintained at 0°C for reaction for 40 minutes, and after post-treatment, a chiral selenoether resin (II) is obtained;

[0030] The 1% cross-linked polystyrene resin (I) was washed as follows before use: 1% cross-linked polystyrene resin (I) was washed with sodium hydroxide (1M), hydrochloric acid (1M), sodium hydroxide (2M) / dioxane (1:2), water, and N,N-dimethylformamide, respectively, at 70°C for 1 hour each, and then washed with hydrochloric acid (2M) / methanol, water, methanol, and methanol / dichloromethane (1:10) at room temperature for 1 hour each, filtered, drained, and vacuum dried at 65°C for 24 hours for use;

[0031] Preferably, the feed ratio of 1% cross-linked polystyrene resin (I), tetramethylethylenediamine, n-butyllithium, and chiral selenium reagent D is 8 g: 74.4 mmol: 96 mmol: 10.0 mmol;

[0032] n-Butyl lithium is fed in the form of a solution dissolved in n-hexane;

[0033] The specific post-treatment method is as follows: after the reaction is completed, quench with water, filter, wash with tetrahydrofuran, water, methanol, dichloromethane, and diethyl ether in sequence, drain the solvent, and dry under vacuum at 65° C. for 24 hours to obtain chiral selenoether resin (II).

[0034] Specifically, the S2 operation method is as follows:

[0035] The chiral selenoether resin (II) is soaked in tetrahydrofuran, and hydrogen peroxide is added under stirring, and the mixture is reacted at room temperature for 4 hours, and then filtered, washed, and dried to obtain a chiral selenium oxidation catalyst (III);

[0036] Preferably, the amount of hydrogen peroxide used is 9 molar equivalents of selenium in the chiral selenoether resin (II);

[0037] The specific washing and drying methods are as follows: after filtering, washing with tetrahydrofuran, water, methanol, dichloromethane (2×20 mL), and ether in sequence, draining off the solvent, and vacuum drying at 65° C. for 24 h to obtain a chiral selenium oxidation catalyst (III).

[0038] The chiral selenium oxidation catalyst of the present invention can be applied to the preparation of visamicinolamine, a key intermediate of voglibose.

[0039] The specific application methods are as follows:

[0040] The chiral selenium oxidation catalyst (III) was soaked in tetrahydrofuran for 2 hours, and the amine exocyclic olefin (IV) and p-toluenesulfonic acid were added under stirring, and the temperature was lowered to 0°C, and an oxidant was added, and the temperature was naturally raised to room temperature for reaction for 1 to 5 hours, and then the temperature was raised to 40 to 70°C for reaction for 1 to 12 hours, and the temperature was cooled to room temperature, filtered, and the filter cake (chiral selenium oxidation catalyst, which can be recycled after washing with THF) and the filtrate (containing compound V) were collected respectively; the filtrate was taken, and an aqueous solution of barium hydroxide octahydrate was added, and the mixture was refluxed under stirring for 3 hours, and then the tetrahydrofuran was evaporated, water was added, and carbon dioxide gas was introduced until the pH was 7 (precipitate was generated), filtered, washed with water, and the combined filtrate was added to CG-50 resin (NH4 + , 70 mL) column, washed with pure water, and then washed with 0.4 M ammonia water, concentrated, and then passed through DOWEX 1×2 resin (OH - , 70 mL), washed with water, the product-containing portion was collected, and freeze-dried to obtain Jinggangmycin amine (VI);

[0041] The feed ratio of Jinggangmycin amine exocyclic olefin (IV) to chiral selenium oxidation catalyst (III) is 10:0.1-0.3, mmol / g;

[0042] The amount of p-toluenesulfonic acid used is 1 to 3% of the molar amount of the amine exocyclic olefin (IV);

[0043] The amount of the oxidant is 2 to 10 molar equivalents of the amine exocyclic olefin (IV); the oxidant is selected from hydrogen peroxide, tert-butyl hydroperoxide, m-chloroperbenzoic acid, etc.;

[0044] The amount of barium hydroxide octahydrate used is 4 molar equivalents of the amine exocyclic olefin (IV).

[0045] The reaction formula is as follows:

[0046]

[0047] In formula (IV) and formula (V), R 1 is benzyl or tert-butyl, and R is acetyl or benzoyl.

[0048] The technical principles of the present invention include:

[0049] The selenium oxidation catalysts reported so far are zero-valent or tetravalent selenium, which have the disadvantages of low catalytic efficiency, large catalyst dosage, slow reaction speed, etc. compared with high-valent hexavalent selenium. Since hexavalent selenium cannot stably exist in small molecule compounds, it will quickly react with low-valent selenium to generate relatively stable tetravalent selenium ("small molecule effect"). The present invention immobilizes chiral selenium compounds on polystyrene resin (I), thereby avoiding the "small molecule effect" and developing a high-performance hexavalent chiral selenium catalyst (III). Furthermore, the present invention uses hydrogen peroxide as an oxidant to achieve efficient and highly selective clean oxidation of jinggangmycinamine exocyclic olefin (IV) to prepare jinggangmycinolamine (VI), a 1,2-diol compound with a specific stereostructure.

[0050] In addition to having strong catalytic oxidation ability, this polymer-supported hexavalent chiral selenium catalyst (III) also has excellent stereoselectivity due to the "steric effect" of polystyrene and the "chiral effect" of the chiral group. Therefore, the hexavalent chiral selenium catalyst (III) prepared by the present invention can be used for the precise stereooxidation of the cyclopentadienylamine (IV) to prepare the 1,2-diol compound cyclopentadienylamine (VI) with a specific stereostructure. In addition, hydrogen peroxide is a cheap, safe and clean oxidant. This discovery lays the foundation for the development of more efficient selenium oxidation catalysts. It contains huge industrial application potential and is worthy of further in-depth research on its industrial application and technology promotion.

[0051] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0052] (1) The present invention provides a new hexavalent chiral selenium catalyst (III);

[0053] (2) This polymer-supported hexavalent chiral selenium catalyst (III) has strong catalytic oxidation ability and stereoselectivity, and can be used for the precise stereooxidation of the exocyclic olefin (IV) of jinggangmycinamine to prepare 1,2-diol compounds with specific stereostructures, jinggangmycinolamine (VI);

[0054] (3) The hexavalent chiral selenium catalyst (III) is easy to separate and can be recycled;

[0055] (4) This oxidation method uses hydrogen peroxide as an oxidant, which is cheap, clean, and safe. It has great industrial application potential and is suitable for industrial application and technology promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 : X-ray photoelectron spectroscopy (XPS) test diagram of polystyrene resin supported chiral selenium oxidation catalyst (III). DETAILED DESCRIPTION

[0057] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention is not limited thereto.

[0058] In the following embodiments,

[0059] 1% cross-linked polystyrene resin was purchased from Tianjin Nankai Hecheng Technology Co., Ltd.;

[0060] Chiral reagent A, i.e., (S)-1-(2-bromophenyl)ethanol, was purchased from Sane Chemical Technology (Shanghai) Co., Ltd.;

[0061] The compound of formula IV was synthesized according to the method in the literature (Cabohydrate Research, 1985, 140, 185-200).

[0062] Example 1: Preparation of chiral selenium oxidation catalyst

[0063] (1) Preparation of chiral selenium reagent D

[0064] The reaction formula is as follows:

[0065]

[0066] Under nitrogen atmosphere, weigh 6.88g (34.2mmol) of chiral compound A into a flask, dissolve it with 60ml THF, stir, and cool the solution to 0℃. Carefully add NaH (60%, dispersed in paraffin liquid, 1.642g, 41.0mmol) washed with anhydrous n-hexane (wash twice, 15ml each time), and stir the mixture for 0.5 hours. Then add 2.6mL MeI (42mmol) to the reaction system, warm the resulting mixture to room temperature, and continue to stir and react for 4 hours. After the reaction is completed, add 100mL of water and extract with ethyl acetate three times, 80mL each time. Combine the organic phases, wash once with water, and dry the organic phase with anhydrous sodium sulfate. After evaporating the organic solvent, the residue is purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1, Rf value 0.4-0.5), and the molar yield of the target compound B is 91%.

[0067] Under nitrogen atmosphere, weigh 0.528g (22mmol) of fresh magnesium powder and add 50mL of anhydrous THF. Dissolve 4.30g (20mmol) of compound B in 10mL of THF and transfer to a constant pressure titration funnel. First, drip about 1mL into the reaction, then add a small particle of I2 and heat with a hair dryer to initiate the reaction. After the reaction is initiated, drop compound B into the reaction. After the addition is complete, the reaction system is heated and reacted in reflux for 3 hours. Add 1.66g (21mmol) of dry selenium powder to the reaction in batches and continue stirring the reaction for 2 hours. The reactant was poured into an appropriate amount of ice-water mixture, the pH was adjusted to 5-6 with 3N hydrochloric acid, and then extracted with methyl tert-butyl ether (80mL×2), transferred to a three-necked flask, stirred, and air was introduced under the liquid surface at 40°C for 48 hours (or oxygen for 12 hours). After the oxidation was complete, the solvent was evaporated to obtain a yellow solid, which was recrystallized with methyl tert-butyl ether and ethanol (volume ratio = 1:4) to obtain chiral selenium reagent D with a molar yield of 73%. Its characterization is as follows:

[0068] =+54.5o(c=1,CHCl3);MS(ESI)m / z431(M+1) + ; 1 H NMR (500MHz, CDCl3): 1.46 (d, J=6.5Hz, 6H), 3.22 (s, 6H), 4.74 (q, J=6.5Hz, 2H), 7.16 (dd, J=7.5H z,J=7.5Hz,2H),7.28(dd,J=7.5Hz,.1=7.5Hz,2H),7.35(d,J=6.5Hz,2H),7.74(d,J=7.5Hz,2H); 77 SeNMR: δ427.7.

[0069] (2) Preparation of polystyrene resin supported chiral selenium oxidation catalyst III

[0070] The reaction formula is as follows:

[0071]

[0072] (a) Washing treatment of polystyrene resin I

[0073] Polystyrene resin I was washed with sodium hydroxide (1M) twice the volume of the resin, hydrochloric acid (1M), sodium hydroxide (2M) / dioxane (1:2), water, and N,N-dimethylformamide, stirred and washed at 70°C for 1 hour each. Then, it was washed with hydrochloric acid (2M) / methanol, water, methanol, and methanol / dichloromethane (1:10) stirred and washed at room temperature for 1 hour each. Filter, drain, and vacuum dry at 65°C for 24 hours.

[0074] (b) Preparation of Chiral Selenide Resin II

[0075] Under nitrogen protection, 8g of washed 1% cross-linked polystyrene was first soaked in 60mL cyclohexane overnight, and 11.2mL (74.4mmol) tetramethylethylenediamine (TMEDA) and 53.4mL (96mmol) n-butyllithium solution (1.80M) were added under stirring at room temperature, and the reaction mixture was heated to 65-70℃ and reacted for 4h. After the resin lithiation reaction was completed, it was cooled, filtered under nitrogen protection, and the resin was washed with anhydrous tetrahydrofuran (3×20mL), and then the resin was transferred back to the reaction bottle with 80mL anhydrous tetrahydrofuran. The resin / tetrahydrofuran mixture was cooled to 0℃, and selenium reagent D (10.0mmol) was slowly added under stirring. The reaction mixture gradually became lighter, and after maintaining 0℃ for 40min, the reaction was quenched with 4mL water, and the resin turned yellow. The mixture was filtered and washed with tetrahydrofuran (2×20 mL), water, methanol (2×20 mL), dichloromethane (2×20 mL) and diethyl ether (2×20 mL) in sequence. The solvent was drained and dried under vacuum at 65°C for 24 h to obtain chiral selenoether resin II.

[0076] (c) Preparation of polystyrene resin supported chiral selenium oxidation catalyst III

[0077] The chiral selenoether resin II prepared in step (b) was soaked with THF twice the volume of the resin, stirred, and 9.0 equivalents of hydrogen peroxide were added, reacted at room temperature for 4 hours, and the resin turned white. Filtered, washed with tetrahydrofuran (2×20mL), water, methanol (2×20mL), dichloromethane (2×20mL) and ether (2×20mL) in sequence, the solvent was drained, and vacuum dried at 65°C for 24h to obtain chiral selenium oxidation catalyst III.

[0078] The characterization of the selenium valence state of chiral selenium oxidation catalyst III is shown in the attached Figure 1 Experimental conditions: The samples were analyzed using a VG Scientific ESCALab220i-XL photoelectron spectrometer. The excitation source was AlKα X-ray with a power of about 300 W. The basic vacuum during analysis was 3×10 -9 mbar. The electron binding energy is corrected by the C1s peak (284.6eV) of contaminated carbon. Analysis: The figure shows that the peak at the binding energy of 60.4eV is the 3d peak of +6 valence selenium. 5 / 2 orbital, the peak at the binding energy of 61.5 eV is the 3d 3 / 2 orbital, indicating that the selenium in the catalyst is in a +6 valence state.

[0079] Example 2: Synthesis of Jinggangmycinamine (VI)

[0080] The reaction formula is as follows:

[0081]

[0082] In the intermediates shown in formula IV and V, R1 is benzyl and R is acetyl.

[0083] 0.2 g of chiral catalyst III was soaked in 60 mL of THF for 2 hours, mechanical stirring was started, 4.194 g (10 mmol) of compound IV and 19.4 mg (0.1 mmol) of p-toluenesulfonic acid were added to the reaction, and after the reaction temperature dropped to 0°C, 9.2 mL (90 mmol) of 30% hydrogen peroxide was added dropwise thereto. After the addition was complete, the ice bath was removed, the temperature was naturally raised to room temperature and the reaction was continued for another hour, and finally the temperature was raised to 50°C and the reaction was continued for 3 hours. After the reaction was complete, stirring was stopped, the reaction mixture was cooled to room temperature, the reaction solution was filtered, the filter cake (chiral catalyst) was washed with 5 mL of THF, and then collected and recycled; the filtrate was combined, transferred to a reaction bottle, 20 mL of an aqueous solution of barium hydroxide octahydrate (2M) was added, the temperature was raised to reflux under stirring, after reflux for 3 hours, THF was evaporated, cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was introduced, a precipitate was generated, the pH was passed to about 7, filtered, the filter cake was washed with 10 mL of water, the filtrate was combined, and CG-50 resin (NH4 + , 70mL) column, washed with pure water, and then washed with 0.4M ammonia water, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH - , 70 mL), washed with water, and the product-containing portion was collected and freeze-dried to obtain 1.69 g of a white solid with a yield of 87.5%. The optical purity was 100% as determined by HPLC, and no isomers of Formula VII were detected.

[0084]

[0085] HPLC detection conditions are as follows:

[0086] (i) Instruments and reagents: Waters e2695 high performance liquid chromatograph; UV detector. Valiolamine (VI) reference substance and 4-methoxybenzenesulfonyl fluoride were purchased from Sane Chemical Technology (Shanghai) Co., Ltd. (Annaiji Chemical); epivaliolamine (VII) isomers were synthesized according to the method in the literature (Cabohydrate Research, 1985, 140, 185-200). Methanol was chromatographic grade and distilled water.

[0087] (ii) Chromatographic conditions: Chiral column: OD-3R, 3μm (filler particle size), 25cm×4.6mm; mobile phase: phase A: phosphate buffer (50mM, pH=3.0); phase B: methanol. All solutions were filtered through a 0.22M membrane filter and sonicated before use. Flow rate: 1.0mL / min; column temperature: room temperature; detection wavelength: 240nm; gradient elution: 88% phosphate buffer (50mM; pH=3.0) and 12% methanol for 23min, then 70% phosphate buffer and 30% methanol for 15min, and finally 88% phosphate buffer and 12% methanol for 5min to re-equilibrate the column.

[0088] (iii) Derivatization of analytical samples

[0089] To a glass vial with a screw cap, add 500 μL (200 mM) Na2HPO4 and 100 μL 4-methoxybenzenesulfonyl fluoride (25 mg / mL acetonitrile solution) in sequence, then add 2 mg of the sample to be tested, and mix after vortexing. Keep the mixture at 30°C for 10 minutes. After filtering through a 0.22 μm membrane, inject the mixture into the analysis system.

[0090] The characterization of mycophenolic acid (VI) is as follows:

[0091] White solid. =+19.8o(c=1,H2O).MS(ESI)m / z194(M+1) + ; 1 H NMR (500MHz, D2O): δ1.82 (m, 1H), 2.09 (m, 1H), 3.5-3.7 (m, 1H), 3.57 (d, J = 10Hz, 1H), 3.65 (s, 2H), 3.74 (dd, J = 4.2, 10Hz, 1H), 4.01 (t, J = 10Hz, 1H); 13 C NMR (125MHz, D2O): δ33.6,51.1,66.4,72.0,74.6,74.6,76.9.

[0092] Example 3: Synthesis of Jinggangmycinamine (VI)

[0093] The reaction formula is as follows:

[0094]

[0095]

[0096] In the intermediates shown in formula IV and V, R1 is benzyl and R is acetyl.

[0097] 0.2 g of chiral catalyst III was soaked in 60 mL of THF for 2 hours, and mechanical stirring was started. 4.194 g (10 mmol) of compound IV and 58.2 mg (0.3 mmol) of p-toluenesulfonic acid were added to the reaction. After the reaction cooled to 0° C., 9.7 mL (70 mmol) of 70% wt. tert-butyl hydroperoxide aqueous solution was added dropwise. After the addition was complete, the ice bath was removed, and the temperature was naturally raised to room temperature and reacted for another 4 hours. Finally, the temperature was raised to 40° C. and reacted for 1 hour. After the reaction was complete, stirring was stopped, and the reaction mixture was cooled to room temperature. The reaction solution was filtered, and the filter cake (chiral catalyst) was washed with 5 mL of 4% t-butyl hydroperoxide. After washing with THF, the mixture was collected and recycled; the filtrates were combined and transferred to a reaction bottle, 20 mL of an aqueous solution of barium hydroxide octahydrate (2 M) was added, and the mixture was heated to reflux under stirring. After reflux for 3 hours, THF was evaporated, the mixture was cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was introduced, and a precipitate was generated. The mixture was passed until the pH was about 7, and the precipitate was filtered. The filter cake was washed with 10 mL of water, the filtrates were combined, and CG-50 resin (NH4 + , 70mL) column, washed with pure water, and then washed with 0.4M ammonia water, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH - , 70 mL), washed with water, and the product-containing portion was collected and freeze-dried to obtain 1.70 g of a white solid with a yield of 88.0%. The optical purity was 100% as determined by HPLC, and no isomers of Formula VII were detected. The HPLC detection conditions were the same as those in Example 2.

[0098] Example 4: Synthesis of Jinggangmycinamine (VI)

[0099] The reaction formula is the same as that of Example 2. In the intermediates shown in formula IV and V, R1 is benzyl and R is acetyl.

[0100] 0.3 g of chiral catalyst III was soaked in 70 mL of THF for 2 hours. With mechanical stirring, 4.194 g (10 mmol) of compound IV and 19.4 mg (0.1 mmol) of p-toluenesulfonic acid were added to the reaction. After the reaction temperature dropped to 0° C., 17.3 mL (100 mmol) of m-chloroperbenzoic acid (MCPBA) was carefully added in batches. Remove the ice bath, naturally raise the temperature to room temperature and react for another 3 hours, finally raise the temperature to 60°C and react for 5 hours, stop stirring, cool to room temperature, filter the reaction solution, wash the filter cake (chiral catalyst) with 5 mL chloroform and 5 mL THF, collect and recycle; combine the filtrates, transfer to a reaction bottle, add 20 mL of octahydrate barium hydroxide aqueous solution (2M), raise the temperature to reflux under stirring, reflux for 3 hours, evaporate THF, cool to room temperature, add water to about 50 mL, pass carbon dioxide gas, precipitate is generated, pass to pH about 7, filter, wash the filter cake with 10 mL water, combine the filtrates, and apply CG-50 resin (NH4 +, 70mL) column, washed with pure water, and then washed with 0.4M ammonia water, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH - , 70mL), washed with water, collected the product-containing portion, and freeze-dried to obtain 1.32g of a white solid with a yield of 68.2%. The optical purity was 100% as determined by HPLC, and no isomers of Formula VII were detected. The HPLC detection conditions were the same as those in Example 2.

[0101] Example 5: Synthesis of Jinggangmycinamine (VI)

[0102] The reaction formula is as follows:

[0103]

[0104]

[0105] In the intermediates shown in formula IV and V, R1 is tert-butyl and R is benzoyl.

[0106] 0.2 g of chiral catalyst III was soaked in 60 mL of THF for 2 hours, and mechanical stirring was started. 4.194 g (10 mmol) of compound IV and 38.8 mg (0.2 mmol) of p-toluenesulfonic acid were added to the reaction. After the reaction cooled to 0° C., 11.1 mL (80 mmol) of 70% wt. tert-butyl hydroperoxide aqueous solution was added dropwise. After the addition was complete, the ice bath was removed, and the temperature was naturally raised to room temperature and reacted for another 5 hours. Finally, the temperature was raised to 40° C. and reacted for 3 hours. After the reaction was complete, stirring was stopped, and the reaction mixture was cooled to room temperature. The reaction solution was filtered, and the filter cake (chiral catalyst) was washed with 5 mL of 4% ethanol. After washing with THF, the mixture was collected and recycled; the filtrates were combined and transferred to a reaction bottle, 20 mL of an aqueous solution of barium hydroxide octahydrate (2 M) was added, and the mixture was heated to reflux under stirring. After reflux for 3 hours, THF was evaporated, the mixture was cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was introduced, and a precipitate was generated. The mixture was passed until the pH was about 7, and the precipitate was filtered. The filter cake was washed with 10 mL of water, the filtrates were combined, and CG-50 resin (NH4 + , 70mL) column, washed with pure water, and then washed with 0.4M ammonia water, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH - , 70 mL), washed with water, the product-containing portion was collected, and lyophilized to obtain 1.71 g of a white solid with a yield of 88.7%. The optical purity was 100% as determined by HPLC, and no isomers of Formula VII were detected. The HPLC detection conditions were the same as those in Example 2.

[0107] Example 6: Synthesis of Jinggangmycinamine (VI)

[0108] The reaction formula is as follows:

[0109]

[0110] In the intermediates shown in formula IV and V, R1 is benzyl and R is acetyl.

[0111] 0.2 g of chiral catalyst III was soaked in 60 mL of THF for 2 hours, mechanical stirring was started, 4.194 g (10 mmol) of compound IV and 19.4 mg (0.1 mmol) of p-toluenesulfonic acid were added to the reaction, and after the reaction temperature dropped to 0°C, 2.04 mL (20 mmol) of 30% hydrogen peroxide was added dropwise thereto. After the addition was complete, the ice bath was removed, the temperature was naturally raised to room temperature and the reaction was continued for another hour, and finally the temperature was raised to reflux for 12 hours. After the reaction was complete, stirring was stopped, the reaction mixture was cooled to room temperature, the reaction solution was filtered, the filter cake (chiral catalyst) was washed with 5 mL of THF, and then collected for recycling; the filtrate was combined, transferred to a reaction bottle, 20 mL of octahydrate barium hydroxide aqueous solution (2M) was added, the temperature was raised to reflux under stirring, after reflux for 3 hours, THF was evaporated, cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was introduced, a precipitate was generated, the pH was about 7, filtered, the filter cake was washed with 10 mL of water, the filtrate was combined, and CG-50 resin (NH4 + , 70mL) column, washed with pure water, and then washed with 0.4M ammonia water, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH - , 70 mL), washed with water, and the product-containing portion was collected and freeze-dried to obtain 1.40 g of a white solid with a yield of 72.3%. The optical purity was 100% as determined by HPLC, and no isomers of Formula VII were detected. The HPLC detection conditions were the same as those in Example 2.

[0112] Example 7: Synthesis of Jinggangmycinamine (VI)

[0113] The reaction formula is as follows:

[0114]

[0115] In the intermediates shown in formula IV, V, and V-1, R1 is benzyl and R is acetyl.

[0116] 4.194 g (10 mmol) of compound IV was added to the reaction flask, dissolved with 60 mL of THF, mechanical stirring was started, 19.4 mg (0.1 mmol) of p-toluenesulfonic acid was added to the reaction, and after the reaction cooled to 0°C, 9.2 mL (90 mmol) of 30% hydrogen peroxide was added dropwise thereto. After the addition was complete, the ice bath was removed, the temperature was naturally raised to room temperature and the reaction was continued for another 3 hours, and finally the temperature was raised to reflux for 7 hours, stirring was stopped, the temperature was cooled to room temperature, 20 mL of octahydrate barium hydroxide aqueous solution (2M) was added, the temperature was raised to reflux under stirring, after reflux for 3 hours, THF was evaporated, the reaction was cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was introduced, a precipitate was generated, the pH was passed to about 7, filtered, the filter cake was washed with 10 mL of water, the filtrate was combined, and CG-50 resin (NH4 + , 70mL) column, washed with pure water, and then washed with 0.4M ammonia water, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH - , 70mL), washed with water, and the product-containing portion was collected and freeze-dried to obtain 1.10g of white solid with a yield of 57.0%. HPLC detection showed that both epivaliolamine (VI) and epivaliolamine isomer (VII) were present, each accounting for 50%. This indicates that there is no chiral catalyst involved, and the selectivity for the oxidative hydrolysis of the double bond of compound IV is 0.

[0117] Example 8: Synthesis of Jinggangmycinamine (VI)

[0118] The reaction formula is as follows:

[0119]

[0120] In the intermediates shown in formula IV, V, and V-1, R1 is benzyl and R is acetyl.

[0121] 4.19 g (10 mmol) of compound IV was added to the reaction flask, dissolved with 95 mL of chloroform, mechanical stirring was started, 4.19 g (0.1 mmol) of anhydrous Na2HPO4 was added to the reaction, and a chloroform solution of m-chloroperbenzoic acid (2.46 g of m-chloroperbenzoic acid dissolved in 50 mL of chloroform) was added dropwise at room temperature. After the addition was complete, the mixture was refluxed for 7 hours, slowly cooled to 0°C, filtered, and then washed with 20% sodium thiosulfate, saturated sodium bicarbonate, and saturated brine in sequence, and concentrated. 70 mL of THF was added, and 20 mL of octahydrate barium hydroxide aqueous solution (2M) was added, and the mixture was heated to reflux under stirring. After reflux for 3 hours, THF was evaporated, cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was introduced, and a precipitate was generated. The pH was about 7, filtered, and the filter cake was washed with 10 mL of water. The filtrate was combined and CG-50 resin (NH4 +, 70mL) column, washed with pure water, and then washed with 0.5M ammonia water, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH - , 70mL), washed with water, and the product-containing portion was collected and freeze-dried to obtain 1.06g of white solid with a yield of 55.3%. HPLC detection showed that both epivaliolamine (VI) and epivaliolamine isomer (VII) were present, accounting for 50% each. This indicates that there is no chiral catalyst involved, and the selectivity for the oxidative hydrolysis of the double bond of compound IV is 0.

[0122] Example 9: Synthesis of Jinggangmycinamine (VI)

[0123] Recovery and regeneration of chiral catalyst III:

[0124] Collect the chiral selenium catalyst used several times, wash with tetrahydrofuran and water in the same volume as the resin, soak with THF in the same volume as the resin, start mechanical stirring, add 9.0 equivalents of hydrogen peroxide, react at room temperature for 4 hours, and the resin turns white. Filter, wash with water, methanol, tetrahydrofuran, and dichloromethane in the same volume as the resin, drain the solvent, and vacuum dry at 65°C for 24 hours to obtain chiral selenium oxidation catalyst III.

[0125]

[0126] In the intermediates shown in formula IV and V, R1 is benzyl and R is acetyl.

[0127] 0.2 g of the chiral catalyst III obtained above was soaked in 60 mL THF for 2 hours, mechanical stirring was started, 4.194 g (10 mmol) of compound IV and 19.4 mg (0.1 mmol) of p-toluenesulfonic acid were added to the reaction, and after the reaction cooled to 0°C, 9.2 mL (90 mmol) of 30% hydrogen peroxide was added dropwise thereto. After the dropping was completed, the ice bath was removed, and the temperature was naturally raised to room temperature for another 4 hours, and finally the temperature was raised to 40°C for 2 hours. After the reaction was complete, stirring was stopped, and the reaction mixture was cooled to room temperature. The reaction mixture was filtered, and the filter cake (chiral catalyst) was washed with 5 mL THF and collected for recycling; the filtrate was combined, transferred to a reaction bottle, 20 mL of octahydrate barium hydroxide aqueous solution (2M) was added, and the temperature was raised to reflux under stirring. After reflux for 3 hours, THF was evaporated, cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was introduced, and a precipitate was generated. The pH was about 7, filtered, and the filter cake was washed with 10 mL of water. The filtrate was combined and CG-50 resin (NH4 + , 70mL) column, washed with pure water, and then washed with 0.4M ammonia water, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH -, 70 mL), washed with water, and the product-containing portion was collected and freeze-dried to obtain 1.68 g of a white solid with a yield of 87.0%. The optical purity was 100% as determined by HPLC, and no isomers of Formula VII were detected. The HPLC detection conditions were the same as those in Example 2.

Claims

1. A chiral selenium oxidation catalyst, as shown in formula (III): In formula (III), Represents 1% cross-linked polystyrene resin.

2. The method for preparing a chiral selenium oxidation catalyst according to claim 1, characterized in that: The preparation method is as follows: S1, 1% cross-linked polystyrene resin (I) is lithiationed with n-butyl lithium, and then undergoes selenization reaction with chiral selenium reagent D to obtain chiral selenoether resin (II); S2, the chiral selenoether resin (II) is oxidized with hydrogen peroxide to obtain a chiral selenium oxidation catalyst (III); The structural formula of chiral selenium reagent D is as follows:

3. The method for preparing a chiral selenium oxidation catalyst according to claim 2, characterized in that: S1 operation method is as follows: Under nitrogen protection, 1% cross-linked polystyrene resin (I) was soaked in cyclohexane for 8-12 hours, and then tetramethylethylenediamine and n-butyllithium were added at room temperature with stirring, and the temperature was raised to 65-70°C for reaction for 4 hours, cooled to room temperature, and filtered under nitrogen protection. The filtered resin was mixed with anhydrous tetrahydrofuran, cooled to 0°C, and chiral selenium reagent D was added with stirring, and the temperature was maintained at 0°C for reaction for 40 minutes. After post-treatment, chiral selenoether resin (II) was obtained.

4. The method for preparing a chiral selenium oxidation catalyst according to claim 3, characterized in that: The feed ratio of 1% cross-linked polystyrene resin (I), tetramethylethylenediamine, n-butyllithium and chiral selenium reagent D is 8 g: 74.4 mmol: 96 mmol: 10.0 mmol.

5. The method for preparing a chiral selenium oxidation catalyst according to claim 2, characterized in that: S2 operation method is as follows: The chiral selenoether resin (II) is soaked in tetrahydrofuran, and hydrogen peroxide is added under stirring. The mixture is reacted at room temperature for 4 hours, and then filtered, washed, and dried to obtain a chiral selenium oxidation catalyst (III).

6. The method for preparing a chiral selenium oxidation catalyst according to claim 5, characterized in that: The amount of hydrogen peroxide used is 9 molar equivalents of selenium in the chiral selenoether resin (II).

7. Use of the chiral selenium oxidation catalyst according to claim 1 in the preparation of voglibose key intermediate virucamide.

8. The use according to claim 7, characterized in that Here’s how: The chiral selenium oxidation catalyst (III) is soaked in tetrahydrofuran for 2 hours, and the amine exocyclic olefin (IV) and p-toluenesulfonic acid are added under stirring, and the temperature is lowered to 0°C, and an oxidant is added, and the temperature is naturally raised to room temperature for reaction for 1 to 5 hours, and then the temperature is raised to 40 to 70°C for reaction for 1 to 12 hours, and the temperature is cooled to room temperature, filtered, and the filter cake and filtrate are collected respectively; the filtrate is taken, and an octahydrate barium hydroxide aqueous solution is added, and the mixture is refluxed under stirring for 3 hours, and then the tetrahydrofuran is evaporated, water is added, and carbon dioxide gas is introduced until the pH value is 7, filtered, washed with water, and the filtrate is combined and applied to a CG-50 resin column, washed with pure water, and then the product is washed with 0.4M ammonia water, concentrated, and then passed through a DOWEX 1×2 resin, washed with water, and the product-containing portion is collected, and freeze-dried to obtain amine (VI); The feed ratio of Jinggangmycin amine exocyclic olefin (IV) to chiral selenium oxidation catalyst (III) is 10:0.1-0.3, mmol / g; The amount of p-toluenesulfonic acid used is 1 to 3% of the molar amount of the amine exocyclic olefin (IV); The amount of the oxidant is 2 to 10 molar equivalents of the amine exocyclic olefin (IV); the oxidant is selected from hydrogen peroxide, tert-butyl hydroperoxide or m-chloroperbenzoic acid; The amount of barium hydroxide octahydrate used is 4 molar equivalents of the amine exocyclic olefin (IV); In formula (IV), R 1 is benzyl or tert-butyl, and R is acetyl or benzoyl.

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