A chiral selenium oxidation catalyst and its application in the preparation of a key intermediate of voglibose, zingiberene amine

Abstract

The application discloses a chiral selenium oxidation catalyst and application thereof in preparation of Jinggangmycin amine, a key intermediate of voglibose; the high polymer loaded hexavalent chiral selenium catalyst (III) provided by the application has strong catalytic oxidation capacity and stereoselectivity, can be used for precise stereoscopic oxidation of Jinggangmycin amine ring outside alkene (IV), and can be used for preparation of 1,2-diol compound Jinggangmycin amine (VI) with specific stereoscopic structure; the oxidation method can use hydrogen peroxide as an oxidant, is cheap, clean and safe, the hexavalent chiral selenium catalyst (III) has a simple separation mode and can be recycled, has great industrial application potential, and is suitable for technical promotion.

Description

Technical Field

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

[0002] Diabetes is a metabolic disorder caused by various factors and characterized by chronic hyperglycemia, accompanied by abnormalities in sugar, fat, and protein metabolism due to defects in insulin secretion or action. The main clinical symptoms of the disease are "three mores and one less": polydipsia, polyphagia, polyuria, and weight loss. Type 2 diabetes, also known as adult-onset diabetes, typically develops after the age of 35-40 and accounts for over 90% of diabetic patients. Because diabetes can lead to a variety of serious complications, such as cardiovascular and cerebrovascular complications, kidney complications, eye diseases, neuropathy, diabetic foot lesions, and diabetic skin lesions, which can be life-threatening in critical cases, diabetes is listed as one of the four most intractable diseases in the world.

[0003] Voglibose (Voglibose, X) is an oral hypoglycemic drug first developed by Takeda Pharmaceuticals of Japan and first marketed in Japan under the trade name Basen. It was subsequently launched in China as a new α-glucosidase inhibitor, following acarbose. Oral administration inhibits the degradation of disaccharides into monosaccharides during the final step of carbohydrate digestion, reducing the formation of D-glucose and thereby suppressing postprandial blood glucose elevation. It is used to treat diabetes, particularly type 2 diabetes. Compared with acarbose, voglibose offers several advantages: First, it boasts high activity, requires a lower dosage, is highly selective for α-glucosidase, and exhibits fewer intestinal side effects. Second, its mechanism of action is to delay glucose production and absorption, resulting in a more stable glucose-lowering effect without stimulating insulin secretion. Consequently, postprandial hyperinsulinemia is avoided, making hypoglycemia less likely. Voglibose is equally effective when used alone or in combination with other glucose-lowering agents, and combined use can even achieve more synchronized glucose-lowering effects.

[0004] Voglibose has become the drug of choice for treating diabetes due to its excellent blood sugar-lowering efficacy and low side effects, and the market demand is enormous. Its 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, and it is a white to off-white crystalline powder with the chemical formula X:

[0005]

[0006] The early reported preparation method of voglibose is prepared from glucose through more than ten steps of chemical reaction, which has low yield, uses many dangerous chemical raw materials, causes great pollution, has low yield, and is difficult to be industrialized. The classical preparation method thereof is to prepare evalidamine from fermentation, to synthesize valiolamine (VI) which is a key intermediate of voglibose from evalidamine (IV) through multi-step chemical synthesis, to dehydrate and condense valiolamine (VI) with 1,3-dihydroxyacetone, and to prepare voglibose through hydrogenation reduction, and the reaction formula is as follows:

[0007]

[0008] However, in the existing production process of the intermediate valiolamine (VI), the stereoselectivity of the key step of preparing diol from evalidamine ring olefin (IV) is poor, the oxidation product is a 1:1 mixture, 50% of the by-product (VII) isomer is generated, and the separation cost is increased, which finally leads to high price of voglibose.

[0009]

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

[0011] (1) No metal residues, eco-friendly: selenium can be metabolized by organisms and is an essential trace element. Appropriate amount of selenium in the environment is beneficial. Organic selenium catalyzed oxidation reaction usually uses clean oxidants such as hydrogen peroxide and oxygen, and does not produce harmful waste, which has high atom economy.

[0012] (2) Low price: China has an exceptionally abundant selenium resource, and the selenium resource reserves in Enshi, Hubei, are the largest in the world.

[0013] (3) Simple reaction system, no ligand and additive.

[0014] Therefore, in recent years, organic selenium catalyzed oxidation reaction has developed rapidly (Jacek M et al. Molecules, 2015, 20, 10205-10243.), for example, Baeyer-Villiger oxidation of aldehyde and ketone, oxidation of o-diketone carbon-carbon bond, oxidative expansion reaction [Oxidation of alcohols, dihydroxylation of alkenes, hydroxy oxidation, amino oxidation, oxidation of allylic C-H bonds, synthesis of aldehydes and ketones from oximes (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 above reactions use zero-valent or tetravalent selenium as catalyst, which still has the disadvantages of low catalytic efficiency, large amount of catalyst and slow reaction rate. Since hexavalent selenium cannot exist stably in small molecules, it will react with low-valent selenium to form relatively stable tetravalent selenium (the "small molecule effect"). The present application immobilizes chiral selenium compounds on polystyrene resin, thereby avoiding the "small molecule effect", developing a high-performance hexavalent chiral selenium catalyst, and realizing efficient and selective clean oxidation of the exocyclic olefin (IV) of Jinggangmycin to prepare the 1,2-diol compound Jinggangmycin (VI) with a specific stereostructure. SUMMARY

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

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

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

[0019]

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

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

[0022] S1, 1% cross-linked polystyrene resin (I) is lithiated by n-butyllithium, and then subjected to selenization reaction with chiral selenium reagent D to obtain chiral selenium ether resin (II);

[0023] S2, the chiral selenium ether resin (II) is treated with hydrogen peroxide to obtain a chiral selenium oxide catalyst (III);

[0024] The reaction formula is as follows:

[0025]

[0026] The structure of the 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 h, then tetramethyl ethylenediamine (TMEDA) and n-butyllithium are added under stirring at room temperature, the temperature is raised to 65-70°C, and reaction is carried out for 4 h, then the temperature is cooled to room temperature, and the resin is filtered under nitrogen protection, mixed with anhydrous tetrahydrofuran, and cooled to 0°C, then the chiral selenium reagent D is added under stirring, and reaction is carried out at 0°C for 40 min, and after treatment, the chiral selenium ether resin (II) is obtained;

[0030] Before use, the 1% cross-linked polystyrene resin (I) is treated as follows: the 1% cross-linked polystyrene resin (I) is sequentially washed with sodium hydroxide (1M), hydrochloric acid (1M), sodium hydroxide (2M) / dioxane (1:2), water, and N,N-dimethylformamide under stirring at 70°C for 1 h each, then sequentially washed with hydrochloric acid (2M) / methanol, water, methanol, and methanol / dichloromethane (1:10) under stirring at room temperature for 1 h each, filtered, dried, and dried under vacuum at 65°C for 24 h for standby use;

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

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

[0033] Specifically, the post-treatment method is as follows: after reaction, the reaction is quenched with water, filtered, and sequentially washed with tetrahydrofuran, water, methanol, dichloromethane, and diethyl ether, the solvent is dried, and the chiral selenium ether resin (II) is obtained by drying under vacuum at 65°C for 24 h.

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

[0035] The chiral selenium ether resin (II) is soaked in tetrahydrofuran, hydrogen peroxide is added under stirring, reaction is carried out at room temperature for 4 h, then the product is filtered, washed, and dried to obtain the chiral selenium oxide catalyst (III);

[0036] The amount of hydrogen peroxide is preferably 9 mole equivalents of selenium in the chiral selenium ether resin (II).

[0037] The specific washing and drying method is as follows: after filtration, the chiral selenium oxide catalyst (III) is washed with tetrahydrofuran, water, methanol, dichloromethane (2 x 20 mL) and ethyl ether in sequence, the solvent is extracted, and the chiral selenium oxide catalyst (III) is dried at 65°C under vacuum for 24 h.

[0038] The chiral selenium oxide catalyst can be applied to the preparation of Jingangmycin amine, a key intermediate of voglibose.

[0039] The specific application method is as follows:

[0040] The chiral selenium oxide catalyst (III) is soaked in tetrahydrofuran for 2 h, Jingangmycin amine exocyclohexene (IV) and p-toluenesulfonic acid are added under stirring, the temperature is lowered to 0°C, an oxidant is added, the temperature is naturally increased to room temperature, and the reaction is carried out for 1-5 h, then the temperature is increased to 40-70°C, and the reaction is carried out for 1-12 h, the temperature is lowered to room temperature, filtration is carried out, and the filter cake (the chiral selenium oxide catalyst can be recycled after washing with THF) and the filtrate (containing compound V) are collected respectively; the filtrate is taken, an aqueous solution of barium hydroxide octahydrate is added, the mixture is refluxed under stirring for 3 h, then tetrahydrofuran is evaporated, water is added, carbon dioxide gas is introduced until the pH is 7 (precipitation is generated), filtration is carried out, the filter cake is washed with water, the filtrate is combined, and the mixture is subjected to column chromatography on a CG-50 resin (NH4 + , 70 mL), the column is washed with pure water, then the product is eluted with 0.4 M aqueous ammonia, the eluate is concentrated, and the mixture is subjected to column chromatography on a DOWEX 1 x 2 resin (OH - , 70 mL), the column is washed with water, the part containing the product is collected, and Jingangmycin amine (VI) is obtained after freeze-drying.

[0041] The feeding ratio of Jingangmycin amine exocyclohexene (IV) to the chiral selenium oxide catalyst (III) is 10:0.1-0.3 mmol / g.

[0042] The amount of p-toluenesulfonic acid is 1-3% of the molar amount of Jingangmycin amine exocyclohexene (IV).

[0043] The amount of the oxidant is 2-10 mole equivalents of Jingangmycin amine exocyclohexene (IV), and the oxidant is selected from hydrogen peroxide, tert-butyl hydroperoxide, m-chloroperbenzoic acid and the like.

[0044] The amount of barium hydroxide octahydrate is 4 mole equivalents of Jingangmycin amine exocyclohexene (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 principle of the present application comprises:

[0049] The reported selenium oxidation catalysts are zero-valent or tetravalent selenium, which has the disadvantages of low catalytic efficiency, large amount of catalyst and slow reaction rate compared with the high-valent hexavalent selenium. Since the hexavalent selenium cannot exist stably in small molecules, it will react with low-valent selenium to form relatively stable tetravalent selenium (the "small molecule effect"). In the present application, the chiral selenium compound is immobilized on polystyrene resin (I), thereby avoiding the "small molecule effect" and developing a high-performance hexavalent chiral selenium catalyst (III). Further, the present application realizes the efficient and selective clean oxidation of Jinggangmycin exocyclene (IV) with hydrogen peroxide as the oxidant to prepare the 1,2-diol compound Jinggangmycin alcohol amine (VI) with a specific stereostructure.

[0050] In addition to the strong catalytic oxidation ability, the hexavalent chiral selenium catalyst (III) supported by the high polymer has excellent stereoselectivity due to the "steric hindrance effect" of polystyrene and the "chiral effect" of the chiral group. Therefore, the hexavalent chiral selenium catalyst (III) prepared in the present application can be used for the precise stereo-oxidation of Jinggangmycin exocyclene (IV) to prepare the 1,2-diol compound Jinggangmycin alcohol amine (VI) with a specific stereostructure. Moreover, hydrogen peroxide is a cheap, safe and clean oxidant, which lays a foundation for developing more efficient selenium oxidation catalysts. The present application has great industrial application potential and is worthy of further research on industrial application and technology popularization.

[0051] Compared with the prior art, the present application has the following beneficial effects:

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

[0053] (2) The hexavalent chiral selenium catalyst (III) supported by the high polymer has strong catalytic oxidation ability and stereoselectivity, and can be used for the precise stereo-oxidation of Jinggangmycin exocyclene (IV) to prepare the 1,2-diol compound Jinggangmycin alcohol amine (VI) with a specific stereostructure;

[0054] (3) The hexavalent chiral selenium catalyst (III) has a simple separation method and can be recycled;

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

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

[0057] The present application is further described in the following specific examples, but the scope of the present application is not limited to them.

[0058] In the following examples,

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

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

[0061] The compound of formula IV was synthesized according to the method of the reference (Carbohydrate 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 a nitrogen atmosphere, 6.88 g (34.2 mmol) of chiral compound A was weighed into a flask, dissolved in 60 mL of THF, and stirred, and the solution was cooled to 0°C. NaH (60%, dispersed in paraffin liquid, 1.642 g, 41.0 mmol) washed with anhydrous n-hexane (washed twice, 15 mL each time) was carefully added, and the mixture was stirred for 0.5 hours. 2.6 mL of MeI (42 mmol) was added to the reaction system, and the resulting mixture was warmed to room temperature and continued to be stirred for 4 hours. After the reaction was completed, 100 mL of water was added, and the mixture was extracted with ethyl acetate three times, 80 mL each time. The organic phases were combined and washed with water once, and the organic phase was dried with anhydrous sodium sulfate. After the organic solvent was evaporated, the residue was 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 was 91%.

[0067] Under nitrogen atmosphere, 0.528 g (22 mmol) of fresh magnesium powder was added to 50 mL of anhydrous THF, 4.30 g (20 mmol) of compound B was dissolved in 10 mL of THF and transferred to a constant pressure dropping funnel, about 1 mL was first dropped into the reaction, then a small piece of I2 was added and heated with a blower to initiate the reaction. After the reaction was initiated, compound B was added dropwise to the reaction, after the addition was completed, the reaction system was heated and refluxed for 3 hours. 1.66 g (21 mmol) of dry selenium powder was added to the reaction in batches, and the reaction was continued to stir for 2 hours. The reaction was poured into an appropriate amount of ice water mixture, the pH was adjusted to 5-6 with 3N hydrochloric acid, then extracted with methyl tert-butyl ether (80 mL x 2), transferred into 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 completed, 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, the molar yield was 73%. Its characterization is as follows:

[0068] = +54.5o (c = 1, CHCl3); MS (ESI) m / z 431 (M + 1) + ; 1 H NMR (500 MHz, CDCl3): 1.46 (d, J = 6.5 Hz, 6H), 3.22 (s, 6H), 4.74 (q, J = 6.5 Hz, 2H), 7.16 (dd, J = 7.5 Hz, J = 7.5 Hz, 2H), 7.28 (dd, J = 7.5 Hz, J = 7.5 Hz, 2H), 7.35 (d, J = 6.5 Hz, 2H), 7.74 (d, J = 7.5 Hz, 2H); 77 Se NMR: δ 427.7.

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

[0070] The reaction formula is as follows:

[0071]

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

[0073] Polystyrene resin I was sequentially washed with 2 times the volume of resin of sodium hydroxide (1M), hydrochloric acid (1M), sodium hydroxide (2M) / dioxane (1:2), water, N,N-dimethylformamide at 70°C for 1 h each. Then sequentially washed with hydrochloric acid (2M) / methanol, water, methanol, methanol / dichloromethane (1:10) at room temperature for 1 h each. Filtered, dried, and vacuum dried at 65°C for 24 h.

[0074] (b) Preparation of chiral selenoether resin II

[0075] The 8 g of washed 1% cross-linked polystyrene was soaked in 60 mL of cyclohexane overnight under nitrogen protection. 11.2 mL (74.4 mmol) of tetramethylethylenediamine (TMEDA) and 53.4 mL (96 mmol) of n-butyllithium solution (1.80 M) were added under stirring at room temperature. The reaction mixture was warmed to 65-70 °C and stirred for 4 h. After the lithiation of the resin was completed, the reaction mixture was cooled and filtered under nitrogen protection. The resin was washed with anhydrous tetrahydrofuran (3 x 20 mL) and then the resin was transferred back to the reaction flask with 80 mL of anhydrous tetrahydrofuran. The resin / tetrahydrofuran mixture was cooled to 0 °C and selenoagent D (10.0 mmol) was added slowly under stirring. The reaction mixture turned light yellow and was maintained at 0 °C for 40 min. The reaction was quenched with 4 mL of water and the resin turned yellow. The resin was filtered and washed sequentially with tetrahydrofuran (2 x 20 mL), water, methanol (2 x 20 mL), dichloromethane (2 x 20 mL) and diethyl ether (2 x 20 mL). The solvent was removed by suction and the resin was dried under vacuum at 65 °C for 24 h to give chiral selenoether resin II.

[0076] (c) Preparation of chiral selenoxide catalyst III supported on polystyrene resin

[0077] The chiral selenoether resin II obtained in experimental step (b) was soaked with 2 resin volumes of THF and stirred. 9.0 equivalents of hydrogen peroxide were added and the reaction was allowed to proceed at room temperature for 4 h. The resin turned white. The resin was filtered and washed sequentially with tetrahydrofuran (2 x 20 mL), water, methanol (2 x 20 mL), dichloromethane (2 x 20 mL) and diethyl ether (2 x 20 mL). The solvent was removed by suction and the resin was dried under vacuum at 65 °C for 24 h to give chiral selenoxide catalyst III.

[0078] The selenium valence state of chiral selenoxide catalyst III was characterized by X-ray photoelectron spectroscopy (XPS) and is shown in the accompanying Figure 1 Figure. Experimental conditions: The sample was analyzed using a VG Scientific ESCA Lab 220 i-XL spectrometer. The excitation source was Al Kα X-rays at a power of approximately 300 W. The base pressure during analysis was 3 x 10 -9 mbar. The electron binding energy was calibrated using the C 1s peak of the contaminant carbon (284.6 eV). Analysis: As shown in the figure, the peak at a binding energy of 60.4 eV is the 3d 5 / 2 peak of +6 valence state selenium and the peak at a binding energy of 61.5 eV is the 3d 3 / 2 peak of +6 valence state selenium, indicating that the selenium in the catalyst is in the +6 valence state.

[0079] Example 2: Synthesis of wellangmycin amine (VI)

[0080] The reaction scheme is as follows:

[0081] The reaction scheme is as follows:

[0082] In the intermediates of Formula IV, V, R1 is benzyl and R is acetyl.

[0083] 0.2 g of chiral catalyst III was soaked in 60 mL THF for 2 hours, mechanical stirring was started, 4.194 g (10 mmol) of compound of Formula IV and 19.4 mg (0.1 mmol) of p-toluene sulfonic acid were added to the reaction, after the reaction was cooled to 0 °C, 9.2 mL (90 mmol) of 30% hydrogen peroxide was added dropwise, after the dropwise addition was completed, the ice bath was removed and the reaction was allowed to warm to room temperature and reacted for 1 hour, then the temperature was raised to 50 °C and reacted for 3 hours, the reaction was complete, the stirring was stopped, the reaction was cooled to room temperature, the reaction solution was filtered, the filter cake (chiral catalyst) was washed with 5 mL of THF and collected for recycling; the filtrate was combined and transferred to a reaction flask, 20 mL of aqueous barium hydroxide octahydrate (2M) was added, the temperature was raised to reflux with stirring, after refluxing for 3 hours, the THF was distilled off, the temperature was cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was bubbled in, a precipitate was formed, the pH was adjusted to about 7, filtered, the filter cake was washed with 10 mL of water, the filtrate was loaded onto a CG-50 resin (NH4 + , 70 mL) column, after washing with pure water, the product was eluted with 0.4M ammonia water, concentrated to about 10 mL, then passed through a DOWEX 1x2 resin (OH - , 70 mL), washed with water, the product-containing portion was collected, and a white solid was obtained after lyophilization, with a yield of 1.69 g, 87.5%, the optical purity was 100% by HPLC detection, and no isomer of Formula VII was detected.

[0084]

[0085] The HPLC detection conditions are as follows:

[0086] (i) Instrument and reagents: Waters e2695 high performance liquid chromatograph; ultraviolet detector. Valiolamine reference substance and 4-methoxybenzenesulfonyl fluoride were purchased from Shanghai Sunny Chemical Technology Co., Ltd. (Anjieji Chemical); epivaliolamine (VII) was synthesized according to the method in the literature (Cabohydrate Research, 1985, 140, 185-200). Methanol was chromatographically pure, and distilled water.

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

[0088] (iii) Analysis of the derivatized sample

[0089] To a screw-capped glass vial was added 500 μL (200 mM) Na2HP04, followed by 100 μL of 4-methoxybenzenesulfonyl fluoride (25 mg / mL in acetonitrile), and 2 mg of sample to be tested. The mixture was vortexed and mixed. The mixture was maintained at 30 °C for 10 minutes. After filtration through a 0.22 μm membrane, the mixture was injected into the analytical system.

[0090] Ijngangmycin amine (VI) was characterized as follows:

[0091] White solid. = +19.80 (c = 1, H20). MS (ESI) m / z 194 (M + 1) + ; 1 H NMR (500 MHz, D20): δ 1.82 (m, 1H), 2.09 (m, 1H), 3.5-3.7 (m, 1H), 3.57 (d, J = 10 Hz, 1H), 3.65 (s, 2H), 3.74 (dd, J = 4.2, 10 Hz, 1H), 4.01 (t, J = 10 Hz, 1H); 13 C NMR (125 MHz, D20): δ 33.6, 51.1, 66.4, 72.0, 74.6, 74.6, 76.9.

[0092] Example 3: Synthesis of Ijngangmycin amine (VI)

[0093] The reaction scheme is as follows:

[0094]

[0095]

[0096] In the intermediates of the formula IV, V, R1is benzyl and R is acetyl.

[0097] 0.2 g of chiral catalyst III was soaked in 60 mL THF for 2 hours, mechanical stirring was started, 4.194 g (10 mmol) of compound of formula IV and 58.2 mg (0.3 mmol) of p-toluenesulfonic acid were added to the reaction, after the reaction was cooled to 0 °C, 9.7 mL (70 mmol) of 70% wt. tert-butyl hydroperoxide aqueous solution was added dropwise, after the dropwise addition was completed, the ice bath was removed, and the reaction was allowed to warm to room temperature for 4 hours, and finally the temperature was raised to 40 °C for 1 hour. The reaction was complete, the stirring was stopped, and the reaction was cooled to room temperature. The reaction solution was filtered, the filter cake (chiral catalyst) was washed with 5 mL THF, and then collected for recycling. The filtrate was combined and transferred to a reaction flask, 20 mL of barium hydroxide octahydrate aqueous solution (2M) was added, and the temperature was raised to reflux under stirring. After refluxing for 3 hours, the THF was evaporated, the temperature was cooled to room temperature, and water was added to about 50 mL. Carbon dioxide gas was introduced until the pH was about 7. Filtration was performed, the filter cake was washed with 10 mL of water, and the filtrate was combined. The combined filtrate was loaded onto a CG-50 resin (NH4 + , 70 mL) column. After washing with pure water, the product was eluted with 0.4M ammonia water. The eluate was concentrated to about 10 mL, and then passed through a DOWEX 1x2 resin (OH - , 70 mL) column. After washing with water, the product-containing portion was collected, and then lyophilized to obtain 1.70 g of white solid, with a yield of 88.0%. The optical purity was 100% as detected by HPLC, and no isomer of formula VII was detected. The HPLC detection conditions were the same as in Example 2.

[0098] Example 4: Synthesis of Jingangmycin amine (VI)

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

[0100] 0.3 g of chiral catalyst III was soaked in 70 mL THF for 2 hours, mechanical stirring was started, 4.194 g (10 mmol) of compound of formula IV and 19.4 mg (0.1 mmol) of p-toluenesulfonic acid were added to the reaction, after the reaction was cooled to 0 °C, 17.3 mL (100 mmol) of meta-chloroperoxybenzoic acid (MCPBA) was added in small portions. The ice bath was removed, and the reaction was allowed to warm to room temperature for 3 hours, and finally the temperature was raised to 60 °C for 5 hours. The stirring was stopped, and the reaction was cooled to room temperature. The reaction solution was filtered, the filter cake (chiral catalyst) was washed with 5 mL chloroform and 5 mL THF, and then collected for recycling. The filtrate was combined and transferred to a reaction flask, 20 mL of barium hydroxide octahydrate aqueous solution (2M) was added, and the temperature was raised to reflux under stirring. After refluxing for 3 hours, the THF was evaporated, the temperature was cooled to room temperature, and water was added to about 50 mL. Carbon dioxide gas was introduced until the pH was about 7. Filtration was performed, the filter cake was washed with 10 mL of water, and the filtrate was combined. The combined filtrate was loaded onto a CG-50 resin (NH4 +, 70 mL) column, washed with pure water, then the product was eluted with 0.4 M ammonia water, concentrated to about 10 mL, and then passed through DOWEX 1 x 2 resin (OH - , 70 mL), washed with water, collected the fraction containing the product, and lyophilized to give 1.71 g of white solid, 88.7% yield, with an optical purity of 100% by HPLC, and no isomer of formula VII was detected. The HPLC detection conditions were the same as in Example 2.

[0101] Example 5: Synthesis of the enantiomeric amine of 19-hydroxyandrost-5-ene- 17-one (VI)

[0102] The reaction scheme is as follows:

[0103]

[0104]

[0105] In the intermediates of formula IV, V, R1is t-butyl, and R is benzoyl.

[0106] The 0.2 g of chiral catalyst III was soaked in 60 mL of THF for 2 hours, and mechanical stirring was started. To the reaction was added 4.194 g (10 mmol) of the compound of formula IV and 38.8 mg (0.2 mmol) of p-toluenesulfonic acid. After the reaction was cooled to 0°C, 11.1 mL (80 mmol) of 70% wt. aqueous t-butyl hydroperoxide was added dropwise. After the dropwise addition was completed, the ice bath was removed, and the reaction was allowed to warm to room temperature and react for 5 hours. The temperature was then raised to 40°C, and the reaction was allowed to proceed for 3 hours. When the reaction was complete, the stirring was stopped, and the reaction was cooled to room temperature. The reaction was filtered, and the filter cake (chiral catalyst) was washed with 5 mL of THF and collected for reuse. The filtrate was combined and transferred to a reaction flask, and 20 mL of aqueous barium hydroxide octahydrate (2 M) was added. The reaction was stirred and heated to reflux for 3 hours. The THF was evaporated, and the reaction was cooled to room temperature. Water was added to a volume of about 50 mL, and carbon dioxide gas was bubbled through the reaction until the pH was about 7. The reaction was filtered, and the filter cake was washed with 10 mL of water. The filtrate was applied to a CG-50 resin (NH4 + , 70 mL) column, washed with pure water, then the product was eluted with 0.4 M ammonia water, concentrated to about 10 mL, and then passed through DOWEX 1 x 2 resin (OH - , 70 mL), washed with water, collected the fraction containing the product, and lyophilized to give 1.71 g of white solid, 88.7% yield, with an optical purity of 100% by HPLC, and no isomer of formula VII was detected. The HPLC detection conditions were the same as in Example 2.

[0107] Example 6: Synthesis of the enantiomeric amine of 19-hydroxyandrost-5-ene- 17-one (VI)

[0108] The reaction scheme is as follows:

[0109] The reaction scheme is as follows:

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

[0111] 0.2 g of chiral catalyst III was soaked in 60 mL THF for 2 hours, mechanical stirring was started, 4.194 g (10 mmol) of compound of formula IV and 19.4 mg (0.1 mmol) of p-toluene sulfonic acid were added to the reaction, after the reaction was cooled to 0 °C, 2.04 mL (20 mmol) of 30% hydrogen peroxide was added dropwise, after the dropwise addition was completed, the ice bath was removed and the reaction was allowed to warm to room temperature for 1 hour, then the temperature was raised to reflux for 12 hours, the reaction was complete, the stirring was stopped, the reaction was cooled to room temperature, the reaction solution was filtered, the filter cake (chiral catalyst) was washed with 5 mL of THF and collected for recycling; the filtrate was combined and transferred to a reaction flask, 20 mL of aqueous barium hydroxide octahydrate (2 M) was added, the temperature was raised to reflux with stirring, after refluxing for 3 hours, the THF was evaporated, the temperature was cooled to room temperature, water was added to about 50 mL, carbon dioxide gas was bubbled through, until the pH was about 7, the solution was filtered, the filter cake was washed with 10 mL of water, the filtrate was combined and passed through a CG-50 resin (NH4 + , 70 mL) column, after washing with pure water, the product was eluted with 0.4 M aqueous ammonia, the eluate was concentrated to about 10 mL, then passed through a DOWEX 1 x 2 resin (OH - , 70 mL), washed with water, the product containing fraction was collected, lyophilized to give 1.40 g of white solid, the yield was 72.3%, the optical purity was 100% by HPLC, no isomer of formula VII was detected. The HPLC detection conditions were the same as in Example 2.

[0112] Example 7: Synthesis of Jingangmycin amine (VI)

[0113] The reaction scheme is as follows:

[0114]

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

[0116] A reaction flask was charged with 4.194 g (10 mmol) of the compound of Formula IV, dissolved in 60 mL of THF, and mechanically stirred. To the reaction was added 19.4 mg (0.1 mmol) of p-toluenesulfonic acid, and the reaction was cooled to 0 °C. To the reaction was then added dropwise 9.2 mL (90 mmol) of 30% hydrogen peroxide. After the dropwise addition was complete, the ice bath was removed, and the reaction was allowed to warm to room temperature for 3 hours. The reaction was then heated to reflux for 7 hours. The stirring was stopped, and the reaction was cooled to room temperature. To the reaction was added 20 mL of an aqueous solution of barium hydroxide octahydrate (2 M). The reaction was heated to reflux for 3 hours. The THF was removed, and the reaction was cooled to room temperature. The reaction was diluted with water to about 50 mL, and carbon dioxide gas was bubbled through the reaction until the pH was about 7. The reaction was filtered, and the filter cake was washed with 10 mL of water. The filtrate was applied to a CG-50 resin (NH4 + , 70 mL) column. The column was washed with water, and the product was eluted with 0.4 M aqueous ammonia. The eluate was concentrated to about 10 mL, and the product was re-adsorbed on DOWEX 1 x 2 resin (OH - , 70 mL). The resin was washed with water, and the product was eluted with water. The eluate was concentrated, and the product was lyophilized to give 1.10 g of a white solid. The yield was 57.0%. The product was analyzed by HPLC, and both isoforms of epivaliolamine (VI) and epivaliolamine (VII) were present in equal amounts, 50% each. This indicated that no chiral catalyst was involved, and the selectivity of the double bond oxidation of the compound of Formula IV was 0.

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

[0118] The reaction is shown in the following scheme:

[0119]

[0120] In the intermediates of Formulas IV, V, and V-1, R1is benzyl, and R is acetyl.

[0121] A reaction flask was charged with 4.19 g (10 mmol) of the compound of Formula IV, dissolved in 95 mL of chloroform, and mechanically stirred. To the reaction was added 4.19 g (0.1 mmol) of anhydrous Na2HPO4. To the reaction was then added dropwise a solution of m-chloroperoxybenzoic acid in chloroform (2.46 g of m-chloroperoxybenzoic acid in 50 mL of chloroform). After the dropwise addition was complete, the reaction was heated to reflux for 7 hours. The reaction was slowly cooled to 0 °C, filtered, and then washed sequentially with 20% sodium thiosulfate, saturated sodium bicarbonate, and saturated brine. The reaction was concentrated. To the reaction was added 70 mL of THF and 20 mL of an aqueous solution of barium hydroxide octahydrate (2 M). The reaction was heated to reflux for 3 hours. The THF was removed, and the reaction was cooled to room temperature. The reaction was diluted with water to about 50 mL, and carbon dioxide gas was bubbled through the reaction until the pH was about 7. The reaction was filtered, and the filter cake was washed with 10 mL of water. The filtrate was applied to a CG-50 resin (NH4 +, 70mL) column, washed with pure water, and then washed with 0.5M ammonia water to remove the product, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH - The reaction mixture was stirred for 2 h at 4 °C for 1 h (70 mL), washed with water, and the product-containing fraction was collected and lyophilized to yield 1.06 g of a white solid (55.3% yield). HPLC analysis revealed the presence of both epivaliolamine (VI) and epivaliolamine (VII) isomers, each accounting for 50%. This indicates that the selectivity for the oxidative hydrolysis of the double bond of compound IV is zero in the absence of a chiral catalyst.

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

[0123] Recovery and regeneration of chiral catalyst III:

[0124] Collect the chiral selenium catalyst used several times and wash it sequentially with 2 times the resin volume of tetrahydrofuran and water. Soak it in 2 times the resin volume of THF, start mechanical stirring, add 9.0 equivalents of hydrogen peroxide, and react at room temperature for 4 hours, until the resin turns white. Filter and wash it sequentially with 2 times the resin volume of water, methanol, tetrahydrofuran, and dichloromethane. Drain the solvent and dry it in a vacuum 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 a benzyl group and R is an acetyl group.

[0127] 0.2 g of the chiral catalyst III obtained above was soaked in 60 mL of THF for 2 hours, mechanically stirred, and 4.194 g (10 mmol) of the compound of formula IV and 19.4 mg (0.1 mmol) of p-toluenesulfonic acid were added to the reaction. After the reaction cooled to 0° C., 9.2 mL (90 mmol) of 30% hydrogen peroxide was added dropwise. After the addition was complete, the ice bath was removed, and the temperature was naturally raised to room temperature for another 4 hours. 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 of THF and collected for recycling. The filtrates were combined and transferred to a reaction flask. 20 mL of an aqueous solution of barium hydroxide octahydrate (2 M) was added. The temperature was raised to reflux with stirring. After reflux for 3 hours, the THF was evaporated, and the mixture was cooled to room temperature. Water was added to about 50 mL, and carbon dioxide gas was introduced to form a precipitate. The pH was adjusted to about 7, filtered, and the filter cake was washed with 10 mL of water. The filtrates were combined and applied to CG-50 resin (NH4 + , 70mL) column, washed with pure water, and then washed with 0.4M ammonia water to remove the product, concentrated to about 10mL, and then passed through DOWEX 1×2 resin (OH -, 70 mL), washed with water, the product containing fraction was collected, and lyophilized to give 1.68 g of white solid, with a yield of 87.0%, and the optical purity was 100% by HPLC, and no isomer of formula VII was detected. The HPLC detection conditions were the same as in Example 2.

Claims

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

2. The method for preparing a chiral selenium oxidation catalyst according to claim 1, wherein The preparation method is as follows: S1. After 1% cross-linked polystyrene resin (I) is lithiated by n-butyllithium, a chiral selenium ether resin (II) is prepared by selenization with chiral selenium reagent D; S2. The chiral selenium ether resin (II) is treated by oxidation with hydrogen peroxide to obtain the chiral selenium oxidation catalyst (III); The structure of chiral selenium reagent D is as follows:

3. The method for preparing a chiral selenium oxidation catalyst according to claim 2, wherein: The operation method of S1 is as follows: Under nitrogen protection, 1% cross-linked polystyrene resin (I) is soaked in cyclohexane for 8-12 h, then tetramethyl ethylenediamine and n-butyllithium are added under stirring at room temperature, the temperature is raised to 65-70℃ and reacted for 4 h, then cooled to room temperature, filtered under nitrogen protection, the filtered resin is mixed with anhydrous tetrahydrofuran, cooled to 0℃, chiral selenium reagent D is added under stirring, and maintained at 0℃ for 40 min, then treated to obtain the chiral selenium ether resin (II).

4. The method for preparing a chiral selenium oxidation catalyst according to claim 3, wherein: The feeding ratio of 1% cross-linked polystyrene resin (I), tetramethyl ethylenediamine, 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, wherein: The operation method of S2 is as follows: The chiral selenium ether resin (II) is soaked in tetrahydrofuran, hydrogen peroxide is added under stirring, and reacted at room temperature for 4 h, then filtered, washed and dried to obtain the chiral selenium oxidation catalyst (III).

6. The method for preparing a chiral selenium oxidation catalyst according to claim 5, wherein: The amount of hydrogen peroxide is 9 mole equivalents of selenium in the chiral selenium ether resin (II).

7. The use of the chiral selenium oxidation catalyst of claim 1 in the preparation of Jingangmycin amine, a key intermediate of voglibose.

8. Use according to claim 7, wherein the compound is ###0002### The method is as follows: The chiral selenium oxidation catalyst (III) is soaked in tetrahydrofuran for 2 h, Jingangmycin amine exocycloalkene (IV) and p-toluenesulfonic acid are added under stirring, the temperature is lowered to 0℃, an oxidant is added, the temperature is naturally raised to room temperature and reacted for 1-5 h, then the temperature is raised to 40-70℃ and reacted for 1-12 h, then cooled to room temperature, filtered, and the filter cake and filtrate are collected respectively; the filtrate is taken, an aqueous solution of barium hydroxide octahydrate is added, refluxed under stirring for 3 h, then tetrahydrofuran is evaporated, water is added, carbon dioxide gas is introduced until pH=7, filtered, washed with water, and the filtrate is combined and passed through a CG-50 resin column, then washed with pure water, and the product is washed out with 0.4M ammonia water, concentrated, passed through DOWEX 1×2 resin, washed with water, the part containing the product is collected, and Jingangmycin amine (VI) is obtained after freeze-drying; The feeding ratio of Jingangmycin amine exocycloalkene (IV) and chiral selenium oxidation catalyst (III) is 10: 0.1-0.3, mmol / g; The amount of p-toluenesulfonic acid is 1-3% of the molar amount of Jingangmycin amine exocycloalkene (IV); The amount of oxidant is 2-10 mole equivalents of Jingangmycin amine exocycloalkene (IV); the oxidant is selected from hydrogen peroxide, tert-butyl hydroperoxide or m-chloroperbenzoic acid; The amount of barium hydroxide octahydrate is 4 mole equivalents of Jingangmycin amine exocycloalkene (IV); In formula (IV), R 1 is benzyl or tert-butyl, and R is acetyl or benzoyl.

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