Preparation method of voglibose
By using selenium resin to participate in the preparation process of voglibose, the problem of poor selectivity of compository synthesis of compository Vb was solved, and the efficient separation of compound Vb and the low-cost preparation of voglibose were achieved, and the by-product compository compository was obtained.
Patent Information
- Application Number
- CN202411956926.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-29
- Publication Date
- 2025-04-11
AI Technical Summary
In the existing preparation methods for vogliposula, the stereoselectivity of vinylamide is poor, resulting in the generation of by-product isomers, which increases the separation cost and the production cost of vogliposula.
The preparation method of vogliposugar with selenium resin is adopted to achieve C-N bond cleavage and intramolecular ring formation of quasi-membered amino sugar by using the sulfuric acid hydrolysis of vincanmycin, separation and purification of oxy-anionic and anion exchange resin, combined with the effects of NBS and ammonia water, and the intramolecular ring formation of quasi-hexane amino sugar is achieved. The carbon-selenium bond is used to solidly load it on the resin, so as to achieve the separation of compound Vb and the efficient preparation of vogliposugar.
The problem of poor selectivity of synthesis of jingamycinamide was solved, efficient separation of compound Vb was achieved, the production cost of vogliposol was reduced, and the by-product of jingamycinamide was obtained with practical value.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing voglibose, in particular to a method for preparing voglibose with the participation of selenium resin. In the method, a valuable byproduct, vincristine, is obtained. Background Art
[0002] Voglibose (I) is an oral hypoglycemic drug developed by Takeda Pharmaceuticals of Japan. It was first marketed in Japan under the trade name Basen and is mainly used in Asia. It is another new α-glucosidase inhibitor after acarbose. Due to its high activity, voglibose has a low dosage and few side effects. For example, it has no significant effect on fasting blood glucose, insulin, body weight, body mass index, adiponectin, triglycerides, total cholesterol and high-density lipoprotein cholesterol levels after medication. It also has potential advantages for patients with impaired glucose tolerance or early T2D. In addition, voglibose is particularly suitable for combination therapy. It is equally effective when used alone or in combination with other hypoglycemic drugs. Combination therapy can also make medication and hypoglycemic effects more synchronized. Validamine (XI) is a pH-dependent and dose-dependent competitive inhibitor of β-glucosidase, IC 50 The value is 2.92mM. It is also one of the intermediates for preparing voglibose.
[0003]
[0004] As the number of diabetes patients increases year by year and gradually becomes younger, the demand for diabetes drugs is increasing, which has promoted the development of diabetes drugs. Since α-glucosidase inhibitors do not stimulate insulin secretion, single-drug use will not cause hypoglycemia reactions; they also have the advantages of lipid-lowering, weight loss, and cardiovascular protection, making them the first choice for diabetic patients. Compared with acarbose and miglitol, voglibose has the advantages of high efficacy and few side effects, making it a representative drug of α-glucosidase inhibitors, but because the existing preparation methods of voglibose are all costly, this disadvantage narrows its audience range.
[0005] Mycophenolic acid, the key intermediate of voglibose, is a multichiral compound. When prepared by conventional methods, another isomer impurity will be produced, which greatly increases the difficulty of production and the separation cost, ultimately leading to the high price of voglibose.
[0006]
[0007] The classic preparation method is to prepare validamycin by fermentation, obtain validamine A through separation and purification, obtain validamine (XI) through multi-step reaction, synthesize the key intermediate validamine (Valiolamine) through multi-step reaction, dehydrate and condense with 1,3-dihydroxyacetone, and finally obtain voglibose (I) through hydrogenation reduction, as shown in the following formula:
[0008]
[0009]
[0010] However, as shown in the above formula, in the existing production process of the intermediate voglibose, due to the poor stereoselectivity of the key step of voglibose exocyclic olefin oxidation to prepare diol, the oxidation product is a 1:1 mixture, 50% of by-product isomers are generated, and the separation cost is increased, which ultimately leads to the high price of voglibose. Summary of the invention
[0011] The present invention aims to provide a method for preparing voglibose with the participation of selenium resin, and at the same time, a valuable byproduct, valienamine, is obtained in the method. Valienamine can be prepared to obtain voglibose by other known methods, such as the literature report: Stereoselective conversion of valienamine and validamine intovaliolamine.Carbohydrate Research, 140 (1985) 185-200.
[0012] The technical solution of the present invention is as follows:
[0013] A method for preparing voglibose, comprising:
[0014] (1) Using Jinggangmycin as the starting material, hydrolyzing it with sulfuric acid, and separating and purifying it with cation and anion exchange resins to obtain Jinggang hydroxylamine A; Jinggang hydroxylamine A is protected with a benzyl group to obtain compound (III);
[0015] (2) Compound (III) undergoes CN bond cleavage in an acetonitrile / water mixed solvent under the action of NBS (N-bromosuccinimide) and aqueous ammonia to obtain a mixture of compound (IVa) and compound (IVb); the mixture of compound (IVa) and compound (IVb) is protected by benzyloxycarbonyl to obtain a mixture of compound (Va) and compound (Vb);
[0016] (3) adding selenium bromide resin to the mixture of compound (Va) and compound (Vb), wherein compound (Va) containing a double bond undergoes intramolecular cyclization to form a rigid lactone compound and is immobilized on the resin via a carbon-selenium bond to form resin (VI), thereby achieving separation from compound (Vb);
[0017] (4) Resin (VI) is cleaved with sodium borohydride to obtain compound (VII); compound (Vb) is deprotected by Pd / C hydrogenation to obtain compound (XI), i.e., jinggangmycin amine with practical value;
[0018] (5) Compound (VII) is hydrolyzed to obtain compound (VIII); compound (VIII) is subjected to dehydration condensation with 1,3-dihydroxyacetone to obtain compound (X); compound (X) is deprotected by Pd / C hydrogenation to obtain voglibose (I);
[0019] The route is as follows:
[0020]
[0021] Specifically, step (2) is performed as follows:
[0022] Compound (III), acetonitrile / water mixed solvent and NBS are mixed, stirred and reacted at room temperature for 5 hours under light-proof conditions, then ammonia water is added, and the mixture is stirred and reacted at room temperature for 8 hours under light-proof conditions, then a saturated sodium chloride solution is added, extracted with ethyl acetate, the organic layer is collected, and evaporated to dryness to obtain a mixture of compound (IVa) and compound (IVb); the mixture of compound (IVa) and compound (IVb) is dissolved in a MeOH / CHCl3 mixed solvent, benzyl chloroformate and NaHCO3 are added, stirred and reacted at room temperature for 5 hours, then a saturated sodium chloride solution is added, extracted with ethyl acetate, the organic layer is collected, concentrated, and purified by silica gel column chromatography to obtain a mixture of compound (Va) and compound (Vb);
[0023] The preferred feed ratio of compound (III), NBS, and aqueous ammonia is 10 mmol: 12 mmol: 2.7 mL;
[0024] A mixed solvent with a volume ratio of acetonitrile to water of 4:1 is preferred;
[0025] Preferably, the feed ratio of compound (III), benzyl chloroformate and NaHCO3 is 10mmol:24mmol:24mmol;
[0026] A mixed solvent with a volume ratio of MeOH / CHCl3 of 2:1 is preferred.
[0027] Specifically, step (3) is performed as follows:
[0028] The mixed solution obtained by soaking the selenium bromide resin in dichloromethane for 1 hour is added dropwise to the mixture of compound (Va) and compound (Vb), reacted at room temperature for 12 hours, and then filtered. The filter cake is washed with dichloromethane and dried to obtain resin (VI); the filtrate is evaporated to dryness and purified by silica gel column chromatography to obtain compound (Vb);
[0029] Preferably, the mass ratio of the mixture of selenium bromide resin, compound (Va) and compound (Vb) is 6.67:12.53;
[0030] Specifically, selenium-bromine resin is prepared as follows:
[0031] S1: Under nitrogen atmosphere, 1% cross-linked polystyrene resin was soaked in cyclohexane for 8-12 hours, then tetramethylethylenediamine (TMEDA) and n-butyl lithium were added under stirring at room temperature, the temperature was raised to 65-70°C for reaction for 4 hours, cooled to room temperature, filtered under nitrogen protection, the filtered resin was mixed with tetrahydrofuran, cooled to 0°C, dimethyl diselenide was added under stirring, the temperature was maintained at 0°C for reaction for 20 minutes, the reaction was quenched with water, filtered, washed, and dried to obtain methyl selenoether resin;
[0032] Preferably, the feed ratio of 1% cross-linked polystyrene resin, tetramethylethylenediamine, n-butyllithium, and dimethyl diselenide is 4 g: 37.2 mmol: 48 mmol: 5.0 mmol;
[0033] S2: Under nitrogen atmosphere, methyl selenide resin was soaked in chloroform for 8-12 hours, bromine / chloroform solution was added at 0°C, stirred and reacted for 30 minutes at 0°C, filtered, the filtered resin was mixed with anhydrous ethanol, reacted at 70°C for 2 hours, filtered, washed and dried to obtain selenium bromide resin;
[0034] Preferably, the concentration of the bromine / chloroform solution is 2M, and the feed ratio of the methyl selenoether resin to the bromine / chloroform solution is 4 g:3.5 mL.
[0035] The technical principles of the present invention are as follows:
[0036] The present invention develops a novel method for preparing voglibose, which uses cheap and easily available virgin aminomycin as a raw material, hydrolyzes it with sulfuric acid, and sequentially removes impurities through cation and anion exchange resins to obtain virgin aminohydroxylamine A with a high yield, and further cleaves its CN bond to form a mixture of two pseudo-hexamembered amino sugars that are difficult to separate. To this end, the pseudo-hexamembered amino sugar (Va) containing a double bond undergoes intramolecular cyclization to form a rigid lactone compound with the participation of selenium resin, and is immobilized on the resin through a carbon-selenium bond to form a resin (VI). This process design simultaneously solves the stereoselectivity problem in the synthesis of the key intermediate jinggangmycin amine and realizes the separation of two pseudo-hexamembered amino sugars (Va) and (Vb), namely: the pseudo-hexamembered amino sugar (Vb), the precursor of jinggangmycin amine (XI), is separated by simple filtration and washing operations; the resin (VI) is cut with sodium borohydride to obtain the lactone compound (VII) in high yield, which is hydrolyzed, dehydrated condensed with 1,3-dihydroxyacetone and hydrogenated to obtain voglibose, greatly reducing the production cost of voglibose.
[0037] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:
[0038] (1) The present invention provides a method for preparing voglibose with the participation of selenium resin, and simultaneously obtains the jinggangmycin amine with practical value. One process is used to prepare two products, thereby improving the utilization of raw materials and reducing process costs.
[0039] (2) The polymer-supported selenium reagent (C) undergoes intramolecular cyclization with the double-bonded pseudo-hexaamino sugar (Va) to form a rigid lactone compound and is immobilized on the resin via a carbon-selenium bond. This process design simultaneously solves the stereoselectivity problem in the synthesis of the key intermediate virgin aminoamine and achieves the separation of the two pseudo-hexaamino sugars (Va) and (Vb), that is, the precursor pseudo-hexaamino sugar (Vb) of virgin aminoamine (XI) is separated by simple filtration and washing operations;
[0040] (3) Resin (VI) can be cleaved with sodium borohydride to obtain lactone compound (VII) in high yield;
[0041] (4) The cut resin can be regenerated by bromination, and its reaction activity is not affected after regeneration.
[0042] (5) The process cleverly combines the deprotection of the protecting group and the reduction of the carbon-nitrogen double bond into one step, shortening the process route. DETAILED DESCRIPTION
[0043] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention is not limited thereto.
[0044] In the following embodiments,
[0045] 1% cross-linked polystyrene A was purchased from Tianjin Nankai Hecheng Technology Co., Ltd.;
[0046] Jinggangmycin was purchased from Tonglu Huifeng Biotechnology Co., Ltd., Zhejiang Province;
[0047] All anion and cation exchange resins used in the present invention were purchased from Tianjin Xijinna Environmental Protection Materials Technology Co., Ltd.
[0048] Dimethyl diselenide was prepared according to the literature (Syper, L.; Mtochowski, J. Synthesis 1984, 5, 439-442).
[0049] Example 1: Preparation of Jinggang Hydroxylamine A
[0050] (1) Pretreatment with Jinggangmycin
[0051] Use a glass measuring cylinder to measure 30mL of concentrated sulfuric acid and 510mL of ultrapure water respectively, add 300mL of ultrapure water to a 1L single-mouth round-bottom flask, and then slowly add 30mL of concentrated sulfuric acid to the round-bottom flask with a glass rod. This process requires constant stirring to dissipate heat and prepare a dilute sulfuric acid solution. Weigh 30.0g of Jinggangmycin on a balance, use the remaining 210mL to completely dissolve the weighed Jinggangmycin, and pour the prepared solution into a single-mouth round-bottom flask. Then put the single-mouth round-bottom flask into a constant temperature magnetic stirrer at 100°C and condense and reflux for 24 hours. Use a thin layer chromatography plate to determine whether the reaction is complete. After determining that the reaction is complete, add an appropriate amount of barium hydroxide octahydrate to adjust the pH to about 6.0, then filter the solution to completely remove the barium sulfate precipitate, and concentrate the obtained filtrate using a rotary evaporator.
[0052] (2) Cationic resin impurity removal experimental operation
[0053] Take 300mL of activated cationic resin (001×7(732)) and load the column, rinse it with ultrapure water until the pH is neutral, then add the concentrated filtrate of step (1) to the rinsed cationic resin, so that it is completely submerged by the cationic exchange resin, keep it for 30 minutes, so that it is adsorbed with the maximum probability, and then rinse the resin with ultrapure water to wash away the impurities and β-D-glucose that are not adsorbed. At this time, the hydroxylamine A is completely adsorbed in the cationic resin. Elute the hydroxylamine A from the cationic column with 1mol / L ammonia water. Concentrate the obtained filtrate with a rotary evaporator. Restore the eluted cationic exchange column with 1mol / L hydrochloric acid and store it with 1mol / L HCl for reuse next time.
[0054] (3) Anion resin impurity removal experiment operation
[0055] Take 100mL of activated anion resin [Trilite MA-20] and load it into the column. Rinse it with ultrapure water until the pH is neutral. Then slowly add the concentrated filtrate after the cation resin is washed to the anion column that has been washed, so that it is completely submerged by the ion exchange resin, and keep it for 30 minutes. Rinse the column slowly with ultrapure water to allow the anion resin to adsorb anionic impurities, and then use a large amount of ultrapure water to completely elute the product in the form of Jinggang Hydroxylamine A. Collect the eluate and concentrate it to dryness to obtain 21.9g of pure Jinggang Hydroxylamine A, with a weight yield of 73%. Restore the eluted anion exchange resin with 1mol / L NaOH and store it with 1mol / L NaOH for reuse next time. The NMR and LC-MS characterizations of Jinggang Hydroxylamine A are as follows:
[0056] 1 H NMR (400MHz, D2O) δ5.89 (d, J = 4.8Hz, 1H), 4.23-3.75 (m, 3H), 3.69-3.34 (m, 6H), 3.29-3.01 (m, 3H), 1.91-1.61 (m, 2H), 1.25-1.06 (m, 1H). 13 C NMR (100 MHz, D2O) δ 139.07, 123.08, 74.20, 73.64, 73.23 (two C overlap), 71.37, 69.28, 62.31, 61.44, 53.89, 52.21, 37.94, 26.76. LC-MS (ESI): m / z 336.3 [M+1] + .
[0057] Example 2: Preparation of Compound III
[0058]
[0059] In a 250mL eggplant-shaped bottle, add 3.35g of the hydroxylamine A (10mmol) of formula II and 70mL of DMF. After stirring and dissolving, the temperature is lowered to -5°C, and NaH (100mmol, 10eq) is added in batches. After stirring for 1h, BnBr (17.1g, 100mmol, 10eq) is added dropwise. The reaction is continued at room temperature for 2 hours. After the reaction is complete, 70mL of water is added and extracted with EtOAc. The organic layer is washed with 70mL of water, the organic layer is concentrated, and the residual BnBr is removed under reduced pressure to obtain compound III (10.56g, 99.9%). The structural characterization is as follows:
[0060] 1H NMR (500MHz, CDCl3) δ7.67-7.30(m,40H),6.17(d,J=3.7Hz,1H),5.13(dd,J=10.9,5.5Hz,2H),4.98(dd,J=2 8.6,11.2Hz,2H),4.91-4.56(m,12H),4.48(d,J=11.9Hz,1H),4.28(d,J=4.3Hz,1H),4.23-4.15(m,2H),4.1 1(d,J=12.0Hz,1H),3.85(dd,J=9.4,4.5Hz,2H),3.75-3.67(m,2H),3.64(d,J=4.1Hz,1H),3.57(d,J=3.5Hz ,1H),3.46(dd,J=9.0,2.5Hz,1H),2.57(td,J=10.3,7.5,3.5Hz,1H),2.17-1.96(m,2H),1.70-1.51(m,1H). 13 C NMR (125MHz, CDCl3) δ143.8,133.4,133.3,133.30,133.28,133.25,133.10,133.02,133.0,132.9,132.8,132.60,132.58,132.55,132.5, 132.44,132.39,132.33,88.7,88.5,86.4,82.9,82.6,82.4,82.2,81 .9,80.6,80.1,78.6,78.3,77.9,75.9,75.3,56.5,56.1,41.6,33.6.
[0061] Example 3: Preparation of selenium-bromine resin C
[0062]
[0063] Under nitrogen atmosphere, 4g of 1% cross-linked polystyrene was first soaked in 30mL cyclohexane overnight, and 5.6mL (37.2mmol) of tetramethylethylenediamine (TMEDA) and 26.7mL (48mmol) of 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. Cooled, filtered under nitrogen protection, the resin was washed with tetrahydrofuran (3×10mL), and then the resin was transferred back to the reaction bottle with 40mL of tetrahydrofuran. The resin / tetrahydrofuran mixture was cooled to 0℃, and dimethyl diselenide (5.0mmol) was slowly added under stirring. The reaction mixture gradually became lighter, maintained at 0℃ for 20min, and then quenched with 2mL of water, and the resin turned yellow. The mixture was filtered, washed with tetrahydrofuran (2×10 mL), water, methanol (2×10 mL), and dichloromethane (2×10 mL) in sequence, the solvent was drained off, and the mixture was dried under vacuum at 65° C. to constant weight to obtain polystyrene-supported methyl selenoether resin B.
[0064] Under nitrogen atmosphere, soak 4g of methyl selenide resin B in 60mL of chloroform overnight. Add 3.5mL of bromine / chloroform solution (2M) at 0℃, stir and react at 0℃ for 30 minutes. Filter, wash with anhydrous ethanol, transfer back to the reaction bottle, add 60mL of anhydrous ethanol, react at 70℃ for 2 hours, at which time the resin changes from yellow to dark red. Filter, wash with ethanol (2×10mL) and dichloromethane (2×10mL) respectively, drain the solvent, and vacuum dry at 50℃ to constant weight to obtain polystyrene-loaded selenium bromide resin C.
[0065] Example 4: Preparation of Resin VI and Compound XI
[0066]
[0067] In a 250 mL eggplant-shaped bottle, add 10.56 g of compound III (10 mmol), 100 mL of a mixed solvent of acetonitrile: water = 4:11, and NBS (2.32 g, 12 mmol, 1.2 eq). Stir and react at room temperature for 5 hours under light-proof conditions, add 2.7 mL of ammonia water (28 wt%) to the reaction, stir and react at room temperature for 8 hours under light-proof conditions, monitor the reaction with a TLC plate (IVa: Pet / EtOAc = 1 / 2, IVb: Pet / EtOAc / MeOH = 2 / 10 / 1), add a saturated sodium chloride solution after the reaction is complete, extract twice with 100 mL EtOAc, collect the organic layer, evaporate the solvent to obtain a mixture of IVa and IVb (10.3 g, 96.0%).
[0068] (It should also be noted that: in the above steps, if no ammonia water is added, that is, if this operation is not performed: "add 2.7 mL of ammonia water (28 wt%) to the reaction, stir and react at room temperature for 8 hours under light-proof conditions", the reaction will finally produce a mixture of four substances IVa, IVb, IVc and IVd, and the yield of the mixture of IVa and IVb will be halved, as shown in the following formula:)
[0069]
[0070] The mixture of IVa and IVb obtained above was dissolved in 210 mL of a mixed solvent of MeOH:CHCl3=2:1, and benzyl chloroformate (3.4 mL, 24 mmol) and NaHCO3 (2.00 g, 24 mmol) were added. The mixture was stirred at room temperature for 5 hours, and the reaction was monitored by a TLC plate (Pet / EtOAc=5 / 1). After the reaction was complete, a saturated sodium chloride solution was added, and the mixture was extracted twice with 100 mL of EtOAc, and the organic layer was collected, concentrated, and purified by silica gel column chromatography (Pet:EtOAc=5:1) to obtain a mixture of Va and Vb (12.53 g, 97.3%).
[0071] In a reaction flask, weigh 6.67g of selenium bromide resin C, soak it in 100mL of dichloromethane for 1 hour, start mechanical stirring, and drop the above-obtained mixture of Va and Vb (dissolved in 60mL of dichloromethane) at room temperature. The addition is completed in about half an hour, and the reaction is continued at room temperature for 12 hours. After the reaction is completed, filter, wash the filter cake (resin) with dichloromethane 2 times the volume of the resin bed 3 times, and dry the washed resin under reduced pressure at 40°C to constant weight to obtain 11.3g of resin VI; combine the filtrate, evaporate the solvent, and purify the crude product by silica gel column chromatography (first use Pet / EtOAc=10 / 1 to elute benzyl bromide, and then use Pet / EtOAc=2 / 1 to elute Vb), to obtain 6.01g of compound Vb, with a molar yield of 89.5% based on compound III.
[0072] In a hydrogenation reactor, the compound Vb (6.15 g, 9.15 mmol) obtained above, 80 mL of a mixed solvent of MeOH:H2O=1:1, and 0.288 g of 10% Pd / C (3% of the molar amount of compound Vb) were added, and hydrogenation was performed at 60°C and a hydrogen pressure of 3 MPa for 48 h. Solid impurities were removed by filtration, and the solvent was evaporated to dryness to obtain 1.56 g of compound XI, with a yield of 96.3%.
[0073] The table characterization of compound XI is as follows:
[0074] = +56° (c = 0.38, H2O). 1H NMR (500MHz, D2O): δ1.38(m,1H),1.68-1.79(m,2H),3.14-3.19(m,2H),3.41(dd,J=5.0,10.4Hz ,1H),3.47(dd,J=10.4,10.4Hz,1H),3.56(dd,J=6.0,11.6Hz,1H),3.65(dd,J=4.0,11.6Hz,1H).
[0075] Example 5: Preparation of Compound VII
[0076] Resin VI (11.3 g) obtained in Example 4 was soaked in DMF (DMF was twice the volume of the resin bed) for 1 hour, mechanical stirring was started, sodium borohydride (0.76 g, 20 mmol, 2.0 eq) was added in batches at room temperature, the reaction was continued for 5 hours, filtered, the filter cake (resin) was washed twice with DMF twice the volume of the resin bed, and the resin was collected for later regeneration. The DMF washings and filtrates were combined, 200 mL of water was added, and 80 mL of EtOAc was used for extraction 3 times. The EtOAc phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 5.13 g of compound VII, which was 88.46% in molar yield based on compound III. The characterization of compound VII is as follows:
[0077] 1 H NMR (500MHz, CDCl3) δ7.64-7.09 (m, 21H), 6.93 (d, J = 5.0Hz, 1H), 4.91 (dd, J = 20. 2,11.0Hz,2H),4.79-4.67(m,4H),4.62(dd,J=25.4,11.7Hz,2H),4.46(d,J=12. 0Hz,1H),4.24(dd,J=8.9,2.8Hz,1H),4.09(d,J=9.4Hz,1H),4.03(t,J=9.1Hz,1 H), 3.85 (d, J = 11.0Hz, 1H), 3.66 (dt, J = 4.9, 3.1Hz, 1H), 3.41 (d, J = 11.0Hz, 1H). 13 C NMR (125MHz, CDCl3) δ152.7,138.2,137.7,137.7,137.6,128.7,128.4,128.4,128. 4,128.2,128.2,128.1,128.1,128.0,127.83,127.75,85.4,82.1,80.5,79.8,76.3 75.6,73.9,73.1,70.6,52.4,40.4.
[0078] Example 6: Preparation of Compound VIII
[0079]
[0080] Into the reaction flask, add 5.79g of compound VII (10mmol), 60mL of a mixed solvent of H2O / THF=1 / 3, and NaOH (0.8g, 20mmol, 2eq), stir at room temperature, and monitor the reaction using a TLC plate (Pet / EtOAc=4 / 1) to see if the reaction is complete. After the reaction is complete, add 100mL of water, extract twice with EtOAc, wash twice with 80mL of a saturated sodium chloride solution, and evaporate the solvent to obtain compound VIII (5.30g, 95.7%).
[0081] 1 H NMR (500MHz, CDCl3) δ7.45-7.39(m,2H),7.39-7.10(m,21H),4.93-4.79(m,5H),4.50(d,J=11.2Hz,1H),4.46-4.34(m,2H),3.93(dd,J= 8.3,3.6Hz,1H),3.83-3.75(m,1H),3.56(d,J=8.7Hz,1H),3.43(dd,J=18.5,9.7Hz,3H),2.67(dd,J=6.0,3.6Hz,1H),2.60-2.54(m,1H). 13 C NMR (125MHz, CDCl3) δ128.39,128.36,128.34,128.05,127.96,127.93,127.84,127.72,127 .69,127.56,80.34,79.51,78.74,75.69,75.59,73.38,72.94,72.68,71.16,37.77,36.12.
[0082] Example 7: Preparation of Compound X
[0083]
[0084] In a reaction flask, add 5.54 g (10 mmol) of compound VIII, dissolve it in 50 mL THF, 1,3-dihydroxyacetone (1.35 g, 15 mmol, 1.5 eq), and 0.5 mL of hydrochloric acid (2 M). Stir the reaction at room temperature for 3 hours. After the reaction is completed, evaporate the solvent, and purify the residue by column chromatography (first eluted with Pet / EtOAc / EtOH=4 / 4 / 1) to obtain 5.74 g of compound X, with a yield of 91.7%.
[0085] 1H NMR (500MHz, CDCl3) δ7.51-7.10 (m, 23H), 4.97-4.75 (m, 4H), 4.69 (d, J = 11.7Hz, 1H) ,4.63(d,J=11.7Hz,1H),4.50(dd,J=14.0,11.5Hz,2H),4.41(d,J=11.9Hz,1H),4.31 -4.23(m,1H),3.93(dd,J=10.4,8.5Hz,1H),3.73(dd,J=8.5,3.1Hz,1H),3.59(d,J= 18.2Hz,1H),3.55-3.38(m,5H),3.33(dd,J=12.1,7.5Hz,1H),2.66(d,J=6.0Hz,1H). 13 C NMR (125MHz, CDCl3) δ138.28,137.88,128.46,128.44,128.40,128.35,128.21,127.97,127.87,127.82,127 .73,127.60,127.55,127.37,81.03,80.05,79.46,75.84,75.71,74.10,73.43,73.03,72.00,64.08,36.99.
[0086] Example 8: Preparation of Voglibose I
[0087]
[0088] In a hydrogenation reactor, the compound X (6.26 g, 10.0 mmol) obtained above, 80 mL of a mixed solvent of MeOH:H2O=1:1, and 0.426 g of 10% Pd / C (4% of the molar amount of compound X) were added, and hydrogenation was performed at 60°C and a hydrogen pressure of 3 MPa for 48 h. Solid impurities were removed by filtration, and the solvent was evaporated to dryness to obtain 2.55 g of compound I with a yield of 95.4%.
[0089] The table characterization of compound I is as follows:
[0090] = +26.1° (c = 1, H2O). 1H NMR(500MHz,D2O)δ3.67(t,J=9.7Hz,1H),3.57-3.45(m,4H),3.42(dd,J=11.5,6.7Hz,1H),3.38-3.29(m,2H),3.24(d ,J=9.4Hz,1H),3.21(q,J=3.4Hz,1H),2.74-2.66(m,1H),1.88(dd,J=15.2,3.2Hz,1H),1.34(dd,J=15.2,2.8Hz,1H). 13 C NMR(125MHz,D2O)δ76.04,73.87,72.92,71.85,64.98,62.02,58.32,56.32,54.25,29.12.LC-MS(EI):m / z 268.12[M+1] + .
[0091] Example 9: Regeneration and recycling of resin C
[0092] Collect the resins used in the previous several times, wash them with tetrahydrofuran, water, tetrahydrofuran, and dichloromethane twice the volume of the resin, and vacuum dry them at 40°C to constant weight. Under a nitrogen atmosphere, weigh 4g of the dried resin and soak it in 60mL of chloroform for 2 hours. Add 3.5mL of bromine / chloroform solution (2M) at 0°C and stir at 0°C for 30 minutes. Filter, wash with anhydrous ethanol, transfer back to the reaction bottle, add 60mL of anhydrous ethanol, and react at 70°C for 2 hours. At this time, the resin turns dark red. Filter, wash with ethanol (2×10mL) and dichloromethane (2×10mL) respectively, drain the solvent, and vacuum dry at 50°C to constant weight to obtain the regenerated polystyrene-loaded selenium bromide resin C.
[0093] Weigh 4.20g of the above-mentioned regenerated selenium bromide resin C in a reaction bottle, soak it with 60mL of dichloromethane for 1 hour, start mechanical stirring, and drop Va and Vb mixture (8.05g is dissolved in 50mL of dichloromethane) at room temperature. The addition is completed in about half an hour, and the reaction is continued at room temperature for 12 hours. After the reaction is completed, filter, wash the filter cake (resin) with dichloromethane 2 times the volume of the resin bed 3 times, and dry the washed resin under reduced pressure at 40°C to constant weight to obtain 7.17g of resin VI; combine the filtrate, evaporate the solvent, and purify the crude product by silica gel column chromatography (first use Pet / EtOAc=10 / 1 to elute benzyl bromide, and then use Pet / EtOAc=2 / 1 to elute Vb), and obtain 3.85g of compound Vb, with a molar yield of 95.5% based on compound Va. The following operating steps are the same as in Example 5, and finally 3.29g of compound VII is obtained, with a molar yield of 94.7% based on compound Va.
Claims
1. A method for preparing voglibose, characterized in that: include: (1) Using Jinggangmycin as the starting material, hydrolyzing it with sulfuric acid, and separating and purifying it with cation and anion exchange resins to obtain Jinggang hydroxylamine A; Jinggang hydroxylamine A is protected by benzyl group to obtain compound (III); (2) Compound (III) undergoes CN bond cleavage in an acetonitrile / water mixed solvent under the action of NBS and ammonia to obtain a mixture of compound (IVa) and compound (IVb); the mixture of compound (IVa) and compound (IVb) is protected by benzyloxycarbonyl to obtain a mixture of compound (Va) and compound (Vb); (3) adding selenium bromide resin to the mixture of compound (Va) and compound (Vb), wherein compound (Va) containing a double bond undergoes intramolecular cyclization to form a rigid lactone compound and is immobilized on the resin via a carbon-selenium bond to form resin (VI), thereby achieving separation from compound (Vb); (4) Resin (VI) is cleaved with sodium borohydride to obtain compound (VII); compound (Vb) is deprotected by Pd / C hydrogenation to obtain compound (XI), namely, jinggangmycinamine; (5) Compound (VII) is hydrolyzed to obtain compound (VIII); compound (VIII) is subjected to dehydration condensation with 1,3-dihydroxyacetone to obtain compound (X); compound (X) is deprotected by Pd / C hydrogenation to obtain voglibose (I); The route is as follows:
2. The method for preparing voglibose according to claim 1, characterized in that: Step (2) is as follows: Compound (III), acetonitrile / water mixed solvent and NBS are mixed, stirred and reacted at room temperature for 5 hours under light-proof conditions, then ammonia water is added, and the reaction is continued to be stirred and reacted at room temperature for 8 hours under light-proof conditions, then a saturated sodium chloride solution is added, extracted with ethyl acetate, the organic layer is collected, and evaporated to dryness to obtain a mixture of compound (IVa) and compound (IVb); the mixture of compound (IVa) and compound (IVb) is dissolved in a MeOH / CHCl3 mixed solvent, benzyl chloroformate and NaHCO3 are added, stirred and reacted at room temperature for 5 hours, then a saturated sodium chloride solution is added, extracted with ethyl acetate, the organic layer is collected, concentrated, and purified by silica gel column chromatography to obtain a mixture of compound (Va) and compound (Vb).
3. The method for preparing voglibose according to claim 2, characterized in that: The feed ratio of compound (III), NBS and aqueous ammonia is 10 mmol:12 mmol:2.7 mL.
4. The method for preparing voglibose according to claim 2, characterized in that: A mixed solvent of acetonitrile / water with a volume ratio of 4:
1.
5. The method for preparing voglibose according to claim 2, characterized in that: The feed ratio of compound (III), benzyl chloroformate and NaHCO3 is 10mmol:24mmol:24mmol.
6. The method for preparing voglibose according to claim 2, characterized in that: A mixed solvent of MeOH / CHCl3 with a volume ratio of 2:
1.
7. The method for preparing voglibose according to claim 1, characterized in that: Step (3) is as follows: The mixed solution obtained by soaking the selenium bromide resin in dichloromethane for 1 hour is added dropwise to the mixture of compound (Va) and compound (Vb), reacted at room temperature for 12 hours, then filtered, the filter cake is washed with dichloromethane and dried to obtain resin (VI); the filtrate is evaporated to dryness and purified by silica gel column chromatography to obtain compound (Vb).
8. The method for preparing voglibose according to claim 7, characterized in that: The mass ratio of the mixture of selenium bromide resin, compound (Va) and compound (Vb) is 6.67:12.
53.
9. The method for preparing voglibose according to claim 7, characterized in that: Selenium bromide resin was prepared as follows: S1: Under nitrogen atmosphere, 1% cross-linked polystyrene resin was soaked in cyclohexane for 8-12 hours, then tetramethylethylenediamine and n-butyllithium were added under stirring at room temperature, the temperature was raised to 65-70°C for reaction for 4 hours, cooled to room temperature, filtered under nitrogen protection, the filtered resin was mixed with tetrahydrofuran, cooled to 0°C, dimethyl diselenide was added under stirring, the temperature was maintained at 0°C for reaction for 20 minutes, the reaction was quenched with water, filtered, washed, and dried to obtain methylselenoether resin; S2: Under nitrogen atmosphere, methyl selenide resin was soaked in chloroform for 8-12 hours, bromine / chloroform solution was added at 0°C, stirred and reacted for 30 minutes at 0°C, filtered, the filtered resin was mixed with anhydrous ethanol, reacted at 70°C for 2 hours, filtered, washed and dried to obtain selenium bromide resin.