Method for separating and purifying vindoline intermediate and diastereoisomer thereof

Abstract

The invention relates to the technical field of organic synthesis, and provides a method for separating and purifying a vindoline intermediate and a diastereoisomer thereof, which comprises the following steps: dissolving a mixture of the vindoline intermediate and the diastereoisomer in a first solvent, adding acid to form salt, precipitating and filtering to obtain a filtrate and a filtrate; and dissolving the filtrate in a second solvent, and adding alkali for dissociation to obtain the vindoline intermediate. The separation and purification method provided by the invention can be used for efficiently separating and purifying the vindoline intermediate and the diastereoisomer thereof generated in the synthesis process of the vindoline, has the advantages of simplicity and convenience in operation, low cost, high separation efficiency and the like, and lays an important foundation for industrial preparation of the vindoline.

Description

Technical Field

[0001] This disclosure relates to the field of organic synthesis technology, and for example to a method for the separation and purification of vendolene intermediates and their diastereomers. Background Technology

[0002] Vendolin 1 belongs to the leucobrine type of monoterpenoid indole alkaloids, possessing a highly functionalized pentacyclic skeleton containing three quaternary carbons and six consecutive chiral centers. Vendolin 1 and vincristine 2 are semi-synthetic raw materials for a series of vincristine antitumor drugs (e.g., vincristine and vinblastine). However, the content of vendolin 1 in its source plant, Madagascar periwinkle, is low (0.04%), limiting its availability. Therefore, developing an efficient total synthetic route is one of the effective ways to obtain vendolin 1 on a large scale. The route for reacting vendolin 1 with vincristine 2 to obtain vincristine 3 and vincristine 4 is as follows:

[0003]

[0004] Since the Büchi group completed the total synthesis of the racemic form of vendolin in 1975, 15 research groups have reported on the synthesis of vendolin, including 7 examples of asymmetric total synthesis. Among the known asymmetric total synthetic routes of vendolin to date, the route developed by the Kuehne group (Kuehne, ME et al. J. Org. Chem. 1987, 52, 347) has the highest synthetic efficiency (7%), the shortest number of steps, and shows promise for industrial application. Its synthetic route is as follows:

[0005]

[0006] The key step in the above synthetic route is the use of indole-aza Intermediate 5 undergoes a condensation / cleavage / intramolecular cycloaddition tandem reaction with chiral lactol 6 to construct the pentacyclic skeleton of vendolin. Compounds 7 and 8, generated in the above process, exist as a pair of diastereomers (dr = 1:4). Intermediate 8 is obtained by silica gel column chromatography, and further transformation of intermediate 8 completes the total synthesis of vendolin. However, the physicochemical properties of compounds 7 and 8 generated in the above process are similar, requiring column chromatography for separation, which is not conducive to industrial production.

[0007] Therefore, developing a simple and efficient method for the separation and purification of vendolene intermediate 8 is of great significance for achieving the total synthesis of this alkaloid and its industrial production in the form of vinblastine drugs. Summary of the Invention

[0008] The purpose of this disclosure is to overcome the shortcomings of the prior art and provide a method for separating and purifying vendolene intermediates and their diastereomers, so as to achieve at least the effects of simple operation, low cost and high separation efficiency.

[0009] The purpose of this disclosure is achieved through the following technical solution:

[0010] On the one hand, a method for separating and purifying a vendolin intermediate and its diastereomers is provided. The method includes: dissolving a mixture of the vendolin intermediate and the diastereomers in a first solvent, then adding acid to form a salt, followed by precipitation and filtration to obtain a filtrate and a filtrate; and dissolving the filtrate in a second solvent, then adding alkali to release it, to obtain the vendolin intermediate.

[0011] The structure of the Vendolene intermediate is shown in Formula I:

[0012]

[0013] The structure of the diastereomer is shown in Formula II:

[0014]

[0015] In some embodiments, the separation and purification method further includes: adding alkali to the filtrate to obtain the diastereomer.

[0016] In some embodiments, the acid includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, acetic acid, citric acid, succinic acid, p-toluenesulfonic acid, oxalic acid, S-mandelic acid, R-mandelic acid, D-camphorsulfonic acid, L-camphorsulfonic acid, D-tartaric acid, and L-tartaric acid.

[0017] In some embodiments, the acid includes S-mandelic acid.

[0018] In some embodiments, the ratio between the sum of the amounts of the vendolene intermediate and the diastereomer and the amount of the acid is 1:1 to 10.

[0019] In some examples, the ratio of the sum of the amounts of the vendolene intermediate and the diastereomer to the amount of the acid is 1:2.

[0020] It should be understood that the types of alkalis include a variety, and any alkaline reagent that can make the filtrate free is included within the scope of protection of this disclosure. Those skilled in the art can make an appropriate selection according to actual needs, and this disclosure does not limit it.

[0021] In some embodiments, the alkali includes one or more of ammonia, triethylamine, diisopropylethylamine, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.

[0022] In some examples, the alkali includes at least one of the sodium carbonate and the sodium hydroxide.

[0023] In some embodiments, the ratio of the sum of the amounts of the vendolene intermediate and the diastereomer to the amount of the base is 1:1 to 10.

[0024] In some embodiments, the first solvent includes one or more of n-hexane, petroleum ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, and ethyl acetate.

[0025] In some embodiments, the second solvent includes one or more of n-hexane, petroleum ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, and ethyl acetate.

[0026] The beneficial effects of this disclosure are:

[0027] This disclosure provides a method for the separation and purification of vendolin intermediates and their diastereomers. By employing acid addition for salt formation, precipitation, filtration, and alkali addition for ionization, this method can efficiently separate and purify vendolin intermediates and their diastereomers generated during the synthesis of vendolin. Compared with the cumbersome column chromatography methods reported in the literature, this method has the advantages of simple operation, low cost, and high separation efficiency, laying an important foundation for the industrial preparation of vendolin. Detailed Implementation

[0028] The technical solutions in some embodiments of this disclosure will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this disclosure, and not all embodiments. Based on the embodiments provided in this disclosure, all other embodiments obtained by those skilled in the art are within the scope of protection of this disclosure.

[0029] Unless the context otherwise requires, throughout the specification and claims, the term "comprising" is interpreted as open and encompassing, that is, "including, but not limited to".

[0030] Hereinafter, the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined with "first," "second," etc., may explicitly or implicitly include one or more of that feature.

[0031] In describing some embodiments, the expressions "at least one of A, B and C" and "at least one of A, B or C" may be used, both of which have the same meaning and include the following combinations of A, B and C: only A, only B, only C, a combination of A and B, a combination of A and C, a combination of B and C, and a combination of A, B and C.

[0032] Example 1

[0033]

[0034] Compound 6 (5.0 g, 18.2 mmol, 1.0 equiv.), compound 5 (4.5 g, 27.3 mmol, 1.5 equiv.), and boric acid (0.18 g, 2.92 mmol, 0.16 equiv.) were placed in a flask, and 75 mL of ultradry methanol was added. The mixture was refluxed for 24 h, and then triethylamine (5.0 mL, 36.4 mmol, 2.0 equiv.) was added, followed by reflux for another 12 h. After the reaction was complete, the mixture was cooled to room temperature, and 50 mL of saturated ammonium chloride solution was added. The mixture was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude 7 / 8 mixture (the ratio was approximately 1:4 according to the 1H NMR spectrum). The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 100 / 1-50 / 1) to give 4.9 g of the pure 7 / 8 mixture, with a yield of 68%.

[0035] Weigh out the pure product of the 7 / 8 mixture obtained in the above steps (dr = 1:4, 1.9 g, 5.00 mmol), dissolve it in methyl tert-butyl ether (20 mL), add S-mandelic acid (1.5 g, 10.0 mmol), stir overnight at room temperature, and a white solid precipitates. Filter to give 2.6 g of product, with a yield of 72%.

[0036] Add 20 mL of ethyl acetate and 10 mL of saturated sodium carbonate aqueous solution to the above product, stir at room temperature for 30 min, and then separate the layers. Extract the aqueous layer with ethyl acetate (10 mL × 2). Combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 8 (white foamy solid, dr > 30: 1, 1.4 g, yield 97%).

[0037] 1H-NMR (400MHz, Chloroform-d) δ8.91 (br s, 1H), 7.06 (d, J=8.0Hz, 1H), 6.40–6.37 (m, 2H), 3.94 (br s,1H),3.77(s,3H),3.76(s,3H),3.15(dt,J=11.2,2.4Hz,1H),2.92(dd,J=8.8,6.4Hz,1H),2.72(dd,J=11.6,2.4Hz,1H),2 .70–2.64(m,2H),2.58–2.53(m,1H),2.45(s,1H),2.08–1.98(m,2H),1.72(dd,J=11.6,4.4Hz,1H),1.40(dd,J=14.8,4.0Hz 1H), 1.04 (dd, J=16.4, 10.4Hz, 1H), 0.62–0.55 (m, 4H).

[0038] 13 C NMR(100MHz,Chloroform-d)δ168.8,167.2,160.0,144.3,130.0,121.4,104.9,96. 7,93.3,73.7,66.6,57.5,55.4,54.6,51.2,50.9,44.9,40.0,38.7,29.5,27.7,7.1.

[0039] Example 2

[0040] Compound 6 (1.0 g, 3.65 mmol, 1.0 equiv.) was prepared into a crude mixture of 7 / 8 according to the above procedure. This mixture was dissolved in 10 mL of ethyl acetate, and S-mandelic acid (1.1 g, 7.30 mmol, 2.0 equiv.) was added. The mixture was stirred overnight at room temperature, resulting in the precipitation of a white solid. 1.2 g of the product was filtered off. 10 mL of ethyl acetate and 8 mL of saturated sodium carbonate aqueous solution were added to the product. The mixture was stirred at room temperature for 30 min, and then separated. The aqueous layer was extracted with ethyl acetate (10 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 8 (white foamy solid, dr > 30:1, 0.65 g, total yield 46%).

[0041] Example 3

[0042] Compound 6 (1.0 g, 3.65 mmol, 1.0 equiv.) was prepared into a crude mixture of 7 / 8 according to the above procedure. This mixture was dissolved in 10 mL of ethyl acetate, and S-mandelic acid (1.1 g, 7.30 mmol, 2.0 equiv.) was added. The mixture was stirred at room temperature for 2 h, resulting in the precipitation of a white solid. 1.2 g of the product was filtered off. 10 mL of ethyl acetate and 8 mL of 5% sodium hydroxide aqueous solution were added to the product. The mixture was stirred at room temperature for 30 min, and then separated. The aqueous layer was extracted with ethyl acetate (10 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 8 (white foamy solid, dr > 30:1, 0.66 g, total yield 47%).

[0043] Therefore, the method for separating and purifying vendolin intermediates and their diastereomers provided in this disclosure can efficiently separate and purify vendolin intermediates and their diastereomers generated during the synthesis of vendolin. Compared with the cumbersome column chromatography method reported in the literature, it has the advantages of simple operation, low cost and high separation efficiency, laying an important foundation for the industrial preparation of vendolin.

[0044] The above description is merely a preferred embodiment of this disclosure. It should be understood that this disclosure is not limited to the forms disclosed herein and should not be construed as excluding other embodiments. It can be used in various other combinations, modifications, and environments, and can be altered within the scope of the concept described herein through the above teachings or techniques or knowledge in related fields. Any modifications and variations made by those skilled in the art that do not depart from the spirit and scope of this disclosure should be within the protection scope of the appended claims.

Claims

1. A method for isolating and purifying vendolene intermediates and their diastereomers, characterized in that, include: The mixture of the vendolin intermediate and the diastereomer is dissolved in a first solvent and then acidified to form a salt. After precipitation and filtration, the filtrate and filtrate are obtained. and The filtrate was dissolved in a second solvent and then alkali was added to release it, yielding the vendolene intermediate. The structure of the Vendolene intermediate is shown in Formula I: The structure of the diastereomer is shown in Formula II:

2. The separation and purification method according to claim 1, characterized in that, Also includes: The filtrate is then alkali-added to release the diastereomer, thus obtaining the diastereomer.

3. The separation and purification method according to claim 1 or 2, characterized in that, The acid includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, acetic acid, citric acid, succinic acid, p-toluenesulfonic acid, oxalic acid, S-mandelic acid, R-mandelic acid, D-camphorsulfonic acid, L-camphorsulfonic acid, D-tartaric acid, and L-tartaric acid.

4. The separation and purification method according to claim 3, characterized in that, The acid includes S-mandelic acid.

5. The separation and purification method according to claim 3, characterized in that, The ratio of the sum of the amounts of the vendolene intermediate and the diastereomer to the amount of the acid is 1:1 to 10.

6. The separation and purification method according to claim 1 or 2, characterized in that, The alkali includes one or more of the following: ammonia, triethylamine, diisopropylethylamine, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.

7. The separation and purification method according to claim 6, characterized in that, The ratio of the sum of the amounts of the vendolene intermediate and the diastereomer to the amount of the base is 1:1 to 10.

8. The separation and purification method according to claim 1, characterized in that, The first solvent includes one or more of n-hexane, petroleum ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, and ethyl acetate.

9. The separation and purification method according to claim 1, characterized in that, The second solvent includes one or more of n-hexane, petroleum ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, and ethyl acetate.

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