Asymmetric synthesis method of allocolchicine

Abstract

The invention relates to an asymmetric synthesis method of allocolchicine, which is characterized in that 3-hydroxyacetophenone is used as an initial raw material, a key chiral center is constructed by using a ruthenium-catalyzed asymmetric reductive amination reaction, three different allocolchicine drugs are rapidly constructed through the steps of intermolecular Suzuki coupling, intramolecular oxidation cyclization and the like, the route is simple and efficient, and the method is suitable for industrial production. The method has the advantages of no introduction and removal of chemical protecting groups, no dangerous reactions such as long-term high-temperature pressurization, hydrogenation and the like, capability of obtaining the allocolchicine compound only through three to four steps of reactions, safety, greenness, environmental protection and low raw material cost.

Description

An asymmetric synthesis method for colchicine Technical Field

[0001] This invention relates to the field of compound synthesis, and specifically to an asymmetric synthesis method for colchicine. Background Technology

[0002] Allocolchicine is an important class of colchicine derivatives, such as J.Nat.Prod.2019,82,2659. 2663. The structural formula of the recorded colchicine is shown below:

[0003] It can selectively destroy tumor blood vessels and has good anti-tumor activity. Compared with the parent colchicine, allocorycin drugs generally have more efficient and less toxic characteristics. However, the acquisition of these drugs often requires degradation of naturally extracted colchicine or complicated chemical synthesis steps. At present, there are only two reported synthesis of allocorycin: (1) Yang Yurong et al. (CN110963937A) started from the raw material isovanillin and used the asymmetric allyl amination of the transition metal iridium and the chiral ligand to obtain a chiral amino compound, and then obtained allocorycin H by palladium catalytic coupling and oxidative cyclization. However, this method requires the use of expensive chiral ligands and noble metal iridium (Ir(cod)Cl2) as chiral catalysts, and the reaction environment is harsh, which makes it difficult to scale up production due to high cost. Its main synthesis route is as follows:

[0004] (2) Wu Zhengzhi et al. (CN114907227A) prepared a biphenyl ring compound using the Aldol condensation reaction and constructed a key chiral amino compound using chiral tert-butylsulfinamide. The compound then underwent oxidative ring closure to obtain colchicine H. This synthetic method involves nine transformations and the introduction and removal of multiple protecting groups and chiral auxiliary groups, making the process cumbersome. Furthermore, the multiple reactions involve high and low temperature environments and hydrogenation reactions, making it an undesirable synthetic route from both an economic and safety / environmental perspective.

[0005]

[0006] In summary, the current focus of colchicine-based drug synthesis technology lies in improving the safety and economy of the synthesis process, avoiding high-risk and high-cost reaction conditions and reagents, in order to meet the standards of modern green chemistry. In existing technologies, some synthetic routes involve extreme high and low temperature environments and hazardous reactions such as Grignard reagents, or are complex and costly, which not only increases operational difficulty and safety risks but also imposes a certain burden on the environment. Therefore, developing a low-cost, simple, safe, and environmentally friendly asymmetric synthesis method for colchicine-based drugs, especially a route capable of divergently synthesizing multiple colchicine drugs, has become an urgent technical problem to be solved. Summary of the Invention

[0007] The purpose of this invention is to overcome the above-mentioned technical deficiencies and provide an asymmetric synthesis method for colchicine, solving the technical problems of high cost and complex process in the synthesis of colchicine in the prior art.

[0008] To achieve the above-mentioned technical objectives, the technical solution provided by the present invention is as follows: Firstly, the present invention provides an asymmetric synthesis method for colchicine, the synthetic route of which is as follows:

[0009] The synthetic method includes the following steps: S1, 3-hydroxyacetophenone undergoes a cross-dehydrogenation coupling reaction in a first solvent under the action of an iron catalyst to generate compound J; compound J is mixed with ammonium formate, ruthenium catalyst, transition metal catalyst and a second solvent, and undergoes an asymmetric reductive amination reaction to generate compound K; the first solvent is N,N-dimethylacetamide; S2, compound K is mixed evenly with a selective hydroboration reagent in a third solvent, and then an aryl bromide and palladium catalyst are added, followed by a Suzuki aryl coupling reaction to obtain compound L; S3, compound L and Lewis acid are... The compound is added to a mixed solution of trifluoroacetic acid, trifluoroacetic anhydride, and a fourth solvent containing an oxidant, and undergoes an intramolecular oxidative coupling reaction to obtain colchicine A; or, it further includes: S4, colchicine A is dissolved in a fifth solvent, potassium carbonate and halomethane are added, and the mixture undergoes a phenolic hydroxymethyl etherification reaction to obtain colchicine B; or, it further includes: S5, colchicine A is dissolved in a sixth solvent, pyridine and trifluoromethanesulfonic anhydride are added, and the mixture is stirred to obtain compound M; compound M is dissolved in a seventh solvent containing methanol, and the mixture is heated under a palladium catalyst and a CO atmosphere to obtain colchicine C.

[0010] Compared with existing technologies, the beneficial effects of this invention include: Using 3-hydroxyacetophenone as a starting material, this invention utilizes ruthenium-catalyzed asymmetric reductive amination to construct key chiral centers, and rapidly constructs three different colchicine-like drugs through intermolecular suzuki coupling and intramolecular oxidative cyclization. The route is simple and efficient, without the introduction and removal of chemical protecting groups, and without dangerous reactions such as prolonged high-temperature and high-pressure treatment or hydrogenation. Only three to four reaction steps are needed to obtain colchicine-like compounds. It is safe, green, and environmentally friendly, with low raw material costs, providing a route reference for the design and synthesis of colchicine and colchicine-like drugs. Attached Figure Description

[0011] Figure 1 is the HPLC chromatogram of compound K in Example 1 of the present invention; Figure 2 is the HPLC chromatogram of racemic compound K; Figure 3 is the HPLC chromatogram of colchicine A in Example 1 of the present invention. 1 1H NMR spectrum; Figure 4 shows colchicine B in Example 1 of this invention. 1 1H NMR spectrum; Figure 5 shows the colchicine C in Example 1 of this invention. 1 H NMR spectrum. Detailed Implementation

[0012] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0013] Terminology Explanation: DMA: N,N-dimethylacetamide; EtOAc: ethyl acetate; (S,S)-Ts-DPEN: (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride; La(OTf)3: lanthanum trifluoromethanesulfonate; THF: tetrahydrofuran; 9-BBN: 9-boronbicyclo[3.3.1]nonane; PhI(TFA)2: bis(trifluoroacetic acid)iodobenzene; DCM: dichloromethane; TFA: trifluoroacetic acid; TFAA: trifluoroacetic anhydride; BF3•Et2O: boron trifluoride ethyl ether; DMF: N,N-dimethylformamide; MeI: iodomethane; Et3N: triethylamine.

[0014] In a first aspect, the present invention provides an asymmetric synthesis method for colchicine, capable of divergently synthesizing three colchicine analogues, the synthetic route of which is as follows:

[0015] The synthetic method includes the following steps: S1, 3-hydroxyacetophenone undergoes a cross-dehydrogenation coupling reaction in a first solvent under the action of an iron catalyst to generate compound J; compound J is mixed with ammonium formate, ruthenium catalyst, transition metal catalyst and a second solvent, and undergoes an asymmetric reductive amination reaction to generate compound K; the first solvent is N,N-dimethylacetamide; S2, compound K is mixed evenly with a selective hydroboration reagent in a third solvent, and then an aryl bromide and palladium catalyst are added, followed by a Suzuki aryl coupling reaction to obtain compound L; S3, compound L and Lewis acid are... The compound is added to a mixed solution of trifluoroacetic acid, trifluoroacetic anhydride, and a fourth solvent containing an oxidant, and undergoes an intramolecular oxidative coupling reaction to obtain colchicine A; or, it further includes: S4, colchicine A is dissolved in a fifth solvent, potassium carbonate and halomethane are added, and the mixture undergoes a phenolic hydroxymethyl etherification reaction to obtain colchicine B; or, it further includes: S5, colchicine A is dissolved in a sixth solvent, pyridine and trifluoromethanesulfonic anhydride are added, and the mixture is stirred to obtain compound M; compound M is dissolved in a seventh solvent containing methanol, and the mixture is heated under a palladium catalyst and a CO atmosphere to obtain colchicine C.

[0016] In the preparation method of this invention, compound J is first prepared by iron-catalyzed cross-dehydrogenation coupling reaction, then compound K is prepared by transition metal-catalyzed asymmetric reductive amination reaction, compound L is prepared by palladium-catalyzed suzuki aryl coupling reaction, and colchicine A is prepared by Lewis acid-catalyzed intramolecular oxidative coupling reaction. Then, colchicine A is used as raw material to prepare colchicine B by phenolic hydroxyl methyl etherification, or colchicine C is prepared by converting phenolic hydroxyl groups to compound M and then by palladium-catalyzed benzene ring carbonylation reaction.

[0017] It should be noted that the N,N-dimethylacetamide used in step S1 and the methanol used in step S5 serve as both reaction solvents and raw materials in the reaction.

[0018] Preferably, in step S1, the iron catalyst includes ferric chloride; the molar ratio of 3-hydroxyacetophenone to the iron catalyst is 1:(0.05~0.15).

[0019] Preferably, in step S1, potassium persulfate is also added to the cross-dehydrogenation coupling reaction, and the molar ratio of 3-hydroxyacetophenone to potassium persulfate is 1:(1.5~2.5).

[0020] Preferably, in step S1, the temperature of the cross-dehydrogenation coupling reaction is 90–100°C, and the time is 2–8 h.

[0021] Preferably, in step S1, after the cross-dehydrogenation coupling reaction is completed, the reaction solution is quenched by saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with brine, dried, acetylated, and concentrated under reduced pressure to obtain compound J.

[0022] Preferably, in step S1, the ruthenium catalyst includes (S,S)-Ts-DPEN; the transition metal catalyst includes lanthanum trifluoromethanesulfonate.

[0023] Preferably, in step S1, the molar ratio of 3-hydroxyacetophenone, ammonium formate, ruthenium catalyst, and transition metal catalyst is 1:(2-4):(0.005-0.015):(0.01-0.1).

[0024] Preferably, in step S1, the temperature of the asymmetric reductive amination reaction is 10–30°C, and the time is 10–14 h.

[0025] Preferably, in step S1, after the asymmetric reductive amination reaction is completed, the reaction solution is quenched by saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with brine, dried, filtered, acetic anhydride is added to the filtrate and concentrated under reduced pressure, and purified by column chromatography to obtain compound K.

[0026] Preferably, in step S1, the second solvent includes methanol.

[0027] Preferably, in step S2, the selective borohydride reagent includes 9-boronbicyclo[3.3.1]nonane; the molar ratio of compound K to the selective borohydride reagent is 1:(2-4).

[0028] Preferably, in step S2, the third solvent comprises tetrahydrofuran.

[0029] Preferably, in step S2, compound K and the selective borohydride reagent are mixed evenly in a third solvent, specifically including: mixing compound K and the selective borohydride reagent in a third solvent at 0-4°C, heating to 10-30°C and stirring for 3.5-4.5 h, then cooling to 0-4°C, quenching with water and continuing to stir for 10-20 min.

[0030] Preferably, in step S2, the molar ratio of compound K to the aryl bromide is 1:(2-4).

[0031] Preferably, in step S2, the palladium catalyst includes Pd(PPh3)4; the molar ratio of compound K to palladium catalyst is 1:(0.02~0.08).

[0032] Preferably, in step S2, K3PO4 is also added to the suzuki aryl coupling reaction, and the molar ratio of compound K to K3PO4 is 1:(2-4).

[0033] Preferably, in step S2, the suzuki aryl coupling reaction is carried out under a protective atmosphere by heating and reflux for 1 to 3 hours.

[0034] Preferably, in step S3, the Lewis acid includes boron trifluoride diethyl ether; the molar ratio of compound L to Lewis acid is 1:(1.5-2.5).

[0035] Preferably, in step S3, the preparation steps of trifluoroacetic acid-trifluoroacetic anhydride-fourth solvent include: first mixing the oxidant and the fourth solvent, then adding trifluoroacetic acid and trifluoroacetic anhydride, mixing evenly and cooling to -45 to -35°C.

[0036] More preferably, the molar ratio of compound L to oxidant is 1:(1.05-1.2), the oxidant includes PhI(TFA)2; the ratio between compound L, trifluoroacetic acid and trifluoroacetic anhydride is 1 mmol:(5-7) mL:(1-2) mL.

[0037] Preferably, in step S3, the intramolecular oxidative coupling reaction is carried out at 10–30°C for 3–5 hours.

[0038] Preferably, in step S3, the fourth solvent includes dichloromethane.

[0039] Preferably, in step S4, the halomethane includes chloromethane, bromomethane, or iodomethane; the molar ratio of colchicine A, potassium carbonate, and halomethane is 1:(1.2-1.4):(1.2-1.4).

[0040] Preferably, in step S4, the temperature of the phenol hydroxymethyl etherification reaction is 10–30°C and the time is 10–24 h.

[0041] Preferably, in step S4, the fifth solvent includes N,N-dimethylformamide.

[0042] Preferably, in step S5, the molar ratio of colchicine A, pyridine and trifluoromethanesulfonic anhydride is 1:(2.4-2.8):(1.5-2.0).

[0043] Preferably, in step S5, the reaction temperature for preparing compound M is 0–4°C, and the reaction time is 2–4 h.

[0044] Preferably, in step S5, the molar ratio of compound M to triethylamine is 1:(12-18).

[0045] Preferably, in step S5, the palladium catalyst includes Pd(dppf)Cl2, and the molar ratio of compound M to palladium catalyst is 1:(0.2-0.4).

[0046] Preferably, in step S5, the heating reaction temperature is 65–75°C and the time is 6.5–7.5 h.

[0047] Preferably, in step S5, the sixth solvent includes dichloromethane; the seventh solvent is a mixture of methanol and DMF in a volume ratio of 2:1.

[0048] The main mechanism and advantages of this invention are: (1) This invention utilizes ruthenium-catalyzed asymmetric reduction amination reaction to construct the key chiral center of drugs such as colchicine. Through intermolecular suzu-coupling and intramolecular oxidative cyclization, three different colchicine drugs are rapidly constructed, which have potential value for medicinal chemistry research and industrial production.

[0049] (2) The route is simple and efficient, without the introduction and removal of chemical protecting groups, and without dangerous reactions such as long-term high temperature and pressure or hydrogenation. It only takes three to four steps to obtain colchicine drug, which is safe, green and environmentally friendly.

[0050] (3) The reagents and catalysts used in this method (Ts-DPEN 50 yuan / g) have a significant price advantage compared with the existing synthetic route (Ir(cod)Cl2 2500 yuan / g), and the steps are simple and easy to operate, with obvious cost advantages.

[0051] (4) One route can be used to synthesize multiple drugs of the colchicine family in a divergent manner, which not only improves the synthesis efficiency and saves production costs, but also provides a model for the design and synthesis of other similar drugs in this family.

[0052] The present invention will be further described in detail below through specific embodiments.

[0053] Example 1: An asymmetric synthesis method for colchicine A, comprising the following steps: S1, 3-hydroxyacetophenone undergoes a cross-dehydrogenation coupling reaction in the presence of an iron catalyst to generate compound J; compound J is mixed with a ruthenium catalyst, a transition metal catalyst, and methanol, and undergoes an asymmetric reductive amination reaction to generate compound K:

[0054] S101, At room temperature, ferric chloride hexahydrate (270 mg, 0.1 equivalent) and potassium persulfate (5.4 g, 2.0 equivalent) were added to a DMA (50 mL) solution of m-hydroxyacetophenone (1.36 g, 10.0 mmol, 1.0 equivalent). The mixture was stirred at 100 °C for 120 min, then quenched with a saturated ammonium chloride aqueous solution. The aqueous phase was extracted with EtOAc (2 × 100 mL), the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound J (no further purification required; the crude product was used directly in subsequent steps).

[0055] In step S102, under a nitrogen atmosphere, the crude product of compound J from the previous step, (S,S)-Ts-DPEN (63 mg, 0.1 mmol, 1 mol%), ammonium formate (1.89 g, 3.0 equivalent), La(OTf)3 (293 mg, 0.05 equivalent), and dry methanol (30 mL) were added to a dry 100 mL round-bottom flask. The reaction mixture was stirred at room temperature for 12 hours, then quenched with a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with EtOAc (2 × 100 mL), the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated with acetic anhydride (2 mL) under reduced pressure. The crude residue was purified by rapid silica gel column chromatography (petroleum ether / EtOAc 1:1) to give a yellow oily product (1.42 g, 75%, two-step yield), denoted as compound K.

[0056] The characterization data for compound K are as follows: thin-layer chromatography shift value Rf = 0.45 (EtOAc). 1 H NMR (400 MHz, CDCl3): δ 7.16 (t, J = 7.8 Hz, 1H), 6.82 (t, J = 2.1Hz, 1H), 6.80 – 6.72 (m, 2H), 6.18 (d, J = 8.4 Hz, 1H), 5.95 (ddd, J = 17.1,10.4, 5.2 Hz, 1H), 5.60 – 5.51 (m, 1H), 5.27 – 5.14 (m, 2H), 2.01 (s, 3H).ppm. 13 C NMR (100 MHz, DMSO-d6): δ 170.4, 157.1, 141.8, 136.9, 130.1,118.4, 116.1, 115.3, 114.8, 55.5, 23.3 ppm.IR (KBr): 3289, 2730, 1852, 1930, 1852, 1136, 1100, 956, 840, 655,420 cm -1 HRMS (ESI): calc. for C 11 H 12 NO2[MH] - 190.0874, found 190.0878. Optical rotation: [α] 20.5D = -54.26° (c 1.01, CHCl3). High-performance liquid chromatography (HPLC) analysis was performed on compound K and a racemic compound K synthesized from a racemic catalyst (only in step S102, (S,S)-Ts-DPEN was replaced with ruthenium trichloride trihydrate (RuCl3·3H2O), while the remaining steps and conditions were the same as those for compound K prepared in Example 1). The chiral column was AD-H; hexanes / i-PrOH = 90 / 10; flow rate was 0.8 mL / min; retention time t1 = 3.791 min; t2 = 4.726 min (major). The results are shown in Figures 1 and 2.

[0057] As shown in Figures 1 and 2, the ee value of compound K is >99%, indicating that the reaction has good enantioselectivity.

[0058] S2, compound K and a selective borohydride reagent are mixed thoroughly in a third solvent, then an aryl bromide and a palladium catalyst are added, followed by a Suzuki aryl coupling reaction to obtain compound L:

[0059] At 0 °C, a solution of 9-BBN (18 mL, 0.5 M in THF, 9 mmol, 3.0 equivalent) was added to a THF (5 mL) solution of compound K (573 mg, 3.0 mmol, 1.0 equivalent). The reaction mixture was slowly heated to room temperature and stirred for 4 hours, then cooled to 0 °C, quenched with H2O (0.8 mL), and stirred for another 15 minutes. 5-Bromo-1,2,3-trimethoxybenzene (2.23 g, 9.0 mmol, 3.0 equivalent), Pd(PPh3)4 (174 mg, 0.15 mmol, 5 mol%), K3PO4 powder (1.91 g, 9.0 mmol, 3.0 equivalent), and DMF (3 mL, 1.0 M) were added sequentially to the resulting mixture. The resulting solution was degassed under a nitrogen stream for 0.5 hours, then heated to reflux and stirred for 2 hours. After cooling the mixture to room temperature, it was quenched with H2O (30 mL) and diluted with EtOAc (100 mL). The mixture was allowed to stand for separation, and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (petroleum ether / EtOAc 1:1 to pure EtOAc) to give the desired white solid compound L (604 mg, 56% yield).

[0060] The characterization data for compound L are as follows: thin-layer chromatography shift value Rf = 0.29 (EtOAc).

[0061] Melting point (mp): 152-154 ℃.

[0062] 1 H NMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.81 (t, J = 2.0 Hz, 1H), 6.74 (dt, J = 8.0, 2.4 Hz, 2H), 6.35 (d, J = 6.8Hz, 3H), 4.91 (q, J = 7.7 Hz, 1H), 3.84 - 3.76 (m, 9H), 2.48-2.51 (m, 2H), 2.15 - 1.96 (m, 2H), 1.92 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): δ 170.6, 157.2, 153.1, 143.2, 137.4, 136.0, 130.0, 117.5, 115.0, 114.5, 105.4, 60.9, 56.1, 53.6, 37.3, 33.0, 23.2 ppm.IR (KBr): 3074, 2737, 2615, 2008, 1954, 1373, 1184, 1038, 973, 941,914, 866, 744, 680, 646 cm -1 HRMS (ESI): calc. for C 20 H 25 NO5 [MH] - 358.1660, found 358.1667. Optical rotation: [α] 21.1 D = -64.15° (c 0.39, CHCl3).S3, compound L and boron trifluoride-diethyl ether were added to a mixed solution of trifluoroacetic acid-trifluoroacetic anhydride-a fourth solvent, and after intramolecular oxidative coupling reaction, colchicine A was obtained:

[0063] Add solid PhI(TFA)₂ (473 mg, 1.1 mmol, 1.1 equivalent) and DCM (4.5 mL) to a dry 50 mL flask. Continue adding TFA (6 mL) and TFAA (1.5 mL), and cool the mixture to -40 °C. Continue adding a DCM (2.5 mL) solution of compound L (360 mg, 1.0 mmol, 1.0 equivalent) and BF₃•Et₂O (256 μL, 2.0 mmol, 2.0 equivalent) to the reaction solution, and slowly raise the reaction mixture to room temperature. After stirring at room temperature for 4 hours, add a saturated NaHCO₃ solution (10 mL) to the resulting dark brown solution. Allow to stand for separation; the aqueous layer is extracted multiple times with DCM. Combine the organic phases, wash with brine, dry on anhydrous Na₂SO₄, and evaporate under reduced pressure. The residue was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate 1:1 to 1:2) to give the desired colchicine A (287 mg, yield 80%) as a white solid.

[0064] The characterization data for colchicine A are as follows: thin-layer chromatography shift value Rf = 0.33 (EtOAc). Melting point mp: 218-220 ℃. 1 ¹H NMR (600 MHz, CD3OD): δ 7.23 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.75 - 6.70 (m, 2H), 4.62 (dd, J = 12.3, 5.8 Hz, 1H), 3.86 (d, J = 9.2 Hz, 6H), 3.49 (s, 3H), 2.52 - 2.46 (m, 1H), 2.27-2.25 (m, 2H), 2.01 (s, 3H), 1.98 - 1.88 (m, 1H) ppm. Detailed spectral data are shown in Figure 3.

[0065] 13 C NMR (150 MHz, CD3OD): δ 172.4, 158.0, 153.7, 142.4, 136.6, 132.1,126.7, 126.5, 114.2, 110.8, 109.0, 61.6, 61.3, 56.6, 50.5, 39.9, 31.5, 22.6ppm.IR (ATR): 3432, 2932, 2854, 1611, 1544, 1432, 1375, 1195, 1085, 1051,1005, 833, 555 cm -1HRMS (ESI): calc. for C 20 H 22 NO5 [MH] - 356.1503, found 356.1512. Optical rotation: [α] 23.4 D = -46.51° (c 0.55, CHCl3). Example 2: An asymmetric synthesis method for allocoryne B, comprising the following steps:

[0066] The colchicine A obtained in Example 1 (35 mg, 0.1 mmol, 1.0 equivalent) was dissolved in DMF (1.5 mL), and then K2CO3 (17 mg, 0.13 mmol, 1.3 equivalent) and MeI (1.3 equivalent) were added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (3 mL), allowed to stand for separation, and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by rapid silica gel column chromatography (petroleum ether / EtOAc 1:1 to EtOAc) to give the desired white solid product, colchicine B (31.5 mg, 85% yield).

[0067] The characterization data for colchicine B are as follows: thin-layer chromatography shift value Rf = 0.52 (EtOAc). Melting point mp: 199-201 ℃. 1 H NMR (600 MHz, DMSO-d6): δ 8.39 (d, J = 8.6 Hz, 1H), 7.25 (d, J =8.4 Hz, 1H), 6.92 - 6.85 (m, 2H), 6.76 (s, 1H), 4.52 (dt, J = 11.9, 7.7 Hz,1H), 3.85 - 3.74 (m, 9H), 3.46 (s, 3H), 2.49 - 2.46 (m, 1H), 2.14 (dq, J =12.7, 6.3 Hz, 1H), 2.04 (td, J = 12.9, 7.1 Hz, 1H), 1.88 (s, 3H), 1.84 (dd, J= (12.1, 7.0 Hz, 1H) ppm. See Figure 4 for detailed spectral data.

[0068] 13C NMR (150 MHz, DMSO-d6): δ 168.4, 158.4, 152.1, 150.3, 141.8,134.8, 130.6, 126.2, 124.3, 110.7, 109.5, 108.1, 60.6, 60.5, 55.8, 55.0,48.1, 38.5, 30.1, 22.7 ppm.IR (KBr): 3281, 3059, 2835, 2650, 1547, 1374, 1170, 963, 728, 703,646, 520 cm -1 HRMS (ESI): calc. for C 21 H 26 NO5[M+H] + 372.1805, found 372.1803. Optical rotation: [α] 23.6 D = -78.64° (c 0.30, CHCl3). Example 3: An asymmetric synthesis method for allocetine C, comprising the following steps:

[0069] The colchicine A obtained in Example 1 (70 mg, 0.2 mmol, 1.0 equivalent) was dissolved in DCM (1.5 mL), and pyridine (42 μL, 0.52 mmol, 2.6 equivalent) was added. The solution was cooled to 0 °C. Trifluoromethanesulfonic anhydride (60 μL, 0.36 mmol, 1.8 equivalent) was added, and the mixture was stirred for 3 hours while the temperature was raised from 0 °C to room temperature. The reaction mixture was quenched with 10% hydrochloric acid (1 mL) and neutralized to alkalinity with saturated sodium bicarbonate aqueous solution. The aqueous phase was repeatedly extracted with DCM, and the organic phases were combined. After removing volatiles, the residue was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate 1:1 to ethyl acetate) to give a white solid compound M (74 mg, 0.151 mmol, 76%).

[0070] The characterization data for compound M are as follows: Thin-layer chromatography shift value Rf = 0.74 (EtOAc). Melting point mp: 161-163 ℃. 11H NMR (600 MHz, DMSO-d6): δ 8.50 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.5, 2.7 Hz, 1H), 7.34 (d, J = 2.7 Hz, 1H), 6.83 (s, 1H), 4.52 (dt, J = 12.1, 7.7 Hz, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.54 (s, 3H), 2.56 (dd, J = 13.3, 6.3 Hz, 1H), 2.21 (tt, J = 12.9, 6.7 Hz, 1H), 2.01 (td, J = 13.1, 7.3 Hz, 1H), 1.91 (dd, J = 12.2, 7.4 Hz, 1H), 1.88 (s, 3H) ppm. 13 13C NMR (150 MHz, DMSO-d6): δ 168.7, 153.1, 150.3, 148.2, 143.7, 140.5, 134.9, 134.7, 131.8, 122.5, 121.5, 119.4, 119.0, 117.2, 116.0, 115.1, 108.3, 60.8, 60.5, 55.9, 48.2, 38.2, 29.8, 22.5 ppm. IR (KBr): 3285, 3076, 2939, 2854, 1669, 1583, 1483, 1375, 1287, 962, 705, 625, 541, 493 cm -1 . HRMS (ESI): calc. for C 21 19 22 F3NO7SNa [M + Na] + 512.0961, found 512.0966. Optical rotation: [α] 24.1 D = -70.21° (c 0.34, CHCl3).

[0071] Compound M (50 mg, 0.1 mmol, 1.0 equivalent) was dissolved in a mixed solution of DMF (0.5 mL) and MeOH (1 mL). Et3N (210 μL, 1.5 mmol, 15.0 equivalent) and Pd(dppf)Cl2 (22 mg, 0.03 mmol, 0.3 equivalent) were added. The reaction mixture was stirred under a CO (1 atm) atmosphere and heated to 70 °C. After 7 hours, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate 1:2 to ethyl acetate) to give compound allocolchicine C as a white solid (31.8 mg, 78%).

[0072] The characterization data for colchicine C are as follows: thin-layer chromatography shift value Rf = 0.28 (EtOAc). Melting point mp: 247-249 ℃. 1 H NMR (600 MHz, DMSO-d6): δ 8.59 (dd, J = 8.2, 2.2 Hz, 1H), 7.97 (d,J = 1.8 Hz, 1H), 7.89 (dd, J = 7.9, 1.9 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H),6.83 (s, 1H), 4.56 (dt, J = 11.8, 7.7 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H),3.79 (s, 3H), 3.51 (s, 3H), 2.54 (dd, J = 13.3, 6.4 Hz, 1H), 2.19 (tt, J =13.0, 6.7 2.00 (td, J = 13.0, 7.4 Hz, 1H), 1.92 (dd, J = 12.3, 7.5Hz, 1H), 1.89 (s, 3H) ppm. See Figure 5 for detailed spectral data.

[0073] 13C NMR (150 MHz, DMSO-d6): δ 168.6, 166.4, 153.1, 150.4, 141.0,140.6, 139.3, 135.0, 130.0, 128.1, 126.9, 124.0, 123.3, 108.3, 60.8, 60.6,55.9, 52.1, 48.1, 38.3, 29.9, 22.6 ppm.IR (KBr): 3421, 3276, 3078, 2928, 2835, 1598, 1412, 1373, 1215, 1159,976, 893, 719, 662, 576, 503 cm -1 HRMS (ESI): calc. for C 22 H 25 NO6Na [M+Na] + 422.1574, found 422.1572. Optical rotation: [α] 24.3 D = -140.49° (c 0.29, CHCl3). The only difference between Comparative Example 1 and Example 1 is that the ruthenium catalyst (S,S)-Ts-DPEN is removed in step S102, and the other steps and conditions are the same as in Example 1.

[0074] The results showed that the reaction could not occur, and intermediate compound K could not be obtained.

[0075] The only difference between Comparative Example 2 and Example 1 is that the additive La(OTf)3 in step S102 is replaced sequentially with Zn(OTf)2, Sc(OTf)3, Bi(OTf)3, and maleic acid. The other steps and conditions are the same as in Example 1.

[0076] The results showed that the yields of intermediate compound K decreased to 19%, 32%, 35%, and 0%, respectively.

[0077] The only difference between Comparative Example 3 and Example 1 is that the catalyst Pd(PPh3)4 in step S2 is replaced with Pd(OAc)2 and Pd(dppf)Cl2 in sequence, while the other steps and conditions are the same as in Example 1.

[0078] The results showed that the yields of intermediate compound L decreased to 22% and 49%, respectively.

[0079] The only difference between Comparative Example 4 and Example 1 is that the reagent PhI(TFA)2 in step S3 is replaced with PhI(OAc)2, while the other steps and conditions are the same as in Example 1.

[0080] The results showed that the yield of colchicine A decreased to 42%, and the product contained pigments that were difficult to remove.

[0081] The only difference between Comparative Example 5 and Example 3 is that in the step of preparing colchicine C from compound M, the reaction time is extended to 24 hours, while the other steps and conditions are the same as in Example 3.

[0082] The results showed that the yield of colchicine C decreased significantly to 20%.

[0083] In summary, this invention uses 3-hydroxyacetophenone as a starting material and utilizes ruthenium-catalyzed asymmetric reductive amination to construct key chiral centers. Through intermolecular suzu-based coupling and intramolecular oxidative cyclization, three different colchicine-like drugs are rapidly constructed. The route is simple and efficient, without the introduction or removal of chemical protecting groups, and avoids dangerous reactions such as prolonged high-temperature and high-pressure treatment or hydrogenation. Only three to four reaction steps are required to obtain colchicine-like compounds. It is safe, environmentally friendly, and uses low-cost raw materials, providing a route reference for the design and synthesis of colchicine and colchicine-like drugs.

[0084] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. An asymmetric synthesis method for colchicine, characterized in that, Its synthetic route is as follows: The synthetic method includes the following steps: S1, 3-hydroxyacetophenone undergoes a cross-dehydrogenation coupling reaction in a first solvent under the action of an iron catalyst to generate compound J; compound J is mixed with ammonium formate, ruthenium catalyst, transition metal catalyst and a second solvent, and undergoes an asymmetric reductive amination reaction to generate compound K; the first solvent is N,N-dimethylacetamide; S2, compound K is mixed evenly with a selective hydroboration reagent in a third solvent, and then an aryl bromide and palladium catalyst are added, followed by a Suzuki aryl coupling reaction to obtain compound L; S3, compound L and Lewis acid are... The compound is added to a mixed solution of trifluoroacetic acid, trifluoroacetic anhydride, and a fourth solvent containing an oxidant, and undergoes an intramolecular oxidative coupling reaction to obtain colchicine A; or, it further includes: S4, colchicine A is dissolved in a fifth solvent, potassium carbonate and halomethane are added, and the mixture undergoes a phenolic hydroxymethyl etherification reaction to obtain colchicine B; or, it further includes: S5, colchicine A is dissolved in a sixth solvent, pyridine and trifluoromethanesulfonic anhydride are added, and the mixture is stirred to obtain compound M; compound M is dissolved in a seventh solvent containing methanol, and the mixture is heated under a palladium catalyst and a CO atmosphere to obtain colchicine C.

2. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, In step S1, the iron catalyst includes ferric chloride; the molar ratio of 3-hydroxyacetophenone to the iron catalyst is 1:(0.05-0.15); potassium persulfate is also added in the cross-dehydrogenation coupling reaction, and the molar ratio of 3-hydroxyacetophenone to potassium persulfate is 1:(1.5-2.5); the temperature of the cross-dehydrogenation coupling reaction is 90-100℃, and the time is 2-8h.

3. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, In step S1, the ruthenium catalyst comprises (S,S)-Ts-DPEN; the transition metal catalyst comprises lanthanum trifluoromethanesulfonate; the molar ratio of 3-hydroxyacetophenone, ammonium formate, ruthenium catalyst, and transition metal catalyst is 1:(2-4):(0.005-0.015):(0.01-0.1); the temperature of the asymmetric reductive amination reaction is 10-30℃, and the time is 10-14h.

4. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, In step S2, the selective borohydride reagent includes 9-boronbicyclo[3.3.1]nonane; the molar ratio of compound K to the selective borohydride reagent is 1:(2-4); the compound K and the selective borohydride reagent are mixed uniformly in a third solvent, specifically including: mixing compound K and the selective borohydride reagent in a third solvent at 0-4°C, heating to 10-30°C and stirring for 3.5-4.5 h, then cooling to 0-4°C, quenching with water and continuing to stir for 10-20 min.

5. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, In step S2, the molar ratio of compound K to the aryl bromide is 1:(2-4); the palladium catalyst includes Pd(PPh3)4; the molar ratio of compound K to the palladium catalyst is 1:(0.02-0.08); K3PO4 is also added in the suzuki aryl coupling reaction, and the molar ratio of compound K to K3PO4 is 1:(2-4); the suzuki aryl coupling reaction is carried out under a protective atmosphere and heated under reflux for 1-3 hours.

6. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, In step S3, the Lewis acid includes boron trifluoride diethyl ether; the molar ratio of compound L to Lewis acid is 1:(1.5-2.5); the preparation steps of trifluoroacetic acid-trifluoroacetic anhydride-fourth solvent include: first mixing the oxidant and the fourth solvent, then adding trifluoroacetic acid and trifluoroacetic anhydride, mixing evenly and cooling to -45 to -35°C; the molar ratio of compound L to oxidant is 1:(1.05-1.2), and the oxidant includes PhI(TFA)2; the ratio between compound L, trifluoroacetic acid and trifluoroacetic anhydride is 1 mmol:(5-7) mL:(1-2) mL; the intramolecular oxidative coupling reaction is carried out at 10-30°C for 3-5 h.

7. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, In step S4, the halomethane includes chloromethane, bromomethane, or iodomethane; the molar ratio of colchicine A, potassium carbonate, and halomethane is 1:(1.2-1.4):(1.2-1.4); the temperature of the phenol hydroxymethyl etherification reaction is 10-30°C, and the time is 10-24 h.

8. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, In step S5, the molar ratio of colchicine A, pyridine and trifluoromethanesulfonic anhydride is 1:(2.4-2.8):(1.5-2.0); the reaction temperature for preparing compound M is 0-4℃ and the reaction time is 2-4h.

9. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, In step S5, the molar ratio of compound M to triethylamine is 1:(12-18); the palladium catalyst includes Pd(dppf)Cl2, and the molar ratio of compound M to palladium catalyst is 1:(0.2-0.4); the heating reaction is carried out at a temperature of 65-75°C for 6.5-7.5 h.

10. The asymmetric synthesis method of colchicine according to claim 1, characterized in that, The second to sixth solvents include one or more of N,N-dimethylformamide, methanol, tetrahydrofuran, and dichloromethane; the seventh solvent is a mixture of methanol and N,N-dimethylformamide in a volume ratio of 2:1.

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