A method for the synthesis of elacridar

Abstract

This invention discloses a method for synthesizing ellastatin, belonging to the field of pharmaceutical synthesis technology. Using compound 1, bis(pinacolyl)diboron, and compound 10 as main raw materials, the method involves reacting these compounds under the combined action of solvent, base, catalyst, and resolving reagent to obtain ellastatin. This invention improves upon existing techniques, reducing the original seven synthetic steps to four, significantly increasing the overall yield and reducing production costs. Simultaneously, it avoids the use of sodium borohydride and elemental iodine, greatly simplifying the production process and making it more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for synthesizing ellastrant. Background Technology

[0002] Elacestrant, developed by Stemline Therapeutics and now part of the Menarini Group, is a novel selective estrogen receptor degrader (SERD). It received FDA approval in January 2023 and European Commission approval in September of the same year. It is primarily used to treat estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer. The target population is postmenopausal women or adult men whose disease has progressed after receiving at least one endocrine therapy. This drug works by binding to the estrogen receptor (ERα), inhibiting its activity and promoting its degradation via the proteasome pathway, thereby blocking estrogen stimulation of tumor cells and slowing or preventing tumor growth and spread.

[0003] The company's patent CN113348163A discloses a synthetic route for arastridium. However, this route has the following limitations: due to the presence of chiral and sensitive functional groups in the substrates for amide reduction, the available reducing reagents are limited, the product has the risk of racemization, the reduction of the ketone carbonyl group of the amide with sodium borohydride requires the addition of a large amount of elemental iodine, and the yield is only 50%; deacetylation requires the use of dilute hydrochloric acid, generating a large amount of waste acid, which is very environmentally unfriendly; the synthetic route is long and the yield is low.

[0004] Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, this invention provides a method for synthesizing ellagic acid, which has a short procedure, high yield, and is suitable for industrial production. The synthetic route is as follows:

[0006]

[0007] The specific preparation steps are as follows: (1) At a certain temperature, compound 1 is mixed with bis(pinacol)diboron, base, catalyst and reaction solvent. After the reaction is completed, compound 10 and base are added to obtain compound 11. (2) At a certain temperature, compound 11, catalyst and reaction solvent are mixed and reacted under a hydrogen atmosphere to obtain compound 12; (3) At a certain temperature, compound 12 was reacted with a resolving agent in an organic solvent to obtain compound 13; (4) At a certain temperature, compound 13 is mixed with compound 14, base, catalyst, ligand and reaction solvent. After the reaction is completed, acid is added to remove protection. After the reaction is completed, sodium hydroxide aqueous solution is added to obtain compound Elacestrant.

[0008] Furthermore, in step (1), The catalyst is any one of Ph(PPh3)4, Ph(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2, and Pd2(bda)3, with Ph(PPh3)2Cl2 being preferred.

[0009] The alkali is any one of K2CO3, KHCO3, Cs2CO3, K3PO4, Na2CO3, NaHCO3, and KOAc, with KHCO3 being preferred.

[0010] The solvent is any one of dioxane, N,N-dimethylformamide, toluene, and ethylene glycol dimethyl ether, preferably ethylene glycol dimethyl ether.

[0011] The molar ratio of compound 1, catalyst, compound 10, and base is in the range of 1:0.005-0.05:1-2:0.5-5, preferably 1:0.02:1:3.1.

[0012] The reaction temperature is 50℃~120℃, and the reaction time is 6~18 h.

[0013] Furthermore, in step (2), The solvent is any one or more of tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide, and acetonitrile, preferably a mixture of tetrahydrofuran and methanol.

[0014] The catalyst is any one of Pd, Pd / C, Pd(OAc)2, PdCl2, and Pd(OH)2 / C, with Pd(OH)2 / C being preferred.

[0015] The molar ratio of compound 11 to the catalyst is in the range of 1:0.05-0.3, preferably 1:0.1.

[0016] The reaction temperature is 0~40℃, and the reaction time is 12~24 h.

[0017] Furthermore, in step (3), The resolving agent is any one of aspartic acid, camphoric acid, dibenzoyl-tartaric acid, di-p-toluyl-tartaric acid, and diacetyl-tartaric acid, preferably (+)-dibenzoyl-tartaric acid.

[0018] The solvent is any one or more of methanol, ethyl acetate, acetonitrile, dichloromethane, toluene, and tetrahydrofuran, preferably a mixture of acetonitrile and dichloromethane.

[0019] The reaction temperature is 10℃~70℃; the reaction time is 4~12 h.

[0020] The molar ratio of compound 12 to the resolving agent is in the range of 1:0.1-2, preferably 1:0.5.

[0021] Furthermore, in step (4), The alkali is any one of K2CO3, KHCO3, Cs2CO3, K3PO4, Na2CO3, KOtBu, and NaOH, with K2CO3 being preferred.

[0022] The catalyst is any one of Ph(PPh3)4, Ph(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2, and Pd2(bda)3, with Pd(OAc)2 being preferred.

[0023] The ligand is one of 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (XantPhos) and 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, preferably 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (XantPhos).

[0024] The solvent is any one of toluene, 1,4-dioxane, N,N-dimethylformamide, and dimethyl oxalate, preferably toluene.

[0025] The acid is any one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and benzenesulfonic acid, with trifluoroacetic acid being preferred.

[0026] The molar ratio of compound 13 to compound 14, base, catalyst, ligand and acid is in the range of 1:1-2:1-4:0.005-0.05:0.005-0.05:1-5, preferably 1:1.2:2:0.02:0.02:2.

[0027] The reaction temperature is 80℃~120℃, and the reaction time is 8~18 h.

[0028] The above method yields a compound called elacestrant.

[0029] The compound ellastrant obtained by the above method has particularly prominent applications in the treatment of advanced or metastatic estrogen receptor-positive (ER+) breast cancer. It is suitable for patients whose disease has progressed after prior endocrine therapy. It blocks tumor proliferation signals by specifically degrading estrogen receptors and has inhibitory effects on both wild-type and mutant ER. It also has the property of penetrating the blood-brain barrier, which has potential efficacy for patients with brain metastases from breast cancer. In addition, it can also be used to prepare drugs for the treatment of estrogen receptor-positive (ER+) endometrial cancer. For cases that are insensitive to or resistant to progesterone therapy, it inhibits tumor growth by degrading estrogen receptors. It can also serve as a research and development direction for drugs for the treatment of other hormone-dependent tumors such as prostate cancer and ovarian cancer, as well as for the preparation of adjuvant drugs to prevent recurrence of estrogen receptor-positive (ER+) breast cancer. After early-stage patients have undergone surgery and endocrine therapy, it can further eliminate residual tumor cells and reduce the risk of recurrence.

[0030] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention provides a simple synthetic method for ellaxitoxin, with a short synthetic route, reducing the reaction steps from the original 7 steps to 4 steps, and increasing the total yield from 8.58% of the original route to 32.30%.

[0031] (2) This invention provides a simple method for synthesizing arastridium, which avoids the use of sodium borohydride and elemental iodine, simplifies production operations, improves process smoothness, and facilitates industrial production.

[0032] Specific implementation methods The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. It should be noted that any processes not specifically described in detail below are those that can be implemented or understood by those skilled in the art by referring to existing technology. Reagents or instruments whose manufacturers are not specified are considered to be conventional products that can be purchased commercially.

[0033] Example 1 This embodiment provides a method for synthesizing ellagic acid, including the following steps:

[0034] Compound 1 (300 g, 951.75 mmol, 1.00 eq), B2Pin2 (314.19 g, 1.24 mol, 1.3 eq), KOAc (289.56 g, 2.95 mol, 3.1 eq), Pd(PPh3)2Cl2 (13.36 g, 19.03 mmol, 2 mol%), and DME (2.1 L, 7 V) were added to the reaction vessel. The mixture was purged with nitrogen three times, heated to 85 °C, and monitored by HPLC. After the reaction was completed, the mixture was cooled to 20 °C, and 25 wt% KHCO3 solution (900 ml, 3 V) and compound 10 (297.83 g, 951.75 mmol, 1.0 eq) were added. The mixture was then heated to 85 °C, monitored by HPLC, and after the reaction was completed, cooled to 55 °C. The mixture was then filtered, and the filter cake was washed with DME. The liquid-liquid phase was separated and discarded. The organic phase was cooled to 20°C and diluted with water (2.1 L, 7 V). The mixture was stirred for 1 h, filtered, and the filter cake was washed with water (900 ml, 3 V) and then dried under vacuum at 50°C. After drying, DCM (3 L, 10 V) was added to dissolve the mixture, and activated carbon (0.25 wt equivalents) was added. The mixture was stirred and refluxed for 7 h, then cooled to room temperature, filtered, washed with DCM (900 ml, 3 V), concentrated under reduced pressure to 4 V, and anhydrous ethanol (600 ml, 2 V) was added dropwise. The mixture was cooled to 20°C to crystallize, filtered, and the filter cake was rinsed with anhydrous ethanol (300 ml, 1 V). The filter cake was then dried under vacuum at 45°C to give 320.56 g of compound 11, with a yield of 79.94%.

[0035]

[0036] Compound 11 (300 g, 712.02 mmol, 1 eq), Pd(OH)₂ / C (10 g, 71.2 mmol, 0.1 eq), THF (2.1 L, 7 V), and MeOH (2.1 L, 7 V) were added to the hydrogenation reactor at 20 °C. The reactor was purged with nitrogen three times, followed by purging with H₂. The reaction mixture was stirred at 100 psi H₂ at 20 °C for 12 hours, and the reaction was monitored for completion. After the reaction was complete, the reactor was purged with N₂ at 20 °C, and the reaction mixture was heated at 40 °C for 1 hour. The mixture was then filtered and washed with THF (450 ml, 1.5 V) and MeOH (450 ml, 1.5 V), respectively. The solution was concentrated under reduced pressure to 2.4V at 45°C, and EtOAc (3.6L, 12V) was added. The solution was then concentrated under reduced pressure to 2.4V at 45°C, and EtOAc (900ml, 3V) was added again. The mixture was stirred at 20°C to induce crystallization. After 1 hour, the mixture was filtered, and the product was collected and washed with EtOAc (420ml, 1.4V). The product was then dried under vacuum at 50°C to give 221.24g of compound 12, with a yield of 93.25%.

[0037]

[0038] Compound 12 (200 g, 600.2 mmol, 1 eq) was dissolved in a 14 V MeCN and a 5 V DCM solution. (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA], 107.53 g, 300.1 mmol, 0.5 eq] was added and the mixture was heated to reflux (approximately 65 °C). The reactor was cooled to 50 °C for approximately 1 hour, to 40 °C for approximately 1 hour, and to 25 °C for approximately 1 hour. The mixture was filtered, and the filter cake was washed with a 2 V (400 ml, 2 V) DCM solution. The wet filter cake was refluxed in a 1.6 L (8 V) DCM solution for 2 hours. The solution was cooled to 25 °C at a rate of 15 °C / h and stirred at 25 °C for 1 hour. Filter the mixture, wash the filter cake with DCM (400 ml, 2 V), then slurry it again with DCM (1.6 L, 8 V) for 1 h, filter, wash with DCM (400 ml, 2 V) and dry. Add a solution of 25% KHCO3 aqueous solution (920 ml, 4.6 V) and water (3 L, 15 V) and methanol (600 ml, 3 V) to the obtained solids, and stir at 25 °C for 1.5 h. Filter and collect the solids, and wash with water (800 ml, 4 V). Adjust the pH of the aqueous layer to 8-9 using 25% KHCO3, and collect the obtained solids by filtration. Wash the filter cake with water (800 ml, 4 V). Add the combined solids to water (800 ml, 4 V), stir the resulting slurry for 1 h, and then collect the solids by filtration. The filter cake was washed with water (800 ml, 4V) and heptane (800 ml, 4V) and dried to give 95.36 g of compound 13, with a yield of 47.68% and a chiral purity of 99.99%ee.

[0039]

[0040] Compound 13 (90 g, 270.09 mmol, 1 eq), compound 14 (99.32 g, 324.11 mmol, 1.2 eq), toluene, and potassium carbonate (74.65 g, 540.18 mmol, 2 eq) were added to the reactor. The mixture was bubbled to remove oxygen for 3 h. Then, palladium acetate (1.21 g, 5.40 mmol, 0.02 eq) and XantPhos (3.13 g, 5.40 mmol, 0.02 eq) were added. The mixture was heated to 110 °C and reacted for 8 h. After the reaction was complete, the mixture was cooled. The mixture was cooled to room temperature, filtered, and the mother liquor was returned to the reactor. Trifluoroacetic acid (61.59 g, 540.18 mmol, 2 eq) was added with stirring, and the mixture was stirred for 2 h. After the deprotection reaction was completed, the pH was adjusted to 7-8 with 1 mol / L NaOH solution. The mixture was separated, the aqueous layer was extracted with dimethane, and the organic layers were combined. The mixture was washed with water, concentrated under reduced pressure to dryness, dissolved in 3V anhydrous ethanol with stirring, and then crystallized by adding 12V ethyl acetate with stirring. The crystals were filtered and dried to obtain 112.56 g of ellagic acid as a white solid, with a yield of 90.87% and an overall yield of 32.30%.

[0041] Example 2 Compound 1 (300 g, 951.75 mmol, 1.00 eq), B2Pin2 (314.19 g, 1.24 mol, 1.3 eq), KOAc (289.56 g, 2.95 mol, 3.1 eq), Pd(PPh3)2Cl2 (13.36 g, 19.03 mmol, 2 mol%), and DME (2.1 L, 7 V) were added to the reaction flask. The mixture was purged with nitrogen three times, heated to 85 °C, and monitored by HPLC. After the reaction was complete, the mixture was cooled to 20 °C, and 25 wt% NaHCO3 solution (900 mL, 3 V) and compound 10 (297.83 g, 951.75 mmol, 1.0 eq) were added. The mixture was then heated to 85 °C, monitored by HPLC, and after the reaction was complete, cooled to 55 °C. The mixture was filtered, and the filter cake was washed with DME. The liquid-liquid phase was separated and discarded. The organic phase was cooled to 20°C and diluted with water (2.1 L, 7V). The mixture was stirred for 1 h, filtered, and the filter cake was washed with water (900 ml, 3V) and then dried under vacuum at 50°C. After drying, DCM (3 L, 10V) was added to dissolve the mixture, and activated carbon (0.25 wt equivalents) was added and stirred under reflux for 7 h. The mixture was then cooled to room temperature, filtered, washed with DCM (900 ml, 3V), concentrated under reduced pressure to 4V, and anhydrous ethanol (600 ml, 2V) was added dropwise. The mixture was cooled to 20°C to crystallize, filtered, and the filter cake was rinsed with anhydrous ethanol (300 ml, 1V). The filter cake was then dried under vacuum at 45°C to give 316.52 g of compound 11, with a yield of 78.93%.

[0042] Compounds 12, 13, and 14, the ellasigroup, were synthesized in the same manner as in Example 1.

[0043] Example 3 Compound 1 (300 g, 951.75 mmol, 1.00 eq), B2Pin2 (314.19 g, 1.24 mol, 1.3 eq), KOAc (289.56 g, 2.95 mol, 3.1 eq), Pd(PPh3)2Cl2 (13.36 g, 19.03 mmol, 2 mol%), and DME (2.1 L, 7 V) were added to the reaction flask. The mixture was purged with nitrogen three times, heated to 85 °C, and monitored by HPLC. After the reaction was complete, the mixture was cooled to 20 °C, and 25 wt% Na2CO3 solution (900 ml, 3 V) and compound 10 (297.83 g, 951.75 mmol, 1.0 eq) were added. The mixture was then heated to 85 °C, monitored by HPLC, and after the reaction was complete, cooled to 55 °C. The mixture was filtered, and the filter cake was washed with DME. The liquid-liquid phase was separated and discarded. The organic phase was cooled to 20°C and diluted with water (2.1 L, 7V). The mixture was stirred for 1 h, filtered, and the filter cake was washed with water (900 ml, 3V) and then dried under vacuum at 50°C. After drying, DCM (3 L, 10V) was added to dissolve the mixture, and activated carbon (0.25 wt equivalents) was added and stirred under reflux for 7 h. The mixture was then cooled to room temperature, filtered, washed with DCM (900 ml, 3V), concentrated under reduced pressure to 4V, and anhydrous ethanol (600 ml, 2V) was added dropwise. The mixture was cooled to 20°C to crystallize, filtered, and the filter cake was rinsed with anhydrous ethanol (300 ml, 1V). The filter cake was then dried under vacuum at 45°C to give 296.32 g of compound 11, with a yield of 73.89%.

[0044] Compounds 12, 13, and 14, the ellasigroup, were synthesized in the same manner as in Example 1.

[0045] Example 4 The synthesis of compounds 11, 13, and 14 (allasinoids) was the same as in Example 1. The synthesis of compound 12 is as follows: Compound 11 (300 g, 712.02 mmol, 1 eq), Pd / C (7.5 g, 71.2 mmol, 0.1 eq), THF (2.1 L, 7 V), and MeOH (2.1 L, 7 V) were added to the hydrogenation reactor at 20 °C. The reactor was purged with nitrogen three times, followed by purging with H2. The reaction mixture was stirred at 100 psi H2 at 20 °C for 12 hours, and the reaction was monitored for completion. After the reaction was complete, the reactor was purged with N2 at 20 °C, and the reaction mixture was heated at 40 °C for 1 hour. The mixture was then filtered and washed with THF (450 ml, 1.5 V) and MeOH (450 ml, 1.5 V), respectively. The solution was concentrated under reduced pressure to 2.4V at 45°C, and EtOAc (3.6L, 12V) was added. The solution was then concentrated under reduced pressure to 2.4V at 45°C, and EtOAc (900ml, 3V) was added again. The mixture was stirred at 20°C to induce crystallization. After 1 hour, the mixture was filtered, and the product was collected and washed with EtOAc (420ml, 1.4V). The product was then dried under vacuum at 50°C to give 216.36g of compound 12, with a yield of 91.19%.

[0046] Comparative Example

[0047] Compound 1 (300 g, 951.75 mmol, 1.00 eq), B2Pin2 (314.19 g, 1.24 mol, 1.3 eq), KOAc (289.56 g, 2.95 mol, 3.1 eq), Pd(PPh3)2Cl2 (13.36 g, 19.03 mmol, 2 mol%), and DME (2.1 L, 7 V) were added to the reaction vessel. The mixture was purged with nitrogen three times, heated to 85 °C, and monitored by HPLC. After the reaction was completed, the mixture was cooled to 20 °C, and 25 wt% KHCO3 solution (900 ml, 3 V) and compound 3 (232.31 g, 951.75 mmol, 1.0 eq) were added. The mixture was then heated to 85 °C, monitored by HPLC, and after the reaction was completed, cooled to 55 °C. The mixture was then filtered, and the filter cake was washed with DME. The liquid-liquid phase was separated and discarded. The organic phase was cooled to 20°C and diluted with water (2.1 L, 7V). The mixture was stirred for 1 h, filtered, and the filter cake was washed with water (900 ml, 3V) and then dried under vacuum at 50°C. After drying, DCM (3 L, 10V) was added to dissolve the mixture, and activated carbon (75 g) was added and stirred under reflux for 7 h. The mixture was then cooled to room temperature, filtered, washed with DCM (900 ml, 3V), concentrated under reduced pressure to 4V, and anhydrous ethanol (600 ml, 2V) was added dropwise. The mixture was cooled to 20°C to crystallize, filtered, and the filter cake was rinsed with anhydrous ethanol (300 ml, 1V). The filter cake was then dried under vacuum at 45°C to obtain 269.02 g of compound 11, with a yield of 70.76%.

[0048] Compound 4 (260 g, 650.83 mmol, 1.00 eq), Pd(OH) / C (26 g), THF (1.8 L, 7 V), and MeOH (1.8 L, 7 V) were added to the reaction vessel, purged with N2, and then purged with H2 at 20 °C. The reaction mixture was stirred at 20 °C for ≥12 h at 100 psi H2, and the reaction was monitored for completion. After purging the reactants with N2 at 20 °C, the reaction mixture was heated at 40 °C for 1 h, filtered, and washed with THF (390 mL, 1.5 V) and MeOH (390 mL, 1.5 V). The solution was concentrated to 600 mL under vacuum at 40 °C, then cooled to 20 °C and stirred for 1 h. The product was collected by filtration, washed with EtOAc (360 mL, 1.4 V), and dried under vacuum to give 170.06 g of compound 5, yield 84.46%.

[0049] A solution containing 1.5 L of MeOH (9 V) and 255 g of concentrated HCl (170 g, 549.51 mmol, 1.00 eq) of compound 5 was heated and stirred under reflux for 16 hours (approximately 65 °C), and the reaction was monitored for completion. The reactants were cooled to 30 °C and concentrated under vacuum at 40 °C to approximately 650 mL. 2-MeTHF (2 L, 12 V) was added, followed by 1 M NaOH (1.7 L, 10 V), and then 25% KHCO3 aqueous solution (255 g) was added dropwise, maintaining an internal temperature ≤35 °C. The internal temperature was adjusted to 20 °C and stirred for 15 minutes. The pH was adjusted / maintained between 8 and 10 using 1 M HCl or 1 M NaOH. Stirring was stopped. After sedimentation, the aqueous layer was separated, water (170 mL) was added, the solution was stirred for 15 minutes, sedimentation was observed, the aqueous layer was removed, an additional 170 mL of water was added, sedimentation was observed, and the aqueous layer was separated. The organic layer was concentrated under vacuum to approximately 510 mL at 40 °C, and heptane (510 mL, 3 V) was added. The mixture was stirred at 20 °C for 12 h. The solid was collected by filtration, and the filter cake was washed with heptane (340 mL, 2 V). The mixture was dried under vacuum at 45 °C to give 121.36 g of compound 6, with a yield of 82.61%.

[0050] A solution containing compound 6 (120 g, 448.89 mmol, 1.00 eq) in MeCN (1.7 L, 14.2 V) and DCM (580 mL, 4.8 V) was heated to 40 °C. (+)-2,3-diphenylmethyl-D-tartaric acid [(+)-DBTA, 80.42 g, 224.45 mmol, 0.50 eq] was added and the mixture was heated to reflux (approximately 65 °C). The reactor was cooled to 50 °C for approximately 1 h, to 40 °C for approximately 1 h, and to 25 °C for approximately 1 h. The slurry was filtered, and the filter cake was washed with 2 volumes of DCM (240 mL, 2 V). The wet filter cake was refluxed in DCM (960 mL, 8 V) (approximately 44 °C) for 1 h. The solution was cooled to 25 °C at a rate of 15 °C / h and stirred at 25 °C for 1.5 h. The slurry was filtered, washed with DCM (240 ml, 2 V), and the filter cake was slurried again with DCM (960 ml, 8 V) at 25 °C for 1 hour, then filtered, washed with DCM (240 ml, 2 V), and dried. A solution of 25% KHCO3 aqueous solution (550 ml, 4.6 V) and water (1800 ml, 15 V) and methanol (360 ml, 3 V) was added to the resulting solid, and the mixture was stirred at 25 °C for 1.5 h. The solid was collected by filtration and washed with water (480 ml, 4 V). The pH of the aqueous layer was adjusted to 8-9 using 25% KHCO3, and the resulting solid was collected by filtration. The filter cake was washed with water (480 ml, 4 V). The combined solids were added to water (480 ml, 4 V), the resulting slurry was stirred for 1 hour, and the solid was collected by filtration. The filter cake was washed with water (480 ml, 4V) and heptane (480 ml, 4V) and dried at 45 °C to give 50.62 g of compound 7, yield 42.18%, chiral purity 99.82%ee.

[0051] A mixture containing compound 7 (50 g, 187.04 mmol, 1.00 eq), 50 g of activated molecular sieve, and anhydrous THF (200 mL, 4 V) was stirred at ambient temperature for 2 hours. The mixture was filtered through THF-compacted diatomaceous earth and washed with THF (500 mL, 10 V). Compound 8 (42.92 g, 224.44 mmol, 1.20 eq), heptane (375 mL, 7.5 V), and DBTA (0.067 g, 0.187 mmol, 0.001 eq) were added to the solution, and the mixture was heated to reflux (approximately 65 °C). The mixture was then distilled under reflux at atmospheric pressure to approximately 500 mL. The reaction was monitored for completion by TLC. After the reaction was complete, heptane (145 mL, 2.9 V) and THF (355 mL, 7.1 V) were added, and the reactants were distilled under reflux at atmospheric pressure to approximately 500 mL. The reaction was monitored for completion by TLC. Cool the solution to 20°C and stir for 5 hours. Filter to collect the solid product, wash with 2 volumes of heptane (100 ml, 2V), dissolve in anhydrous THF (2 L, 40V), and treat with NaBH(OAc)3 (178.44 g, 841.68 mmol, 4.50 eq). Heat the mixture to 50°C and react for 16 hours, monitoring with TLC. Add another 178.44 g, 841.68 mmol, 4.50 eq. Cool the reaction to 20°C and quench with 3M NaOH (750 ml, 15V). Stir the solution / mixture for ≥30 minutes, adjust the pH to 8-9 with 9% NaHCO3 aqueous solution (600 ml, 14V), separate the aqueous layer, and concentrate the organic layer to approximately 200 ml under vacuum at 45°C. Dilute the resulting solution with EtOAc (500 ml, 10V) and concentrate to approximately 200 ml under vacuum at 45°C. The solution was treated with 10 volumes of EtOAc (500 ml, 10 V) and 5.6% NaCl (250 ml, 5 V), stirred, and then allowed to settle to remove the aqueous layer. The mixture was dried over 200 g of Na₂SO₄, filtered, and concentrated to approximately 200 ml under vacuum at 45 °C. It was then treated with heptane (500 ml, 10 V) and concentrated to approximately 200 ml under vacuum at 45 °C. The solution was then treated with THF (500 ml, 10 V) and dried under vacuum at 45 °C. The solution was then treated with 5 volumes of THF (250 ml, 5 V) and used for the next reaction.

[0052] Add THF (350 ml, 7V) and 2.5 equivalents of NaBH4 to the reactor, cool to 0°C, and add a THF solution of compound 9 obtained in the previous step to the solution, while maintaining the reactor temperature ≤5°C. Stir the solution while adjusting the internal temperature to -25°C. Add a THF solution containing 50 ml of I2 (47.47 g, 187.04 mmol, 1.00 eq) to the solution, while maintaining the temperature ≤-10°C and stirring for 30 minutes. Then heat to reflux and stir at reflux (approximately 66°C) for 4 hours. Monitor the reaction completion by HPLC. Cool the reaction mixture to 0°C, quench with 25 ml of concentrated hydrochloric acid while maintaining the reaction mixture temperature above -10°C, and then treat with water (750 ml, 15V). Adjust the pH to less than 1.5 with concentrated hydrochloric acid. Then heat the solution to reflux and distill at atmospheric pressure until the internal temperature reaches 80°C. Cool the reaction mixture to 15-25°C, stir for 6 hours, and separate the solids by filtration. Return the solid to the reactor along with EtOAc (500 ml, 10V) and 1M NaOH (250 ml, 5V), and stir the mixture at 10-20°C for 20 minutes. Adjust the pH to 8-9 with 1M NaOH. Separate the organic and aqueous layers, and remove the aqueous layer by washing with EtOAc (500 ml, 10V). Remove the aqueous layer and wash the combined organic layer with a 5% sodium thiosulfate solution (250 ml x 2, 5V). Then wash the organic layer with a 1% NaCl solution (500 ml x 4, 10V). Remove the aqueous layer and concentrate the organic layer to 150 ml at an external temperature up to 45°C. Repeat three times, dissolving the residue in EtOH (500 ml, 10V) and concentrating to 150 ml at ≤45°C. The solution was dried over Na₂SO₄ and filtered. The filtrate was added to a reactor and treated with EtOAc (50 ml, 1V) while stirring. A solution of EtOH in 3.3M HCl (70 ml, 1.4V) was added, and the mixture was stirred at 15–25°C for 2 h. The solution was then concentrated to 230 ml at 45°C. The solution was treated with EtOAc (620 ml, 12.4V) and stirred at 15–25°C for 2 h. The solid was collected by filtration and washed with EtOAc (155 ml, 3.1V). The filter cake was dried at 50°C to give 40.67 g of ellastatin hydrochloride, with a two-step yield of 41.22% and an overall yield of 8.58%.

[0053] The NMR characterization results of the compounds allergic groups prepared in the above examples and comparative examples are as follows: 1 H NMR (400MHz, Chloroform- d): δ 0.94-1.09 (m, 6H), 1.65-1.84 (m,2H), 2.38-2.46 (m,2H), 2.66-2.89 (m, 8H), 2.88-2.94 (m, 2H ), 3.62-3.69 (m,1H), 3.80 (s, 3H), 3.94-4.02 (m, 2H), 6.56-6.64 (m, 2H), 6.70-6.78 (m, 2H), 6.94-7.02 (m, 3H), 7.14-7.18 (m, 3H). By comparison, it can be seen that the present invention provides a simple synthetic method for ellastatin, with a shorter synthetic route, reducing the reaction steps from 7 steps in the comparative example to 4 steps, and increasing the overall yield from 8.58% in the original route to 32.30%. At the same time, it avoids the use of sodium borohydride and elemental iodine, simplifies the production operation, improves the process flow, and facilitates industrial production.

Claims

1. A method for synthesizing ellagic groups, characterized in that, The synthesis route is as follows: The specific steps are as follows: (1) Compound 1 was mixed with bis(pinacol)diboron, base, catalyst and reaction solvent. After the reaction was completed, compound 10 and base were added to obtain compound 11. (2) Compound 11, catalyst and reaction solvent are mixed and reacted under hydrogen atmosphere to obtain compound 12; (3) Compound 12 was reacted with a resolving agent in an organic solvent to obtain compound 13; (4) Compound 13 and compound 14, base, catalyst, ligand and reaction solvent are mixed. After the reaction is completed, acid is added to remove protection. After the reaction is completed, sodium hydroxide aqueous solution is added to obtain compound alastan.

2. The synthesis method according to claim 1, characterized in that, In step (1), The alkali is any one of K2CO3, KHCO3, Cs2CO3, K3PO4, Na2CO3, NaHCO3, and KOAc; The catalyst is any one of Ph(PPh3)4, Ph(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2, and Pd2(bda)3; The solvent is any one of dioxane, N,N-dimethylformamide, toluene, and ethylene glycol dimethyl ether.

3. The synthesis method according to claim 1, characterized in that, In step (1), The molar ratio of compound 1, catalyst, compound 10, and base is in the range of 1:0.005-0.05:1-2:0.5-5; The reaction temperature is 50℃~120℃, and the reaction time is 6~18h.

4. The synthesis method according to claim 1, characterized in that, In step (2), The solvent is any one or more of tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide, and acetonitrile; The catalyst is any one of Pd, Pd / C, Pd(OAc)2, PdCl2, and Pd(OH)2 / C.

5. The synthesis method according to claim 1, characterized in that, In step (2), The molar ratio of compound 11 to the catalyst ranges from 1:0.05 to 0.

3. The reaction temperature is 0~40℃, and the reaction time is 12~24h.

6. The synthesis method according to claim 1, characterized in that, In step (3), The resolving reagent is any one of aspartic acid, camphoric acid, dibenzoyl-tartaric acid, di-p-toluyl-tartaric acid, and diacetyl-tartaric acid; The solvent is any one or more of methanol, ethyl acetate, acetonitrile, dichloromethane, toluene, and tetrahydrofuran.

7. The synthesis method according to claim 1, characterized in that, In step (3), The reaction temperature is 10℃~70℃; the reaction time is 4~12h; The molar ratio of compound 12 to the resolving agent is in the range of 1:0.1-2.

8. The synthesis method according to claim 1, characterized in that, In step (4), The alkali is any one of K2CO3, KHCO3, Cs2CO3, K3PO4, Na2CO3, KOtBu, and NaOH; The catalyst is any one of Ph(PPh3)4, Ph(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2, and Pd2(bda)3; The ligand is one of 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene and 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl; The solvent is any one of toluene, 1,4-dioxane, N,N-dimethylformamide, and dimethyl oxalate; The acid mentioned is any one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and benzenesulfonic acid.

9. The synthesis method according to claim 1, characterized in that, In step (4), The molar ratio of compound 13 to compound 14, base, catalyst, ligand and acid is in the range of 1:1-2:1-4:0.005-0.05:0.005-0.05:1-5.

10. The synthesis method according to any one of claims 1-9, characterized in that, In step (4), The reaction temperature is 80℃~120℃, and the reaction time is 8~18 h.

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